Neuroprotective Benefits of Rosmarinus officinalis and Its Bioactives against Alzheimer’s and Parkinson’s Diseases

Featured Application

Utilization of Rosmarinus officinalis extracts and/or its bioactives as ingredients in functional products, foods, cosmetics, and pharmaceuticals, with anti-inflammatory health-promoting neuroprotective effects against inflammation-related neurodegenerative disorders, such as Alzheimer’s and Parkinson’s Diseases.

Abstract

Neurodegenerative disorders (NDs) are conditions marked by progressively escalating inflammation that leads to the degeneration of neuronal structure and function. There is an increasing interest in natural compounds, especially those from pharmaceutical plants, with neuroprotective properties as part of potential therapeutic interventions. Thus, the rich bioactive content of the perennial herb rosemary (Rosmarinus officinalis) is thoroughly reviewed in this article, with an emphasis on its pleiotropic pharmacological properties, including its antioxidant, anti-inflammatory, and neuroprotective health-promoting effects. In addition, a comprehensive analysis of the existing scientific literature on the potential use of rosemary and its bioactive constituents in treating neurodegenerative disorders was also conducted. Rosemary and its bioactives’ chemical properties and neuroprotective mechanisms are discussed, focusing on their ability to mitigate oxidative stress, reduce inflammation, and modulate neurotransmitter activity. The role of rosemary in enhancing cognitive function, attenuating neuronal apoptosis, and promoting neurogenesis is outlined. Key bioactive components, such as rosmarinic acid and carnosic acid, are also highlighted for their neuroprotective act. The promising outcomes of the conducted pre-clinical studies or clinical trials confirm the efficacy of rosemary in preventing or alleviating Alzheimer’s and Parkinson’s diseases both in vitro (in cells) and in vivo (in animal models of NDs). From this perspective, the applications of rosemary’s bio-functional compounds and extracts in the food, cosmetics, and pharmaceutical sectors are also presented; in the latter, we discuss their use against neurodegenerative disorders, either alone or as adjuvant therapies. This paper critically evaluates these studies’ methodological approaches and outcomes, providing insights into the current state of the clinical research and identifying potential avenues for future investigation. All findings presented herein contribute to the growing body of literature and support the exploration of natural compounds as promising candidates for novel applications and neuroprotective interventions, paving the way for more applied scientific research.

1. Introduction

Rosmarinus officinalis (RO), also called rosemary, is a Lamiaceae family herb mainly grown in the Mediterranean, Europe, Asia, and Africa. Aromatic plants, including RO, have been utilized in alimentation as aromatics and preservatives and for folk medicine since ancient times [1,2,3]. In recent years, though, these herbs have been discovered to have significant properties as drug replacements because of their limited negative impact and fewer side effects [1,2,4]. RO has been established as “Generally Recognized as Safe (GRAS)” by the FDA in the USA, leading to its high global usage. Many of RO’s bioactive compounds may also work synergistically to maximize their therapeutic activity [4]. The herb’s antioxidant properties are well complemented by its anti-inflammatory, hepatoprotective, antinociceptive, antifungal, and neuroprotective effects that are also significant [1,4,5,6,7,8].

RO extract activity depends the main chemotype of the herb used. Chemotypes describe the plant profile with its main compounds, which affect its corresponding properties, and may vary according to geographical region. At the same time, other factors that affect them are climate changes, weather conditions, seasons, and the soil where the plant grows. Dominant chemical profiles that have been thoroughly investigated are camphor, verbenone, cineole, α-pinene, p-cymene, and linalool chemotypes. Also, studies defined chemotypes based on some compounds, mostly 1,8 cineole/camphor, 1,8 cineole/linalool, and 1,8 cineole/camphor/borneol [7]. Common RO compounds with excellent properties that are the focus of our present study are rosmarinic acid (RA) and carnosic acid (CA) [9,10,11,12,13,14,15,16,17].

It must be highlighted that RO exhibits very high antioxidant activity against reactive oxygen species (ROS) due to its high polyphenolic content [18]. Plants’ polyphenols are generally reported to display exceptional antioxidant activity due to their role in restraining the aggregation of proteins into amyloid formations, while inhibiting lipid peroxidation in brain diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD), which are currently two of the most dominant and common neurodegenerative diseases (NDs) [19]. NDs are conditions affecting the nervous system, characterized by neuronal loss and apoptosis, which are attributed to the impact of various factors, causing the degeneration of neuronal cells [20]. In 2019, approximately 50 million people had a neurodegenerative disease, which is predicted to reach 152 million by 2060 [21]. This constant increase in the population affected by NDs and the limited remedial but not curative medications creates a significant demand for better solutions. The present study will discuss AD and PD as the main diseases.

2. Methods

All the data were gathered by searching for articles from Scopus, ScienceDirect, Elsevier, PubMed, and Google Scholar sources. The keywords used were “neurodegenerative disorders”, “Alzheimer’s disease”, “Parkinson’s disease”, “neuroprotection”, “rosemary”, “inflammation”, “oxidative stress”, “anti-inflammatory”, “antioxidant”, “extract”, and “essential oil”. For Parkinson’s, 11 papers on RO, RA, and CA were analyzed in this review, where 9 listed experiments that were conducted in vitro and 5 that were conducted in vivo. A total of 19 studies—10 in vitro and 9 in vivo—were found that studied RO as an intervention for Alzheimer’s. From all the retrieved data, reviews that mentioned RO compounds (without a direct mention of rosemary) were also evaluated to support our hypothesis further. The years of interest were 1995–2024. Chemical constituents, animal models, doses, administration time, duration, study formation, duration, behavioral changes, parameters, biochemical, and historical assessments were also evaluated to achieve an overall medical profile of rosemary’s potent benefits for NDs.

3. AD and PD and Bioactive Rosemary Compounds with Health-Promoting Effects

3.1. Neurodegenerative Diseases

NDs are age-related diseases, arising primarily among older adults due to multiple mechanisms, mainly via inflammation and oxidative stress. External factors contributing to NDs include bad dietary habits, alcohol consumption, and environmental conditions. However, gene mutations that result in alterations in the neurons and the possible formation of NDs must not be neglected [21]. The most common NDs are Parkinson’ disease (PD), Alzheimer’s disease (AD), Huntington’s disease, and multiple sclerosis (MS) [20].

NDs are frequently driven by two prevalent factors: neuro-inflammation and oxidative stress [22,23]. The connection between these two causes is the profuse formation of ROS as a result of dysfunctional mitochondria. At the same time, common triggers inducing inflammation are trauma, infections, neurodegeneration, etc. [23]. The dysfunction of mitochondria eventually leads to the impairment of neurons and subsequently triggers the excretion of cytosol-related factors that can stimulate neighboring microglia and astrocytes. These activated cells respond by releasing pro-inflammatory cytokines, ROS, and reactive nitrogen species (RNS), further exacerbating the inflammatory response and stimulating additional neuronal impairment. Consequently, the persistent activation of glial cells may ultimately establish a feedback loop that perpetuates chronic neurodegeneration [24]. Moreover, heightened levels of inflammation have been linked to an elevated propensity for the onset of diabetes and atherosclerosis, as well as unfavorable effects of metabolic syndrome [25,26]. Thus, considering that inflammatory mechanisms are thought to be contributing to the pathophysiology of cognitive impairment, subclinical inflammation might contribute to any correlation between metabolic syndrome and cognitive decline [27].

3.2. Parkinson’s Disease

Parkinson’s disease (PD), commonly known as “Shaking Palsy”, is the second most common chronic neurodegenerative disorder (ND) affecting people, especially those at advanced ages, and is mainly attributed to the absence of dopaminergic (DAergic) neurons in the substantia nigra (SN). The SN is a part of the brain responsible for the movement of the human body, where DArgic neurons control the production of the neurotransmitter dopamine (DA) in the striatum. DA is responsible for regulating some functions in the human body, including the functioning of the hormonal and cardiovascular systems [9,28,29]. In 2019, almost 8.5 million people had PD according to the World Health Organization (WHO) [22,30]. The neurons implicated in PD are more vulnerable to oxidative stress and inflammation due to their elevated levels of lipids and fatty acids (FAs), which lead to lipid peroxidation. DA is also vulnerable to auto-oxidation, resulting in high levels of catecholamine quinones (DAQs) and H₂O₂ (an ROS), thus leading to oxidative damage [1,22,28,31,32,33].

There are various factors involved in the genesis of PD. An enzyme known as tyrosine hydroxylase (TH) facilitates the initial synthesis of the hormone DA within the neurons by catalyzing the conversion of L-tyrosine to L-dopa. L-dopa serves as a progenitor to DA, and its deficiency might lead to low DA levels and PD [10,34,35,36,37]. Concurrently, additional factors able to trigger the loss of DA are Lewy bodies (LBs), a result of α-synuclein (α-syn) aggregation in dopaminergic neurons, and ubiquitins, which are complement and structural cytoplasmic proteins [23]. α-syn is a protein located mainly in the central nervous system (CNS). The main functions of α-syn involve regulation of memory, recognition, neurotransmitter release, presynaptic vesicle trafficking, and immunomodulation. Aggregation of this protein may be linked to mitochondrial dysfunction and oxidative stress [19,23,35,38,39]. Mitochondria are the principal organelles that excessively generate ROS, which can impair mitochondrial constituents like proteins or lipids, and finally lead to mitochondrial dysfunction and the degeneration of mitochondrial components [22,40]. Glutathione (GSH) is also vital as a thiol tripeptide that functions as an antioxidant against ROS.

The symptoms of PD may vary from one individual to another, and can severely affect the patients’ lives. The most common symptoms are motor ones, including bradykinesia, lack of postural stability, a resting tremble, and stiffness, but also non-motor symptoms like depression, dementia, sleep disorders, sensory symptoms, and lack of writing and talking abilities [1,10,22,23,31,32,35,38,39,41]. The current medications used to mitigate PD symptoms are synthetic products that have prominent side effects and are relatively unaffordable [42]. The accepted pharmacotherapies for PD include levodopa (L-dopa), catechol-o-methyl transferase inhibitors (COMT-Is), and monoamine oxidase inhibitors (MAO-Is) [39,42,43]. L-dopa, specifically, is effective for treating the motor manifestations of PD with fewer side effects; however, nausea or postural hypotension are possible, while extended administration may result in dangerous symptoms like stroke or dementia [44], as well as dyskinesia [41,45]. L-dopa, when administered to patients, crosses the blood–brain barrier (BBB) and transforms into DA in the brain, thus preventing the symptoms of PD [41]. With an emphasis on keeping DA levels high, MAO inhibitors like monoamine oxidase type B inhibitors (MAO-BIs) may inhibit DA and levodopa collapse in the brain and alleviate depression in the initial stages of PD [41,44]. Also, COMT inhibitors are of great interest as they function as enzymes that aid the transportation of L-dopa to the brain, where it undergoes conversion into DA or increases synaptic DA levels. However, problems may arise from COMT-moderated levodopa metabolism (high levels of homocysteine), which can result in cardiovascular diseases (CDs), osteoporosis, and cognitive decline [41]. Finally, the consumption of such inhibitors, like tolcapone, may be toxic to the liver [43]. The inflammation mechanism attributed to PD in the cerebrum is displayed in Figure 1.

Figure 1. Connections between neuroinflammation, systemic inflammation, and PD occurrence in the cerebrum. Factors like TNF-α and IL-6, as well as blood cells including eosinophils, neutrophils, lymphocytes, and monocytes, are able to induce many proinflammatory cytokines that can initiate the degeneration of neurons via a-syn in the process of ongoing neuroinflammation, which induces the progression of PD.

3.3. Alzheimer’s Disease (AD)

Alzheimer’s disease (AD) is characterized as a divergent neurological impairment, and is currently thought to stem from a variety of different causes and influences. AD’s target group is primarily those aged 65 and over [46]. The disease’s pathophysiological features, such as amyloid plaque deposits, neurofibrillary tangles, acetylcholine deficiency, lost neuronal connections, hippocampal shrinkage, and others, have been thoroughly investigated and identified in the brains of afflicted patients [47]. The most prominent explanations for the causes of AD are the cholinergic hypothesis, amyloid cascade hypothesis, mitochondrial cascade hypothesis, and oxidative stress theory [48]. It is posited that the pivotal factor in provoking AD is oxidative stress. As a result of its heightened oxygen expenditure, the cerebral region is explicitly susceptible to oxidative stress. Whether this phenomenon is a causative agent or manifests as a direct consequence of AD remains a subject of ongoing investigation [49,50]. It is intimately connected with the existence of β-amyloid oligomers and specifically pertains to the incapacity to eliminate the neuro-disrupting compound known as 4-hydroxynonenal (HNE) which is significantly associated with the increased probability of disease development and augmentation [51].

Empirical work has indicated that apolipoprotein E (APOE) has the lion’s share in upholding body homeostasis by regulating the oxidative damage status [52]. The inheritance of the apolipoprotein E4 (APOE4) allele is implicated in the progression of AD. This mutated protein is ineffective at HNE elimination [53]. Furthermore, APOE4 may catalyze HNE formation and facilitate binding to nerve proteins [54]. The presence of APOE4 is causatively linked to neuronal dysfunction, potentially due to the absence of cysteine (Cys) residues, which are pivotal in averting lipid peroxidation [55,56]. Hence, possessing the APOE4 allele is closely correlated with elevated peroxidized lipid levels [52]. APOE4 also can trigger oxidative stress through its interaction with mutated manganese superoxide dismutase (MnSOD). Notably, individuals carrying this gene exhibit dysfunctional glucose metabolism at a young age, preceding the manifestation of the disorder’s symptoms [54].

The mitochondrial aging hypothesis arose because β-amyloid (Aβ) affects the activity of mitochondrial enzymes [57,58]. In light of this fact, scientists have investigated the functioning of the mitochondrial complexes (I, II, III, and IV). The most conspicuous alterations were detected in complexes I and II. Inhibition of complex I correlated with diminished tau protein production and Aβ production. Furthermore, complex I played a crucial role in the nexus between oxidative stress and AD [58,59]. As the body ages, reactive ROS accumulate, thereby fostering the development of oxidative stress. Moreover, the mitochondria house indispensable enzymes responsible for combating ROS. Specifically, mitochondrial dysfunction can be conspicuously observed in the cerebral regions associated with the genesis of AD [59,60]. Scientists embarked on an inquiry to elucidate the correlation between NADPH oxidase (NOX), responsible for ROS generation, and AD [61]. The NOX protein causes lipid peroxidation and cell death in cancerous cells, among its various roles. Moreover, it mediates ROS generation by upregulating the extracellular signal-regulated kinase (ERK) mechanism. Upon scrutinizing the cerebrum of AD-afflicted mice, an elevated level of NOX-responsive interposed compounds was discerned. Presently, different NOX inhibitor medications are under investigation as candidate therapeutic agents.

While medications for AD do not provide a cure, they have the potential to enhance the quality of life and extend the patient’s independence. Two classifications of drugs have been authorized for treating AD: those that offer temporary relief from AD symptoms and those that may downregulate the progression of the disease. The Food and Drug Administration (FDA) has approved two types of drugs, namely cholinesterase inhibitors and memantine. Cholinesterase inhibitors function by augmenting the levels of acetylcholine, a critical chemical messenger involved in alertness, memory, cognition, and judgment, through the prevention of its breakdown in the brain; however, these inhibitors are unable to cure AD or halt the degeneration of neuronal cells. Over time, their efficacy diminishes as the disease causes a decline in the production of acetylcholine by brain cells. Three frequently prescribed cholinesterase inhibitors are galantamine (Razadyne, for mild AD, two times per day), donepezil (Aricept, for all disease stages, oral administration once a day), and rivastigmine (Exelon, for moderate AD, available as a pill or a skin patch for severe cases). Memantine (Namenda), which was also approved by the FDA, is indicated for counteracting moderate and severe AD (syrup or pill administration). The underlying mechanism includes regulating the activity of glutamate, a chemical messenger that contributes to various cerebral functions, such as memory and learning. Additionally, aducanumab is an intravenous infusion therapy, among other medical approaches used in AD therapy, yet this drug is exclusively authorized for patients with mild dementia and cognitive debilitation caused by AD and functions by reducing Aβ protein levels in the brain. Significantly, in 2023, the FDA approved a similar drug called lecanemab [62,63,64].

The frequently observed negative outcomes of cholinesterase inhibitors include diarrhea, nausea, and vomiting, effects that may be minimized by commencing treatment at a low dosage and gradually increasing the dose or taking it with food. At the same time, individuals with cardiac arrhythmias should not consume such inhibitors. The notable effects of other drugs include dizziness, headache, confusion, and agitation, as well as amyloid-related imaging abnormalities-edema (ARIA-E), characterized by cerebral swelling, and amyloid-related imaging abnormalities-hemosiderin deposition (ARIA-H), involving micro-hemorrhages and superficial siderosis [62,63,64].

So, it is clear enough that alternative solutions are needed with fewer adverse effects than the established drugs. Scientists have examined the potential of utilizing certain plants suitable for alleviating or even curing NDs, which are widely known as medicinal and aromatic plants (MAPs).

3.4. Rosemary and Its Bioactive Compounds

According to the WHO, almost 80% of the global population still uses conventional medicine for fundamental healthcare needs [65]. The therapeutic ability of MAPs lies in their secondary metabolites—plant substances that not sustains the plant’s life but also protect the plant from environmental factors like herbivorous animals [66,67,68]. These substances are also responsible for the anti-inflammatory, antioxidant, and antimicrobial activity of the plant and consist of characteristic groups like alkaloids, ketones, terpenes, and phenols [65,69,70,71].

The essential oils (EOs) of plants are volatile solutions that rarely dissolve in water, are soluble in alcohol, and have similar properties to regular oils. EOs have critical medicinal traits because of their secondary metabolites, which contribute to their antioxidant, anti-inflammatory and antiviral effects [69,72,73]. MAP EOs can be used to produce scents, perfumes, and other products that have pleasant odors [72]. These EOs are mainly obtained from distillation techniques, such as hydro-distillation and steam distillation performed on the leaves, flowers, stems, and roots of the plant [2,69,74]. Extracts, on the other hand, are solutions that contain the desired constituents depending on the solute and the method of extraction used. Polar solutes, such as water and ethanol, extract polar compounds, while non-polar solutes, such as hexane, extract hydrocarbon (non-polar) compounds. Some standard techniques are microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE), and liquid–liquid extraction (LLE) [75].

EOs and extracts mostly come from herbs belonging to the Apiaceae, Verbenaceae, Myrtaceae, Rutaceae, Zingiberaceae, and Lamiaceae families. The most common EOs come from lavender, sage, and rosemary, known for their marvelous antioxidant, anti-inflammatory, and neuroprotective effects [2,42]. Rosemary is part of the Lamiaceae family and investigations have showcased similar and even better effects compared to synthetic drugs for curing NDs but with fewer side effects to the consumer.

RA is a hydroxylated polyphenolic chemical consisting of an ester linkage between caffeic acid and 3,4-dihydroxyphenyllactic acid [76]. It can be found in many aromatic plants and has been thoroughly examined for its antioxidant, anti-inflammatory, antimutagenic, neuroprotective, and many other biological characteristics [9,12,76]. CA is, on the other hand, a phenolic diterpene that is primarily obtained from RO and exhibits—like RA—antioxidant, anti-inflammatory, anticarcinogenic, and neuroprotective activities [16,77]. Carnosol is also a phenolic diterpene that derives from the oxidization of CA [7] and shows similar properties to carnosic acid but has received little attention from researchers. Camphor, eugenol, 1,8 cineole, a-pinene, luteolin, ursolic acid, and rosmanol are some of the other important RO compounds that will be discussed shortly, mainly for their pharmaceutical effect of neuroprotection against NDs.

It should also be stressed out that according to the Directive of the European Parliament and of the Council Concerning the Protection of Animals Used for Scientific Purposes, the number of experiments involving the use of animals needs to be reduced. The methods which can replace animal testing include computational prediction methods, including the quantitative structure–activity relationship (QSAR) in silico modeling approach. These methods are designed to find a cohesive relationship between differences in the values of the properties of molecules and the biological activity of a series of test compounds. More specifically, QSAR models are used to predict the biological activities and undesired effects of untested or novel compounds and to provide insights into relevant and consistent chemical properties or structural features that define the biological activities. One of the chemical properties of bioactives that can be predicted by QSAR is the determination of the n-octanol/water partition coefficient (log Kow value), which is an index of their polarity and can be estimated based on the chemical structure of the target compound. Thus, insight into the behavior of the bioactives is given and the outcome can enhance further research on rosemary’s bioactives and their functionality.

Several rosemary-derived bioactives have been proposed to possess health-promoting effects against AD and PD, such as a-pinene, camphor, eucalyptol, eugenol, luteolin, carnosol, rosmanol, rosmarinic acid, and ursolic acid, most of which are of amphiphilic semi-polar lipid nature along with the more non-polar carnosic acid, according to the physicochemical properties of these molecules that was predicted from their structures and molecular weight using QSAR (Figure 2).

Figure 2. Predicted polarity and lipophilicity of rosemary bioactive, according to their logKow values (Kow = n-octanol/water partition coefficient).

Such an amphiphilic nature for these molecules is important as it suggests that these molecules can cross the BBB, as well as be diffused and translocate from cell membranes to intracellular sites that facilitate their proposed neuroprotective properties by being able to affect specific intracellular signaling pathways and gene expression [78].

3.5. Carnosic Acid

3.5.1. In Vitro Health-Promoting Effects of Carnosic Acid against AD and PD

Starting with Parkinson’s, a study investigated the potential in vitro neuroprotection of CA in SH-SY5Y cells. Pretreatment with this phenolic diterpene led to a rise in the protein expression of γ-glutamate–cysteine ligase catalytic subunit, γ-glutamate-cysteine ligase modifier subunit, superoxide dismutase, and glutathione reductase. The presence of a p38 (mitogen-activated protein kinase (MAPK)) inhibitor or a JNK (c-Jun N-terminal kinase 1) inhibitor in these cells counteracted the decrease in the Bcl-2 (B-cell lymphoma 2)/Bax ratio, the activation of caspase-3 cleavage, and the rise in poly (ADP-ribose) polymerase (PARP) cleavage by 6-hydroxydopamine (6-OHDA) shown in immunoblots. Nevertheless, a Bax enhancer, BAM7, weakened the impact of CA on cell death [10]. Another study on these cells was conducted, where CA effectively reverted the upregulation of ubiquitinated proteins and the phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1) depletion, as well as the depletion of parkin protein, in the cells treated with 6-OHDA [16]. CA was also examined in these cells, and it serves as a neuroprotective agent by stimulating autophagy via parkin and Beclin1. The results showed higher levels of parkin protein, autophagy-related markers and gene 7, phosphatidylinositol 3-kinase p100, Beclin1, and microtubule-associated protein 1 light chain 3-II. 6-OHDA-treated cells had decreased levels, but pretreatment with CA reversed these effects. Last but not least, tests showed that the interface between parkin and beclin1 was minimized by an oxidizing agent, but CA in the cells helped reverse those effects. Thus, the earlier hypothesis was confirmed [79].

Further studies were conducted on the neuroprotective function of CA against PD in a paraquat (PQ) model of the disease, as measured by redox indicators in the cells and mitochondria. The outcomes showed that the symptoms of the PQ model were blocked by CA, which protected the cells by reducing ROS and RNS production of the PQ and minimizing the toxicity that surfaced as mitochondrial dysfunction. Inhibiting the Pi3K pathway using LY294002 or suppressing the expression of nuclear factor erythroid-3-related factor 2 (Nrf2) resulted in some abrogation of the reversal of redox dysfunction triggered by CA. So, CA stimulation of Nrf2 through the regulation of the phosphatidylinositol 3-kinase (Pi3K)/Akt pathway led to an increased concentration of antioxidant enzymes, accounting for the neuroprotective activity of CA [17]. Moreover, taking a look into an older paper about 6-OHDA-treated cells and CA, immunoblots showed that the phosphorylation of JNK and p38, caused by 6-OHDA, were reduced by CA pretreatment. GSH levels were increased, and so were the levels of the γ-glutamate–cysteine ligase catalytic subunit and γ-glutamate-cysteine ligase modifier subunit in the presence of CA. It is worth mentioning that there was also an increase in Nrf2 activation, antioxidant response element (ARE)–luciferase reporter activity, and DNA connecting to the ARE, indicating that CA may be a potential neuroprotective agent against PD [15]. Lastly, in a study on rat cerebellar granule neurons (CGNs), there was an investigation on the factors that caused oxidative stress to neurons. CA decreased the CGN apoptosis initiated by an oxidizing factor, nitric oxide contributor (NO contributor), and sodium nitroprusside (nitrosative stress) and saved the rat’s brain neurons from caspase-dependent death caused by a reduction in depolarizing extracellular potassium levels (5K apoptotic condition). The results also showed that CA could shield CGNs against 5 K-induced apoptosis by activating a PI3K mechanism that promotes cell survival [12].

Regarding Alzheimer’s, in vitro studies of CA found that it displays inhibition abilities for both AChE and BChE (acetylcholinesterase and butyrylcholinesterase, respectively) enzymes [80]. In a human dopaminergic neuroblastoma cell line (SH-SY5Y), the possible use of CA to counteract methylglyoxal (MG)-induced disease was investigated. MG is an effective activator of AGEs (which are present in AD). CA pretreatment alleviated cytotoxicity, and apoptosis was induced by MG by activating the PI3K/Akt/Nrf2 signaling pathway and antioxidant Nrf2-dependent enzymes. Therefore, its use can be beneficial in combating AD [81]. CA was investigated at 30 mM regarding Aβ production in SH-SY5Y human neuroblastoma cells, where it was found to diminish Aβ secretion via α-tumor necrosis factor (TNFα)-converting enzyme (TACE), without affecting the b-secretase BACE1 [82]. The researchers also suggested that Aβ has an immediate effect on SH-SY5Y cell death due to PARP cleavage and the stimulation of caspases 3, 8, and 9, while pretreatment with 10 mM CA produced a fragmentary decrease in apoptosis and downregulation of the cellular Aβ content [83].

CA, in general, is considered a pro-electrophilic drug (PED) and is pathologically activated via stimulation of the Nrf2 pathway. CA, which is commonly extracted from Rosmarinus officinalis or synthesized, acts as a catechol-type PED drug. To accomplish oxidative activation of the pro-electrophilic state to the electrophilic state, electron acceptors, including ROS, tend to play a pivotal role. As a result, the quinone compound reacts with cysteine thiols. During this process, a cysteine thiol stimulates a nucleophilic attack of the electrophilic compound to constitute the addition product, CA, and hence, changes from an inactive (pro-electrophilic) state to an active (electrophilic) state when oxidative stress is present.

Consequently, CA transforms into its active state in conditions where oxidative and inflammatory stress are present in the tissue, protecting the tissue from stress in disorders including AD. This is accomplished by stimulating the KEAP1/Nrf2 mechanism via the quinone formation of CA. The Nrf2/KEAP1 pathway is one of the main constituents of the cellular defense mechanisms combating oxidative and inflammatory stress. Nrf2 works as a transcription factor responsible for the expression of phase II antioxidant and anti-inflammatory enzymes. KEAP1 protein, under normal conditions, is connected to Nrf2 and operates as an adaptor protein for cullin 3 (Cul3 in humans) E3 ubiquitin ligase, which ensures that Nrf2 is polyubiquitinated. Subsequently, Nrf2 is degraded by the proteasome.

Therefore, the transcriptional activity of Nrf2 is regulated and inhibited when pathogenesis is not present. KEAP1 consists of vital cysteine thiols that interact with CA after electrophilic conversion, as previously described. This reaction hinders KEAP1 from causing the ubiquitination and degradation of Nrf2. Nrf2, therefore, can be isolated from the cytoplasmic complex with KEAP1, and they can reach the nucleus and bind to AREs (antioxidant response elements) to induce target phase II genes in the well-coordinated formation of antioxidant as well as anti-inflammatory enzymes. These enzymes are responsible for the production of one major cellular antioxidant: glutathione (GSH). Thus, it can be concluded that Nrf2 activators have a protective role in numerous cell types, neurons included, via the regulation of chemical redox. In the brain, the upregulation of Nrf2 takes place predominantly in astrocytes as well as microglial cells; this biochemical pathway is shown in Figure 3 [84].

Figure 3. Stimulation of the Nrf2 pathway to induce phase II gene activation by CA pro-drugs like catechol. Catechol is at first transformed to a CA congener called quinone, an active electrophilic drug, which undergoes a nucleophilic attack in its electron deficient carbon by the Keap1 target protein that carries the Nrf2 factor. This factor consequently translocates to the nuclei where phase II gene activation occurs.

3.5.2. In Vivo Health-Promoting Effects of Carnosic Acid against AD and PD

Taking a look into the in vivo studies on CA, a transgenic OW13 Caenorhabditis elegans model of PD was examined. The outcome suggested that a dose-dependent reduction of CA in human α-syn aggregation was found in the roundworm muscle cells. In the same study, in ROS-treated rats, the immunoblots displayed the same results as in the cells, meaning that the diterpene attenuated the upregulation of ubiquitinated proteins and reduced PINK1 and parkin protein levels [16]. Rats administered CA before exposure to 6-OHDA showed an enhancement of locomotor activity and reduction in the apomorphine-induced rotation. Also, the rats pretreated with CA showed increased defenses against the lipid peroxidation and GSH downregulation caused by 6-OHDA. Lastly, like in the in vitro experiment in the same study, pretreatment with CA led to a rise in the levels of the γ-glutamate–cysteine ligase catalytic subunit and γ-glutamate-cysteine ligase modifier subunit, superoxide dismutase, and glutathione reductase. CA treatment reversed the activation of JNK terminal kinase and p38, the reduction in the Bcl-2/Bax ratio, the increase in the cleaved caspase 3/caspase 3 and cleaved PARP/PARP ratios, as well as the decrease in tyrosine hydroxylase (TH) levels [10]. Another in vivo study in rats revealed that CA can effectively reverse the upregulation of ubiquitinated proteins and the decrease in PINK1 and parkin protein levels in the rats exposed to 6-OHDA, similar to the results of the in vitro experiment [16]. In an in vivo experiment for AD, CA administration in hAPP-J20 mice ameliorated the memory and learning deficits in the Morris water maze test [85].

The first appearance of the favorable effect of CA in vivo was witnessed in an experimental rat model of AD. This study suggested that CA (3 mg/kg) prevented hippocampal neurons from undergoing apoptosis, specifically those in the cornu ammonis 1 (CA1) region of the hippocampus, which impeded Aβ-related neurodegeneration [86]. The effect of CA (3 mg/kg) on memory and behavioral alterations caused by Aβ was also explored, which found that the molecule could reduce spatial and learning memory loss [87]. CA also diminished the dendritic spine loss in rat neurons treated with oligomeric Aβ [85], while its administration further ameliorated the memory and learning of hAPP-J20 mice in the Morris water maze test [85].

3.6. Rosmarinic Acid

3.6.1. In Vitro Health-Promoting Effects against AD and PD

The effects of RA were also investigated in a study on PD using the rat CGNs mentioned above. The findings suggested that RA could also decrease the CGN death caused by nitric oxide (NO) donors and sodium nitroprusside (nitrosative stress). Lastly, in contrast to CA’s function, RA protected CGNs from glutamate-induced excitotoxicity [12]. RA has also been investigated in SH-SY5Y cells induced with the ROS H₂O₂ that causes cell apoptosis. RA reduced the cell death caused by ROS, decreased the upregulation of Bax and downregulation of Bcl2, and activated the heme oxygenase-1 (HO-1) enzyme, thus making RA a potential neuroprotective agent [13]. Another study in H₂O₂-treated cells (N2A mouse neuroblastoma cells) examined the neuroprotective effect of RA. The results of the experiments claimed that RA prevented the toxicity of the induced ROS. Moreover, RA lessened the interference from lactate dehydrogenase, the mitochondrial membrane potential, and ROS production in the cells. Adding to the above, RA prevented genotoxicity and increased the levels of TH and brain-derived neurotrophic factor genes to reduce the ROS-induced cell damage, making it a potential neurodegenerative agent to treat NDs, like PD [88].

Concerning AD, a study that tested RA against cholinesterase enzymes proved that the compound was more active towards BChE than AChE after utilizing molecular docking studies [89]. In another trial, RA was also investigated for its AChE and BChE inhibition properties and the findings found that the induction of 85.8% inhibition against AChE required a concentration of just 1.0 mg/mL [90]. A similarly structured evaluation of the AChE inhibition ability and the antioxidant properties of RA confirmed noteworthy contraction responses in isolated guinea pig ilea. RA demonstrated higher radical scavenging abilities. Docking data for RA indicated strong similarities with AChE. In this study, in vitro and ex vivo studies and in silico docking of RA were synchronously utilized for the first time. In all the methods tested, RA showcased promising results [91]. On a comparative note, RA appears to be more effective than caffeic acid (one of its monomer structural components) in terms of anti-AChE activity. However, caffeic acid was found to be an essential structural feature that is responsible for RA’s binding ability [92,93]. Another study that investigated RA’s ability to inhibit fibrillization further observed morphological changes in atomic force microscopy (AFM) images after saturation. More specifically, RA bound to tau protein in vitro, resulting in a downregulation in amide regions I and III and, as a result, proves that this structure halts β-sheet aggregation [94]. More specific studies based on the “amyloid-β aggregation hypothesis”, which posits that Aβ aggregation inhibitors as therapeutic or preventive agents for AD, investigated the structure–reactivity relationships of RA-derived compounds and Aβ aggregation prevention abilities (molecular docking simulations and MSHTS assays). The study outcomes showed radical-scavenging abilities and simultaneously displayed significant hindrance to Aβ1-42 aggregation [93]. In cultures of PC12 cell lines that were exposed to Aβ1-42, cytotoxicity in connection with ROS formation, DNA fragmentation, lipid peroxidation, tau protein hyperphosphorylation, and caspase-3 activation were all found to be suppressed by RA [95]. Figure 4 summarizes all the above observations.

Figure 4. RA downregulates Aβ-induced oxidative stress (ROS activity) by activating Nrf2 and Akt/GSK-3β/Fyn pathways in PC12 cells. RA crosses the cell membrane and induces the activation of a series of crucial factors in the Akt/GSK-3β/Fyn pathway inside the nucleus. Nrf2 increases in quantity and, via AREs, induces the activation of factors including HO-1, GCLc, NQO1, and TrxR, which inhibit the ROS activity that was previously initiated via Aβ’s action.

3.6.2. In Vivo Health-Promoting Effects against AD and PD

In an in vivo study on PD, RA was used in 6-OHDA-treated rats. The ROS reduced the DA levels in the striatum, while RA reversed these changes. Once again, the oxidizing factor increased the Bax/Bcl-2 ratio at the gene level, while RA attenuated this increase, demonstrating a neuro-rescue effect [9]. Another in vivo study in mice induced with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), along with treatment with RA, was performed to evaluate RA’s potential protective properties. RA alleviated the hyper-locomotive activity of MPTP-treated animals. Moreover, DA signaling was increased under RA treatment, which also boosted the monoaminergic system in healthy untreated mice (without MPTP). Lastly, the MAO content was upregulated in the MPTP+AR group [96].

In an AD study that used Wistar rats, RA prevented the cholinergic damage and oxidative imbalances caused by Aβ, and was hypothesized to aid in the improvement of neural network synapses and auditory processes [97]. RA also significantly improved cognitive function and object perception in male ICR mice (intracerebroventricular injection) with aggregated Aβ25-35-induced AD [98]. Similar research also examined the protective effects of RA, which was hypothesized to be a natural scavenger of ONOO⁻, regarding memory impairment in mice subjected to acute i.c.v. injection of Aβ25-35. Co-injection of ONOO⁻, a compound lacking memory-impairing effects, with Aβ25-35, impeded the favorable effects of RA (0.25 mg/kg). The authors concluded that the beneficial memory effects of RA in Aβ25-35-induced neurotoxicity are a result of its ability to scavenge ONOO−, and consistent consumption of RA could serve as a protective agent against the memory loss observed in AD [99]. A study performed on female Wistar rats investigated the effects of RA administration on the pathology related to ovariectomy and D-galactose injection as a double-insult model for AD. This study concluded that RA could prevent both the biochemical and psychological alterations in the cerebrum in this AD model, which was attributed to its ability to attenuate lipid peroxidation and the inflammatory response [100]. The properties of RA for combating AD in vivo, via tau protein regulation, have been studied in adult and middle-aged male C57BL/6 mice, where it was discovered that the amount of phosphorylated tau protein increased as a result of aging and chronic restraint stress (CRS) [101].

3.7. Other Bioactive Compounds for Treating NDs

Carnosol does not appear in as many reports as RA and CA for neuroprotection against PD. One in vitro study in neuronal cells, specifically HT22 cells, had been found. The results showed an increase in ARE activity and GSH synthesis. In the PC12 cell line, there was a stimulation of ERK, JNK, p38, and PI3K/Akt; PI3K/Akt-dependent activation of Nrf2; an increase in HO-1; and a decrease in H₂O₂ toxicity [14,40]. Moreover, an older study on rotenone-induced neurotoxicity in SN4741 cells examined the neuroprotective effect of carnosol. The outcome was indeed proved the neuroprotective ability of carnosol, as cell viability was improved through inhibiting caspase-3. Moreover, CS increased the levels of TH, Nurrl, and extracellular signal-regulated kinase 1/2 [11]. In vivo, carnosol had an anti-depressant effect in mice [14].

Another RO compound investigated for its neuroprotective effect is eugenol or 2-methoxy-4-(2-propenyl-phenol). Eugenol was used in a study in PC12 cells examining cell viability and the regulation of DA release, and concluded that the compound may be beneficial against the symptoms of PD, as it can increase the hormone’s availability [102]. In an in vivo study, MPTP led to motor impairment in a mouse model, and a decrease in glutathione levels and lipid peroxidation, while treatment with the phenylpropanoid reversed these effects. Lastly, eugenol can reduce the possibility of PD development but it cannot cure PD [103]. Another in vivo study analyzed the effect of combining eugenol with levodopa in 6-OHDA-stimulated Wistar rats. The findings showed that the combination of these chemicals decreased the PD-associated symptoms, in contrast to L-dopa alone, and increased GSH synthesis [104]. Luteolin, a flavonoid compound of the herb, was also used in 6-OHDA-treated PC12 cells. Overall, cell pretreatment with luteolin reduced the ROS production induced by 6-OHDA and downregulated the p53, UPR (unfolded protein response), and Nrf2–ARE pathways, making it a potential neuroprotective agent against PD [105]. Also, a luteolin derivative, luteolin-7-O-glycoside (LUT-7-G), was given before the MPTP and 1-methyl-4-methylpyridinium (MPP⁺) treatment of SH-SY5Y cells, resulting in an extension of the cells’ life. On the one hand, there was an increase in the Bcl-2/Bax ratio, while on the other hand, the cleaved caspase-3 level was reduced. Additionally, there was an increase in estrogen receptor (ER), Erα, and Erβ levels, and a boost in the activation of the ERK1/2 (extracellular signal-regulated kinase 1/2)/STAT3 (signal transducer and activation of transcription 3)/c-Fos pathway.

In vivo, LUT-7-G pretreatment enhanced bradykinesia and muscle strength while balancing the capacity of the mice treated with MPTP. Lastly, the cells containing TH were protected from injury, TH nerve fibers were found at higher quantities, and MPTP-induced gliosis in the SN was reduced, making LUT-7-G a potential neuroprotective candidate [106]. Additionally, 1,8-cineole and a-pinene were examined in PC12 cells. Pretreatment with the two terpenes increased cell survival while inhibiting intracellular ROS accumulation and increasing the presence of antioxidant enzymes. The low levels of caspase-3 revealed minimal levels of apoptosis. Eliminating ROS and activating the Nrf2 factor through induction led to another conclusion: the two terpenes possess antioxidant effects and may be protective against diseases associated with oxidative stress, like Parkinson’s [107]. Lastly, ursolic acid (UA), another rosemary compound, was used in vivo in rotenone-treated rats, revealing its potential as a neuroprotective agent against PD. Treatment with UA protected TH-positive cells, enhanced cognitive function in the Barnes maze (BMT), and minimized the oxidative stress and inflammation caused by the rotenone infusion. Also, it mitigated the complex I inhibition to a significant level and facilitated the promotion of mitochondrial biogenesis (MB), making it a potential therapeutic agent to treat PD [108].

In AD models, the potency of different diterpenes isolated from Rosmarinus officinalis meant to act as AChE-inhibiting agents has been investigated. The use of in silico and molecular docking techniques aimed to explore how these molecules interact with the active region of AChE. Rosmanol was suggested as the candidate with the most potential for further clinical trials and research to validate the molecule’s efficacy in preventing and/or treating AD [109]. In an in vitro study, a-pinene and 1,8-cineole were found to be the main monoterpenes in the Rosmarinus officinalis essential oil (RO EO), and the conclusions suggested that the AChE-inhibiting properties of the RO EO was suspected to be based on a synergistic interaction between these different oil components [90]. 1,8-cineole has the ability to modulate tau phosphorylation via the downregulation of GSK-3β and Aβ production, which can be obtained by interacting with the active site of BACE-1, which was shown in vivo as well as in vitro. After this research, it was established that 1,8-cineole could be used in a therapeutic sense in the management of AD and in DM-related AD as well [110]. Eugenol at 10 or 30 mg/kg/day as a course of treatment for eight-month-old 5xFAD mice over a 2-month period successfully regulated the cognitive and neural losses as well as Aβ aggregation [111]. Eugenol, at 0.01 mg/kg, ameliorated the memorization deficits and suppressed the formation of amyloid deposits in AD rat models [112]. Lastly, eugenol exerted anti-amnesic activity in scopolamine-induced AD in rodents by diminishing hippocampal cholinergic deterioration, glutamate neurotoxicity, and mitochondrial dysfunction [113].

RA, CA, and CS, along with other RO components reported to have biological functions, are listed in Table 1. The studies of the aforementioned bioactive constituents are presented in Table 2, along with the experimental procedures that were used.

3.8. More Neuroprotective Properties of RO and Its Compounds

Rosmarinic and caffeic acids have also been investigated in mice, and were shown to be neuroprotective against oxidative stress and DNA damage [114]. In male Wistar rats, RA protected the spinal cord from injury, and demonstrated neuroprotection by decreasing the levels of cytokines, such as TNF-a and Nrf2, which are oxidative stress indicators, and other antioxidant enzymes [115]. In another study, including young and aged mice, the outcome indicated that the EO of R. officinalis improves memory in both age groups. Still, its efficacy was more apparent in aged mice [116]. In vivo, studies in humans also support the role of rosemary EOs in short-term image and numerical memory in secondary school students, as well as in the amelioration of cognition and the subjective state in healthy volunteers, with emphasis being given to the link between 1,8-cineole levels and their beneficial effect [117,118,119]. All the previous studies utilized inhalation as the administration method. As a noteworthy comment, it is interesting to mention that when comparing rosemary and lavender, it is clear that rosemary is better at ameliorating cognitive performance [117,119].

Moreover, CA presents potent inhibition of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome both in vitro and in vivo. CA downregulates NLRP3 expression by inhibiting NF-κB, while at the same time, it acts on NLRP3 inflammasome formation and induction by reducing mitochondrial ROS and stopping NLRP3–NIMA-related kinase (NEK7) synergy [120]. CA is a potent blocking agent of the activation of superoxide anion via the xanthine oxidase pathway. It has promising protective abilities towards dopaminergic neuronal cells, protecting them from toxicity by boosting neurotrophic factors and slowing down cell death processes [121]. In another study evaluating the properties of an RO extract and spearmint extract (with the main constituents being CA and RA) on cognition and recall in a SAMP8 mouse model of rapid aging, improved performance was observed in most tests [122]. Camphor was found to have neuroprotective properties against depression. In Wister albino male rats, depression was induced by ciprofloxacin. The results after treatment with camphor showed an increase in catalase and Nrf2 activities and a downregulation of NO, malondialdehyde (MDA), TNF-α, and Toll-like receptor 7 (TLR4) serum levels, while there was also a rise in serotonin, DA, GABA (gamma-amino butyric acid), and Rho family GTPase-activating guanosine-5′-triphosphate (P190-RHO GTP) protein levels, with non-pathogenic neuronal cells in the front cortex of the brain, making camphor a potential neuroprotective compound against major depression [123]. Furthermore, the ability of RA to prevent spinal cord injury (SCI) and promoting nerve repair in an in vivo SCI rat model is shown in Figure 5.

Figure 5. Pathways affected by RA as a protective agent against SCI while assisting in nerve restoration. RA displays neuroprotective properties, combating oxidative stress and inflammation by stimulating the Nrf2/HO-1 signaling pathway and inhibiting the NF-κB signaling mechanism in SCI rat models. RA: rosmarinic acid; SCI: spinal cord injury; TNF-α: tumor necrosis factor-α; IL-6: interleukin-6; IL-1β: interleukin-1β; MDA: malondialdehyde; SOD: superoxide dismutase; CAT: catalase; GSH-Px: glutathione peroxidase; ROS: reactive oxygen species; Casp-8: caspase-8; Casp-9: caspase-9; Casp-3: caspase-3; Bax: B-cell lymphoma 2-associated X; Bcl-2: B cell lymphoma 2; Cyto-C: cytochrome C; Nrf2: nuclear factor erythroid-derived 2-related factor 2; Keap: kelch-like ECH-associated protein; ARE: antioxidant responsive element; HO-1: heme oxygenase-1; NQO1: NAD(P)H quinone oxidoreductase 1; Maf: musculoaponeurotic fibrosarcoma; TLR4: Toll-like receptor 4; MyD88: myeloid differentiation factor-88; IKK: inhibitor of NF-κB kinase; Ub: ubiquitin; IκB: inhibitory IκB family; NF-κB: β-nuclear factor kappa.

Table 1. Rosemary’s bioactive compounds and their reported biological activities and associated health-promoting effects.

Compound	Chemical Group	Structure	Effect	Reference(s)
Rosmarinic acid	Phenolic acid		Neuroprotective, antioxidant	[12]
Carnosic acid	Phenolic diterpene		Neuroprotective, antioxidant, anti-inflammatory	[12,14]
Carnosol	Phenolic diterpene		Neuroprotective, antioxidant, anti-inflammatory	[14]
Eugenol	Phenylpropanoid		Anti-inflammatory, immunomodulatory, antioxidant	[103,104,124]
Camphor	Monoterpenoid		Neuroprotective, antioxidant, anti-inflammatory	[123]
Luteolin	Flavonoid		Neuroprotective, antioxidant	[125]
Eucalyptol/1,8-cineole	Monoterpenoid		Antioxidant, anti-inflammatory	[126]
Ursolic acid	Triterpene		Antioxidant, anti-inflammatory, neuroprotective	[127]
a-pinene	Monoterpene		Neuroprotective, antioxidant	[107,128]
Rosmanol	Flavonoid		Neuroprotective	[109]

Table 1. Rosemary’s bioactive compounds and their reported biological activities and associated health-promoting effects.

Compound	Chemical Group	Structure	Effect	Reference(s)
Rosmarinic acid	Phenolic acid		Neuroprotective, antioxidant	[12]
Carnosic acid	Phenolic diterpene		Neuroprotective, antioxidant, anti-inflammatory	[12,14]
Carnosol	Phenolic diterpene		Neuroprotective, antioxidant, anti-inflammatory	[14]
Eugenol	Phenylpropanoid		Anti-inflammatory, immunomodulatory, antioxidant	[103,104,124]
Camphor	Monoterpenoid		Neuroprotective, antioxidant, anti-inflammatory	[123]
Luteolin	Flavonoid		Neuroprotective, antioxidant	[125]
Eucalyptol/1,8-cineole	Monoterpenoid		Antioxidant, anti-inflammatory	[126]
Ursolic acid	Triterpene		Antioxidant, anti-inflammatory, neuroprotective	[127]
a-pinene	Monoterpene		Neuroprotective, antioxidant	[107,128]
Rosmanol	Flavonoid		Neuroprotective	[109]

Table 2. Experimental data on rosemary extracts and EOs, RA, CA, and other bioactive compounds of rosemary in neuroprotection against PD, AD, and other neurodegenerative conditions.

Hypothesis and Intervention 1	Experimental Details	Study Results	Year of Study	Reference
The neuroprotective effect of a rosemary EO was examined in vitro through the evaluation of H2O2-induced apoptosis in SH-SY5Y cells	SH-SY5Y cells were treated with R. officinalis extract for 12 h at a concentration ranging from 1–100 μg/mL In a similar way, all cells were treated with H2O2 for 12 h, at a concentration ranging from 1–300 μM The R. officinalis extract treatment was added 1 h before the H2O2 treatment	A significant suppression of H2O2-induced cytotoxicity was observed The herb EO mitigated mitochondrial membrane disruptions and ROS-initiated apoptotic cell death R. officinalis also attenuated the increase in expression of Bax, Bac, and caspase-3 and -9 and prevented the downregulation of Bcl-2 Lastly, it inhibited the downregulation of TH and AADC in these human cells	2010	[129]
The impact of an R. officinalis EO on AD was examined in a mouse model	Mice inhaled the EO The AD-type dementia was induced using scopolamine Cognitive function was assessed via the appropriate Y-maze test (a test used for the assessment of short-term memory in mice)	The EO produced a notable increase in the spontaneous alternation behavior The predominant EO components detected in the brain were namely 1,8-cineole and α- and β-pinene	2018	[130]
The beneficial effects of an aromatherapy procedure in 28 older adults, where 17 of them had developed AD-type dementia, were evaluated	An aromatherapy procedure for 28 days, followed by a control period of 28 days was conducted for all patients, followed by a wash-out period lasting another 28 days Rosemary and lemon EOs were utilized in the morning and lavender and orange EOs were used in the evening aromatherapy routine The effects of aromatherapy were determined via the evaluation of all the patients’ scores in the tests: GBSS-J, FAST, HDS-R, and TDAS Patients were examined four times, including before and after the control period, after the aromatherapy, and after the wash-out period	All participants displayed noteworthy amelioration regarding both the TDAS and the GBSS-J tests that measure cognitive function AD patients showed an improvement in their total TDAS score No side effects were observed following the aromatherapy procedure Aromatherapy was an efficacious nonpharmacological treatment for dementia, especially in AD	2009	[131]
The memory enhancement of an R. officinalis EO was explored in young and aged mice	This study utilized five different young and aged groups of mice 200, 400, 600, and 800 mg/kg doses of R. officinalis EO were administered intraperitoneally to all young and aged mice groups, except for the control group, once a day for 7 days	The outcome indicated that the R. officinalis EO can enhance memory in both young and aged mice The EO’s efficacy was more apparent in aged mice than younger ones	2014	[116]
The study describes the effect of EOs on human short-term image and numerical memory	79 secondary school students between the ages of 13 and 17 years (34 boys and 45 girls) participated and were divided into test groups	The statistical analysis revealed differences in the short-term memory of the subjects in the different groups The rosemary EO significantly improved image memory compared to the control The rosemary EO enhanced number memorization abilities; however, lavender EO inhalation diminished this ability	2017	[117]
This study evaluated the effect of lavender and rosemary EOs on the mood and cognitive performance of healthy volunteers	144 participants were divided into test groups Researchers studied the participants’ performance of the Cognitive Drug Research (CDR) and the computerized cognitive assessment battery in a cubicle containing a lavender EO, rosemary EO, or control odor	The lavender EO resulted in a visible deterioration in working memory and slowed down response times in tasks assessing memory and attention The rosemary EO, on the other hand, resulted in a notable improvement in memory	2003	[119]
This unprecedented study investigated the impact of a combination of rosemary and two other herbs on verbal recall in healthy humans and their clinical value for memory and brain function	Forty-four normal healthy subjects were part of this, not only double-blind but also placebo-controlled, pilot study The participants were split into two groups: an active group and a placebo group An ethanol SRM extract was characterized using LC/UV/MS/MS Immediate and delayed word recall tested the subjects’ memory after the administration of the SRM extract or placebo	Remarkable improvements in delayed word recall were observed in the active group consisting of people under the age of 63 No side effects were observed	2017	[132]
This study identified the antioxidative agents in rosemary and characterized their antioxidant effects in biological systems	CA, carnosol, rosmanol, and epirosmanol antioxidative agents were isolated from R. officinalis leaves using fractionation bioassays	The superoxide anion activity was attenuated by diterpenoids existent in the xanthine-xanthine oxidase system Diterpenoids affected both microsomal and mitochondrial lipid peroxidation that was induced by the oxidation at 3–30 pM of NADH or NADPH CA prevented oxidative hemolysis in red cells, on the contrary	1995	[121]
The effects of a rosemary extract and a spearmint extract, which both contained CA and RA, on cognition and memory in a SAMP8 mouse model that displayed rapid aging were studied	R. officinalis EOs contained CA at 10 or 60%, while one spearmint extract contained 5% rosmarinic acid The examined doses were 0, 1.6, 16, and 32 mg/kg 90 days after the treatment’s termination, the mice were tested using T-maze, object recognition, and lever press assessments	A rosemary extract with 60% or 10% of CA boosted the performance in the conducted tests	2016	[122]
Comparison of neuroprotective effect of R. officinalis RA and CA constituents through their impact on primary cultures of CGNs subjected to a variety of stressors	CGNs were treated with a glutamate and glycine combination as well as SNP CGNs were co-treated with either CA or RA, and with either SNP at 100 μM or the glutamate/glycine combination at a concentration ratio of 100 μΜ/10 μΜ for 24 h	CGN death induced by the NO donor, namely SNP (nitrosative stress), was decreased in the presence of both polyphenols RA shielded CGNs from glutamate-induced excitotoxicity CA, on the other hand, was the only constituent able to protect CGNs from the caspase-dependent apoptosis that was accelerated by the disposal of depolarizing extracellular potassium (5K apoptotic condition) CA also shielded CGNs from the 5K-induced apoptosis through the activation of a phosphatidylinositol 3-kinase pro-survival pathway	2018	[12]
The influence of RA and CA on seizures induced by PTZ were evaluated in this study	Male CF-1 mice were administered 1, 2, or 4 mg/kg i.p. RA; 1, 4, or 8 mg/kg i.p. CA; 1 mg/kg diazepam (controls); or 600 mg/kg p.o. vigabatrin once every 3 days for 16 days, and 30 min prior to the administration of 50 kg/mg s.c. PTZ The cortex was collected afterwards in an attempt to fully assess free radical levels, superoxide dismutase activity, and any genotoxic activity	Some defined doses of CA and RA exhibited a strong neuroprotective action against the induction of oxidative stress and DNA damage	2015	[114]
In vivo study of RA effects in rats that were treated with 6-OHDA	Following the treatment with 6-OHDA, rats were treated orally with RA	DA levels in the striatum were reduced by 6-OHDA RA reversed these changes RA also attenuated the increase in the ratio of Bax/Bcl-2 at the gene level that was induced by 6-OHDA, thereby demonstrating a neuro-rescue effect	2012	[9]
and SH-SY5Y cells treated with H2O2	RA was added 30 min before the treatment with the ROS	RA reduced the cell death that was initiated by H2O2 and attenuated the upregulation of Bax and downregulation of Bcl-2 RA also stimulated HO-1	2008	[13]
RA activity in MPTP-treated mice	Four groups of mice were tested: CN (control/saline), Ra (RA/vehicle), MPTP (MPTP/saline), and MPTP+RA (MPTPT/RA) Oral administration of RA for 14 days, 1 h prior to MPTP or saline injection The MPTP groups were given this drug for 5 days, once a day	RA alleviated the hyper-locomotive activity of MPTP-treated animals RA also increased DA signaling and boosted the monoaminergic system in healthy mice (not treated with MPTP) Lastly, an upregulation of the expression of MAO-A in the MPTP+RA group was found	2022	[96]
RA in H2O2-treated N2A cells	Cells were pretreated and treated RA	RA prevented the toxicity induced by ROS and reduced the interference from lactate dehydrogenase RA also decreased the mitochondrial membrane potential and ROS production within the cells Adding to the above, RA prevented genotoxicity, and increased the levels of TH and brain-derived neurotrophic factor (BDNF) to reduce ROS cytotoxicity in induced cells	2014	[88]
The inhibitory impact on AChE and BChE, as well as the metal-chelating ability, of 12 diterpenes including RA was examined	RA’s effect against AChE, BChE, and QSAR was evaluated at a concentration of 10 mg/mL via ELISA microfilter assays and molecular docking studies	RA was more effective towards BChE than AChE The assessment of BChE inhibitors is of vital importance since such compounds could be promising candidates for AD therapy	2016	[89]
RA’s inhibitory activity towards AChE and BChE was examined (RA was isolated from an R. officinalis extract and EO)	The Ellman method via an ELISA microplate reader was conducted at the predetermined concentrations of 0.2, 0.5, and 1.0 mg/mL HPLC and GC-MS were the utilized techniques	RA caused 85.8% inhibition of AChE, even at a concentration of only 1.0 mg/mL	2007	[90]
AChE inhibition activity and antioxidant capacity of RA were examined to determine its potential as a candidate compound for AD treatment	The Ellman method and isolated guinea pig ilea were used in this study The antioxidant capacity was measured via DPPH The AChE inhibition activity of RA was evaluated by in silico docking and isolated guinea pig ileum techniques	RA displayed a crucial contraction response using the guinea pig ileum method RA also demonstrated a high scavenging potential and high affinity for AChE (docking study)	2014	[91]
This study measured the AChE activities of phenolic acids and flavonoids individually or in combination	Ellman’s modified spectrophotometry and an assessment of the false-positive molecular results were performed	RA is more potent than its structural monomer, caffeic acid, in terms of anti-AChE activity	2015	[92]
The study assessed the structure–activity synergistic action of RA derivatives in terms of their anti-aggregation, antioxidant, and xanthine oxidase inhibition properties	MSHTS, ThT assays, docking studies, XOD, and DPPH inhibition evaluations were performed	Caffeic acid is a significant structural feature responsible for RA’s binding abilities RA demonstrated radical-scavenging effects In parallel, RA displayed good inhibitory activity against Aβ1-42 aggregation	2017	[93]
RA’s ability to inhibit fibrillization was assessed	In vitro tau fibrillization, AFM, and molecular docking studies were performed	RA inhibits the aggregation of tau at a percentage of over 50% at a concentration of 50 μΜ The downregulation in amide regions I and II was induced by RA Therefore, RA prevents b-sheet assembly	2017	[94]
The study examined the effect of RA on Alzheimer amyloid peptide (A)-induced toxicity in cultured rat PC12 cells	RA was used for the treatment of PC12 cells, 10 min before the Aβ-42 treatment (1 g/mL)	RA reduced ROS formation, DNA fragmentation, lipid peroxidation, tau protein hyperphosphorylation, and caspase-3 activation	2006	[95]
In an attempt to clarify whether RA prevents Aβ-induced peroxidation of lipids, and antioxidant defense and/or cholinergic damage, in addition to the main auditory deficits, Wistar rat were utilized	The bilateral injection of Aβ-42 peptide (2.2 nmol/10 μL) created a Wistar rat model of AD 50 mg/kg of RA was orally administered on a daily basis for a span of 14 days after the injection Auditory event-related potentials were assessed and similar tests were performed This experiment was followed by histological and biochemical analyses	RA prevents cholinergic damage and Aβ-induced antioxidant–oxidant imbalances This realization may aid in the advancement of treatments for neural network synapses and possibly many other auditory procedures	2018	[97]
The study assessed, in an Aβ25-35-injected mouse model, whether the administration of RA improved cognitive function	Mice were administered several RA doses i.p. daily after injection of A25-35	0.25 mg/kg of RA was preventative against protein nitration in the hippocampus, a fact that implied that RA is an indirect indicator of ONOO− damage	2016	[98]
An examination of the protective ability of RA as a natural ONOO− scavenger and preventing memory deterioration was conducted on a mouse model that was given an acute i.c.v. injection of A25-35	Mice were administered several doses of RA i.p. daily after the injection of A25-35	0.25 mg/kg of RA was preventative against protein nitration in the hippocampus, a fact that implied that RA is an indirect indicator of ONOO− damage, similar to findings of the previous study	2007	[99]
The effects of RA on the pathology related to ovariectomy and D-galactose injection (i.e., a double-insult in an AD model) were thoroughly assessed	100 female Wistar rats were utilized and separated into different groups 80 mg/kg/day of D-galactose was injected i.p. 50 mg/kg/day was also administered for a period of 60 days Locomotor activity and short-term special memory was assessed by open field and Y-maze tests The experiment included both biochemical and histopathological analyses of the rats’ brain tissues	The addition of RA notably restored the altered locomotor activity and cognitive functions The RA treatment inhibited cyclooxygenase-2 expression and lipid peroxidation, and reduced prostaglandin E2 levels The alterations in the brain tissues in the rat model of AD were prevented by the addition of RA, which was able to inhibit lipid peroxidation and the inflammatory response	2015	[100]
The outcomes of aging in a stress-induced tauopathy mouse model of chronic restraint stress and its possible effect were evaluated	The mice were placed in 50 mL tubes with holes in order to be exposed to ventilation for 30 min each day for 18 days for the repeated stress test An intraperitoneal RA (2 mg/kg) or saline injection was given to all the mice 30 min before the induction of the chronic restraint stress	RA effectively downregulated the R-tau formation caused by the CRS, especially in middle-aged mice RA could act as a potent beneficial compound for stress-derived tauopathy	2015	[101]
The study investigated whether RA is able to suppress TAC’s hepatotoxicity to slow down the progression of AD in mice	Wild-type and APP/PS1 Tg mice were randomly divided A series of experiments was carried out using open field tests, Morris water maze tests, hematoxylin–eosin (HE) and Nissl staining, as well as biochemical, immunofluorescence, and western blotting analyses	RA with TAC may inhibit AD progression in mouse brain tissues The synergistic effect of these drugs could potentially both decrease brain damage and enhance cognitive behavior in AD mice though reductions in the expression of Aβ oligomers and Aβ deposition, the inhibition of AChE’s activity, and the upregulation of ACh levels in the hippocampus	2023	[133]
This study aimed to thoroughly assess the value of RA in protecting against SCI	Male Wistar rats were divided into different groups and given an RA treatment (10 mg/kg) After the administration, the spinal tissues were assessed for possible oxidative stress by determining the levels of ROS, protein damage, and lipid peroxidation, and antioxidant enzyme efficacies To determine the activity of the selected oxidative stress factors (NF-κΒ and Nrf2), western blot analysis was used Pro-inflammatory cytokines were analyzed by ELISA	An amelioration of the antioxidant status and a downregulation of the oxidative stress conditions in Wistar rats with an SCI were observed after RA treatment Inflammatory mechanisms that suppress NF-κΒ and pro-inflammatory cytokines post SCI were improved by RA	2016	[115]
Investigation of CA’s neuroprotective effects and its effects on behavioral activity in a rat model of PD, which was induced by 6-OHDA	20 mg/kg body weight of CA was given to rats for 3 weeks before 6-OHDA exposure SH-SY5Y cells were used	An improvement in locomotor activity and a reduction in apomorphine-induced rotation was observed in all rats Pretreated rats showed improved protection against lipid peroxidation and a reduction in GSH levels Pretreatment with CA resulted in an increase in the levels of γ-glutamate-cysteine ligase catalytic and ligase modifier subunit, as well as GSH reductase and superoxide dismutase compared to 6-OHDA-treated rats The Bcl-2/Bax ratio was reduced and caspase-3 cleavage was induced In parallel, the induction of PARP cleavage by 6-OHDA was reversed by treatment of the SH-SY5Y cells with SB203580 or SP600125 CA treatment in rats reversed the 6-OHDA-mediated activation of c-Jun NH2-terminal kinase P38 decreased the Bcl-2/Bax ratio, downregulated tyrosine hydrolase protein, induced the upregulation of cleaved caspase 3/caspase 3, and increased the PARP/PARP ratio However, the activator of Bax, BAM7, attenuated CA’s effect on apoptosis in the SH-SY5Y cells	2014	[10]
Investigation of whether autophagy is correlated with CA’s neuroprotective activity against 6-OHDA-induced neurotoxicity in SH-SY5Y cells	Human SH-SY5Y neuronal cells were pretreated with 1 μΜ CA for 18 h and then incubated with 100 μΜ 6-OHDA for 12 or 18 h In the autophagy inhibition experiment, 0.5 μΜ wortmannin or 0.5 nM bafilomycin-A1 was added 1 h before CA treatment All control cells were treated with 0.3% DMSO only	The results showed higher levels of parkin protein, autophagy markers, phosphatidylinositol 3-kinase p 100, Beclin1, autophagy-related gene 7, and microtubule-associated protein 1 light chain 3-II 6-OHDA -treatment decreased these levels, but pretreatment with CA prevented these effects Tests showed that parkin–beclin1 interactions were minimized by 6-OHDA CA addition reversed such effects	2017	[79]
Investigation of whether CA is neuroprotective against a paraquat (PQ)-induced PD in terms of cellular and mitochondrial-related redox parameters	CA was used for the treatment of SH-SY5Y cells for 12 h, which were then exposed to 100 μΜ PQ (24 h)	CA protected the cells against all symptoms seen in the selected PQ model, by reducing ROS and NOS CA minimized the toxicity caused by the mitochondrial dysfunction PI3K pathway inhibition by LY294002 suppresses the expression of Nrf2, which was partially responsible for the lack of reversal of the redox dysfunction that was triggered by CA Nfr2’s activation by CA is via the modulation of the PI3K/Akt pathway, which led to high antioxidant enzyme levels and thus the neuroprotective activity of CA	2016	[17]
Study on whether R. officinalis-derived CA is able to protect against 6-OHDA-induced neurotoxicity via the upregulation of parkin both in vivo and in vitro in SH-SY5Y cells	The selected cells were incubated for 8 h with 1 mM CA Afterwards, all the cells were treated with 100 mM 6-OHDA for 18 h 6-OHDA was administered as a single injection into the right striatum of male Wistar rats	CA was able to reverse the upregulation of ubiquitinated protein, which was observed using immunoblots Also, CA was responsible for a reduction in PINK1 and parkin protein levels in the cells and rats that were treated with 6-OHDA CA produced an obvious reduction in the aggregation of α-syn in muscle cells of roundworms and in transgenic OW13 Caenorhabditis elegans	2016	[16]
The established mechanism used by CA in the modulation of the neurotoxic impact of 6-OHDA in SH-SY5Y cells was observed	CA was given to cells for 12 h as a pretreatment, followed by treatment with 100 μM 6-OHDA for 12 or 24 h	Immunoblots showed that the phosphorylation of the c-Jun NH2-terminal kinase, JNK, and p38 caused by 6-OHDA was minimized by pretreatment with CA The levels of GSH, γ-glutamate–cysteine ligase catalytic subunit, and γ-glutamate–cysteine ligase modifier subunit were increased in the presence of CA An increase in Nfr2 activation, ARE–luciferase reporter activity, and amount of DNA binding to AREs were mentioned	2012	[15]
The determination of whether CA can protect hippocampal neurons by reversing neurodegeneration in rats was this study’s main aim	Every group of rats received 10 mg/kg CA by an intraperitoneal injection one hour before surgery and then 3-4 h after receiving 3 mg/kg of CA The process was repeated for 12 days 4 μL of Aβ protein (1.5 nmol/μL) was injected bilaterally into the hippocampus After 14 days, the rats’ brains were histologically examined	CA pretreatment was able to diminish cellular death in the cornu ammonis 1 (CA1) region located in the hippocampus	2011	[86]
The study assessed whether CA’s administration owns a protective effect against memory loss induced by β-amyloid toxicity in rats	Injection of Aβ (1-40) into the CA1 region of the rats’ hippocampus was performed CA was administered intraperitoneally, both before and after surgery The evaluation included the shuttle box and Y-maze tests Fluoro-jade b staining was used to detect degenerating hippocampal neurons	Aβ(1-40) caused potent neurodegeneration in the CA1 hippocampus region The conducted behavioral tests revealed higher test scores in the Aβ+CA group compared to the Aβ control group The spatial and learning memory deficits induced by Aβ in the rat hippocampus may be improved with CA	2013	[87]
The study in vitro examined the protective abilities of CA on primary neurons that were treated with oligomeric Aβ. In vivo on mouse models of AD after the delivery of CA, investigated learning and memory ability as well as synaptic damage	CA was utilized in vitro on primary neurons treated with oligomeric Aβ In the in vivo studies, two transgenic mouse models of AD ((hAPP)-J20 and triple transgenic (3xTg AD) mice) were used Trans-nasal administration of CA twice a week for over 3 months in mice was also conducted Histological and neurobehavioral assessments were performed	In vitro, CA diminished dendritic spine loss In vivo, CA treatment of hAPP-J20 mice models ameliorated the mice’s learning and memory abilities in the Morris water maze test CA was able to increase dendritic and synaptic markers and decrease astrogliosis, Ab plaque number, and phospho-tau staining in the hippocampus	2016	[85]
This study investigated the possible use of CA to prevent MG-induced neurotoxicity	The SH-SY5Y cell line was used Dopaminergic toxicity was induced by methylglyoxal at 500 mM CA was used at concentrations of 0.1–2 mM for different periods of time	CA pretreatment (1 mM for 12 h), proved cytoprotective abilities and tackled the damage caused by MG in SH-SY5Y cells CA prevented the loss of the mitochondrial membrane polarity and the cytochrome’s c release by the inhibition of pro-apoptotic caspase enzyme’s activation CA aided vitally against oxidative and nitrosative damage, while neurotoxicity was combated by the activation of the PI3K/Akt/Nfr2 signaling pathway and the antioxidant enzymes transcribed by the Nrf2 factor	2015	[81]
The effect of CA on the production of Aβ1-42 peptides (Aβ42) and on the expressed genes in human neuroblastoma SH-SY5Y cells were explored	Human neuroblastoma SH-SY5Y cells were pretreated with the inhibitor 1 h prior to the addition of 30 mM CA RNA interference, real-time quantitative PCR, ELISA, and immunoblot analysis techniques were utilized	Treatment of SH-SY5Y cells with CA was observed to diminish A42 secretion (61% at 30 M) The mRNA expression of secretases RACE (tumor necrosis factor-converting enzyme, ADAM17) and ADAM10 was enhanced by the CA treatment CA did not impact the expression of the secretase BACE1	2012	[82]
Investigation of CA’s impact on the apoptosis induced by A42 or A43 peptides in cultured SH-SY5Y human neuroblastoma cells	Cells were treated with Aβ42 or Aβ43 (10 μM)	The apoptosis induced by Aβ42 or Aβ43 peptides was alleviated by a pretreatment of the cells with 10 M CA; the results were confirmed by the observed cleavage of PARP and AIF Furthermore, Aβ42 and Aβ43 levels were diminished in the presence of CA Overall, CA reduced the activation of the Casp cascades induced by Aβ through the downregulation of the intracellular oligomerization of Aβ42/43 monomers	2014	[83]
This study investigated the effects of CA on NLRP3 activation using in in vitro and in vivo experiments	8–10-week-old male WT C57BL /6 mice were utilized Primary peritoneal macrophages were collected Cell viability, inflammasome activation, ASC oligomerization, immuno-precipitation, western blot, ELISA, and histological analyses were used	CA displayed potent inhibition of the NLRP3 inflammasome both in vitro and in vivo NLRP3 expression was downregulated by CA via its blockage of NF-κΒ CA also affected NLRP3 inflammasome formation and activation by reducing mitochondrial ROS and by halting NLRP3–NEK7 interactions In the in vivo experiments using mouse models, CA prevented lipopolysaccharide-induced acute systemic inflammation and MSU-induced peritonitis (NLRP3 pathway)	2023	[120]
This study compared the phytochemical content and the biological properties of R. officinalis samples	Eight Rosmarinus officinalis populations were collected RA and CA were measured using the NMR technique Non-polar constituents were analyzed through the utilization of GC-MS Antioxidant properties and activity were assessed using in vitro assays	The CA content was greater than that of RA The isolated extracts could inhibit AChE and BChE	2013	[80]
The impact of carnosol on rotenone-induced neurotoxicity in cultured SN4741 dopaminergic cells was studied	Cells were first treated with rotenone When it was indicated, CA was added an hour before rotenone treatment and maintained for the reminder of the incubation period	Cell viability was improved by inhibiting caspase-3 Moreover, CS increases TH levels, Nurrl, and extracellular signal-regulated kinase ½	2006	[11]
The effect of eugenol in a mouse model induced with MPTP was studied	The mice were treated with eugenol before and after MPTP induction	MPTP led to motor inability, glutathione decrease, and lipid peroxidation, while treatment with the phenylpropanoid reversed those complications	2022	[103]
The effect of eugenol along with levodopa in 6-OHDA-stimulated Wistar rats was studied	Rats were induced with 6-OHDA and then with eugenol, levodopa, or their combination	The combination increased the neuroprotection against PD-associated symptoms, in contrast to L-dopa alone GSH synthesis was induced	2020	[104]
The efficacy of eugenol on AD pathologies was explored using a 5X familiar AD mouse model (5XFAD)	8-month-old 5X FAD and WT mice were treated with 10 or 30 mg/kg/day p.o. of eugenol for over 2 months The Morris water maze and Y-maze tests were used to determine cognitive function Biochemical analysis was used to study the underlying mechanism of eugenol	Eugenol treatment could combat cognitive deterioration in mice This result was correlated with aiding AD pathologies (neuronal apoptosis and Aβ fibrillization) Eugenol upregulated microglial phagocytosis	2023	[111]
This study assessed the effect of eugenol on the amyloid plaques present in AD rat models	Aβ fibrils were administered into the rats’ hippocampus Then, after a week, 0.01 or 0.02 mg/kg of eugenol was given to the rats for 2 weeks Both passive avoidance learning and memory performance were assessed The amyloid plaques were assessed and analyzed using ANOVA	0.01 mg/kg of eugenol ameliorated memory and suppressed positively amyloid plague’s formation	2019	[112]
This study aimed to explore the anti-amnesic effect of eugenol in scopolamine-treated AD rodents	3 mg/kg/day i.p. scopolamine and 12.5, 25.0, and 50.0 mg/kg eugenol were administered to male rats for 14 consecutive days at a time lag of 30 min	Doses of 25.0 and 50.0 mg/kg of eugenol alleviated scopolamine-induced deterioration in the learning ability and memory function of mice Eugenol diminished hippocampal cholinergic dysfunction (acetylcholine levels), glutamate neurotoxicity, and mitochondrial dysfunction	2019	[113]
The activity of luteolin in 6-OHDA-treated PC12 cells	The cells were pretreated with luteolin before their exposure to the ROS	Pretreatment of cells with luteolin reduced ROS production induced by 6-OHDA and downregulated the p53, UPR, and Nrf2-ARE pathways, making it a potential PD neuroprotective agent	2014	[105]
Effect of 1,8 cineole and a-pinene as neuroprotective in H2O2-treated cells	The cells were pretreated with the two terpenes before exposure to ROS species	An increase in cell survival, inhibition of intracellular ROS production, and enhancement of antioxidant enzyme activity were observed Low levels of caspase-3 revealed minimum apoptosis Elimination of ROS and activation of the Nrf2 factor through induction proved that the two terpenes had antioxidant effects and could protect against diseases associated with oxidative stress, including PD	2016	[107]
The potent pharmacological connection between 1,8-cineole, mood, and cognitive performance after exposure to R. officinalis aroma was assessed	Twenty healthy volunteers were tested for subtraction and visual information processing, while exposed to rosemary aroma Venous blood was drawn from all participating subjects Mood assessments were made before and after testing Levels of 1,8-cineole, cognitive performance, and mood changes were assessed	Performance in cognitive tasks was adequately linked to the concentration of 1,8-cineole, with ameliorated results at higher concentrations The link between 1,8-cineole levels and mood was less profound	2012	[118]
This study experimented on AGE-induced neuronal injury and intracerebroventricular AGE animals, as candidate AD models. Additionally, the impact of CIN on AD and the mechanisms both in vitro and in vivo were also investigated	SH-SY5Y cells were incubated for 48 h with different AGE conc. (100, 200, 300, 400, and 500 μg/mL) MTT assays were used to estimate the cell viability	CIN alleviated the expected tau phosphorylation through the suppression of efficient GSK-3β and tau phosphorylation CIN also diminished Aβ excretion by affecting BACE-1 activity, in vivo and in vitro CIN was concluded to have therapeutic potential for AD treatment	2022	[110]
RA isolated from an R. officinalis extract and EO was evaluated for its AChE and BChE inhibition activity	The Ellman method using an ELISA microplate reader using 0.2, 0.5 and 1.0 mg/mL concentrations of RA was chosen HPLC and GC-MS were used	The major monoterpenes in this R. officinalis EO were 1,8-cineole and α-pinene The AChE activity of the RO EO is suspected to exist due to a synergistic interaction between all the different oil components	2007	[90]
UA’s effect on rotenone-treated rats was studied	Rats were given stereotaxic bilateral injections of rotenone into their SN Then, they were treated orally with UA for 30 days	Treatment with UA protected TH-positive cells, enhanced cognitive function in the Barnes maze (BMT), and minimized the oxidative stress and inflammation caused by rotenone infusion It also mitigated the complex I inhibition and facilitated the promotion of mitochondrial biogenesis (MB)	2020	[108]
Camphor’s ability to treat depression in rats was studied	Depression was induced with ciproflaxin The rats were divided into five groups	An increase in catalase and Nrf2 action, downregulation of NO, MDA, TNF-α, TLR4 serum levels, and rise in the levels of serotonin, DA, GABA (gamma-amino butyric acid), and P190-RHO GTP protein in normal neuronal cells in the frontal cortex of the brain were observed	2021	[123]
The study assessed the potency of different diterpenes that were isolated from rosemary to function as AChE inhibitors	The use of in silico and molecular docking techniques helped in exploring how these molecules interact with the active site of AChE	Rosmanol was proposed as the candidate with the most potential for further clinical trials and research to validate the molecule’s potency	2024	[109]

¹ In vitro and in vivo studies on the major R. officinalis compounds for treating NDs.

Table 2. Experimental data on rosemary extracts and EOs, RA, CA, and other bioactive compounds of rosemary in neuroprotection against PD, AD, and other neurodegenerative conditions.

Hypothesis and Intervention 1	Experimental Details	Study Results	Year of Study	Reference
The neuroprotective effect of a rosemary EO was examined in vitro through the evaluation of H2O2-induced apoptosis in SH-SY5Y cells	SH-SY5Y cells were treated with R. officinalis extract for 12 h at a concentration ranging from 1–100 μg/mL In a similar way, all cells were treated with H2O2 for 12 h, at a concentration ranging from 1–300 μM The R. officinalis extract treatment was added 1 h before the H2O2 treatment	A significant suppression of H2O2-induced cytotoxicity was observed The herb EO mitigated mitochondrial membrane disruptions and ROS-initiated apoptotic cell death R. officinalis also attenuated the increase in expression of Bax, Bac, and caspase-3 and -9 and prevented the downregulation of Bcl-2 Lastly, it inhibited the downregulation of TH and AADC in these human cells	2010	[129]
The impact of an R. officinalis EO on AD was examined in a mouse model	Mice inhaled the EO The AD-type dementia was induced using scopolamine Cognitive function was assessed via the appropriate Y-maze test (a test used for the assessment of short-term memory in mice)	The EO produced a notable increase in the spontaneous alternation behavior The predominant EO components detected in the brain were namely 1,8-cineole and α- and β-pinene	2018	[130]
The beneficial effects of an aromatherapy procedure in 28 older adults, where 17 of them had developed AD-type dementia, were evaluated	An aromatherapy procedure for 28 days, followed by a control period of 28 days was conducted for all patients, followed by a wash-out period lasting another 28 days Rosemary and lemon EOs were utilized in the morning and lavender and orange EOs were used in the evening aromatherapy routine The effects of aromatherapy were determined via the evaluation of all the patients’ scores in the tests: GBSS-J, FAST, HDS-R, and TDAS Patients were examined four times, including before and after the control period, after the aromatherapy, and after the wash-out period	All participants displayed noteworthy amelioration regarding both the TDAS and the GBSS-J tests that measure cognitive function AD patients showed an improvement in their total TDAS score No side effects were observed following the aromatherapy procedure Aromatherapy was an efficacious nonpharmacological treatment for dementia, especially in AD	2009	[131]
The memory enhancement of an R. officinalis EO was explored in young and aged mice	This study utilized five different young and aged groups of mice 200, 400, 600, and 800 mg/kg doses of R. officinalis EO were administered intraperitoneally to all young and aged mice groups, except for the control group, once a day for 7 days	The outcome indicated that the R. officinalis EO can enhance memory in both young and aged mice The EO’s efficacy was more apparent in aged mice than younger ones	2014	[116]
The study describes the effect of EOs on human short-term image and numerical memory	79 secondary school students between the ages of 13 and 17 years (34 boys and 45 girls) participated and were divided into test groups	The statistical analysis revealed differences in the short-term memory of the subjects in the different groups The rosemary EO significantly improved image memory compared to the control The rosemary EO enhanced number memorization abilities; however, lavender EO inhalation diminished this ability	2017	[117]
This study evaluated the effect of lavender and rosemary EOs on the mood and cognitive performance of healthy volunteers	144 participants were divided into test groups Researchers studied the participants’ performance of the Cognitive Drug Research (CDR) and the computerized cognitive assessment battery in a cubicle containing a lavender EO, rosemary EO, or control odor	The lavender EO resulted in a visible deterioration in working memory and slowed down response times in tasks assessing memory and attention The rosemary EO, on the other hand, resulted in a notable improvement in memory	2003	[119]
This unprecedented study investigated the impact of a combination of rosemary and two other herbs on verbal recall in healthy humans and their clinical value for memory and brain function	Forty-four normal healthy subjects were part of this, not only double-blind but also placebo-controlled, pilot study The participants were split into two groups: an active group and a placebo group An ethanol SRM extract was characterized using LC/UV/MS/MS Immediate and delayed word recall tested the subjects’ memory after the administration of the SRM extract or placebo	Remarkable improvements in delayed word recall were observed in the active group consisting of people under the age of 63 No side effects were observed	2017	[132]
This study identified the antioxidative agents in rosemary and characterized their antioxidant effects in biological systems	CA, carnosol, rosmanol, and epirosmanol antioxidative agents were isolated from R. officinalis leaves using fractionation bioassays	The superoxide anion activity was attenuated by diterpenoids existent in the xanthine-xanthine oxidase system Diterpenoids affected both microsomal and mitochondrial lipid peroxidation that was induced by the oxidation at 3–30 pM of NADH or NADPH CA prevented oxidative hemolysis in red cells, on the contrary	1995	[121]
The effects of a rosemary extract and a spearmint extract, which both contained CA and RA, on cognition and memory in a SAMP8 mouse model that displayed rapid aging were studied	R. officinalis EOs contained CA at 10 or 60%, while one spearmint extract contained 5% rosmarinic acid The examined doses were 0, 1.6, 16, and 32 mg/kg 90 days after the treatment’s termination, the mice were tested using T-maze, object recognition, and lever press assessments	A rosemary extract with 60% or 10% of CA boosted the performance in the conducted tests	2016	[122]
Comparison of neuroprotective effect of R. officinalis RA and CA constituents through their impact on primary cultures of CGNs subjected to a variety of stressors	CGNs were treated with a glutamate and glycine combination as well as SNP CGNs were co-treated with either CA or RA, and with either SNP at 100 μM or the glutamate/glycine combination at a concentration ratio of 100 μΜ/10 μΜ for 24 h	CGN death induced by the NO donor, namely SNP (nitrosative stress), was decreased in the presence of both polyphenols RA shielded CGNs from glutamate-induced excitotoxicity CA, on the other hand, was the only constituent able to protect CGNs from the caspase-dependent apoptosis that was accelerated by the disposal of depolarizing extracellular potassium (5K apoptotic condition) CA also shielded CGNs from the 5K-induced apoptosis through the activation of a phosphatidylinositol 3-kinase pro-survival pathway	2018	[12]
The influence of RA and CA on seizures induced by PTZ were evaluated in this study	Male CF-1 mice were administered 1, 2, or 4 mg/kg i.p. RA; 1, 4, or 8 mg/kg i.p. CA; 1 mg/kg diazepam (controls); or 600 mg/kg p.o. vigabatrin once every 3 days for 16 days, and 30 min prior to the administration of 50 kg/mg s.c. PTZ The cortex was collected afterwards in an attempt to fully assess free radical levels, superoxide dismutase activity, and any genotoxic activity	Some defined doses of CA and RA exhibited a strong neuroprotective action against the induction of oxidative stress and DNA damage	2015	[114]
In vivo study of RA effects in rats that were treated with 6-OHDA	Following the treatment with 6-OHDA, rats were treated orally with RA	DA levels in the striatum were reduced by 6-OHDA RA reversed these changes RA also attenuated the increase in the ratio of Bax/Bcl-2 at the gene level that was induced by 6-OHDA, thereby demonstrating a neuro-rescue effect	2012	[9]
and SH-SY5Y cells treated with H2O2	RA was added 30 min before the treatment with the ROS	RA reduced the cell death that was initiated by H2O2 and attenuated the upregulation of Bax and downregulation of Bcl-2 RA also stimulated HO-1	2008	[13]
RA activity in MPTP-treated mice	Four groups of mice were tested: CN (control/saline), Ra (RA/vehicle), MPTP (MPTP/saline), and MPTP+RA (MPTPT/RA) Oral administration of RA for 14 days, 1 h prior to MPTP or saline injection The MPTP groups were given this drug for 5 days, once a day	RA alleviated the hyper-locomotive activity of MPTP-treated animals RA also increased DA signaling and boosted the monoaminergic system in healthy mice (not treated with MPTP) Lastly, an upregulation of the expression of MAO-A in the MPTP+RA group was found	2022	[96]
RA in H2O2-treated N2A cells	Cells were pretreated and treated RA	RA prevented the toxicity induced by ROS and reduced the interference from lactate dehydrogenase RA also decreased the mitochondrial membrane potential and ROS production within the cells Adding to the above, RA prevented genotoxicity, and increased the levels of TH and brain-derived neurotrophic factor (BDNF) to reduce ROS cytotoxicity in induced cells	2014	[88]
The inhibitory impact on AChE and BChE, as well as the metal-chelating ability, of 12 diterpenes including RA was examined	RA’s effect against AChE, BChE, and QSAR was evaluated at a concentration of 10 mg/mL via ELISA microfilter assays and molecular docking studies	RA was more effective towards BChE than AChE The assessment of BChE inhibitors is of vital importance since such compounds could be promising candidates for AD therapy	2016	[89]
RA’s inhibitory activity towards AChE and BChE was examined (RA was isolated from an R. officinalis extract and EO)	The Ellman method via an ELISA microplate reader was conducted at the predetermined concentrations of 0.2, 0.5, and 1.0 mg/mL HPLC and GC-MS were the utilized techniques	RA caused 85.8% inhibition of AChE, even at a concentration of only 1.0 mg/mL	2007	[90]
AChE inhibition activity and antioxidant capacity of RA were examined to determine its potential as a candidate compound for AD treatment	The Ellman method and isolated guinea pig ilea were used in this study The antioxidant capacity was measured via DPPH The AChE inhibition activity of RA was evaluated by in silico docking and isolated guinea pig ileum techniques	RA displayed a crucial contraction response using the guinea pig ileum method RA also demonstrated a high scavenging potential and high affinity for AChE (docking study)	2014	[91]
This study measured the AChE activities of phenolic acids and flavonoids individually or in combination	Ellman’s modified spectrophotometry and an assessment of the false-positive molecular results were performed	RA is more potent than its structural monomer, caffeic acid, in terms of anti-AChE activity	2015	[92]
The study assessed the structure–activity synergistic action of RA derivatives in terms of their anti-aggregation, antioxidant, and xanthine oxidase inhibition properties	MSHTS, ThT assays, docking studies, XOD, and DPPH inhibition evaluations were performed	Caffeic acid is a significant structural feature responsible for RA’s binding abilities RA demonstrated radical-scavenging effects In parallel, RA displayed good inhibitory activity against Aβ1-42 aggregation	2017	[93]
RA’s ability to inhibit fibrillization was assessed	In vitro tau fibrillization, AFM, and molecular docking studies were performed	RA inhibits the aggregation of tau at a percentage of over 50% at a concentration of 50 μΜ The downregulation in amide regions I and II was induced by RA Therefore, RA prevents b-sheet assembly	2017	[94]
The study examined the effect of RA on Alzheimer amyloid peptide (A)-induced toxicity in cultured rat PC12 cells	RA was used for the treatment of PC12 cells, 10 min before the Aβ-42 treatment (1 g/mL)	RA reduced ROS formation, DNA fragmentation, lipid peroxidation, tau protein hyperphosphorylation, and caspase-3 activation	2006	[95]
In an attempt to clarify whether RA prevents Aβ-induced peroxidation of lipids, and antioxidant defense and/or cholinergic damage, in addition to the main auditory deficits, Wistar rat were utilized	The bilateral injection of Aβ-42 peptide (2.2 nmol/10 μL) created a Wistar rat model of AD 50 mg/kg of RA was orally administered on a daily basis for a span of 14 days after the injection Auditory event-related potentials were assessed and similar tests were performed This experiment was followed by histological and biochemical analyses	RA prevents cholinergic damage and Aβ-induced antioxidant–oxidant imbalances This realization may aid in the advancement of treatments for neural network synapses and possibly many other auditory procedures	2018	[97]
The study assessed, in an Aβ25-35-injected mouse model, whether the administration of RA improved cognitive function	Mice were administered several RA doses i.p. daily after injection of A25-35	0.25 mg/kg of RA was preventative against protein nitration in the hippocampus, a fact that implied that RA is an indirect indicator of ONOO− damage	2016	[98]
An examination of the protective ability of RA as a natural ONOO− scavenger and preventing memory deterioration was conducted on a mouse model that was given an acute i.c.v. injection of A25-35	Mice were administered several doses of RA i.p. daily after the injection of A25-35	0.25 mg/kg of RA was preventative against protein nitration in the hippocampus, a fact that implied that RA is an indirect indicator of ONOO− damage, similar to findings of the previous study	2007	[99]
The effects of RA on the pathology related to ovariectomy and D-galactose injection (i.e., a double-insult in an AD model) were thoroughly assessed	100 female Wistar rats were utilized and separated into different groups 80 mg/kg/day of D-galactose was injected i.p. 50 mg/kg/day was also administered for a period of 60 days Locomotor activity and short-term special memory was assessed by open field and Y-maze tests The experiment included both biochemical and histopathological analyses of the rats’ brain tissues	The addition of RA notably restored the altered locomotor activity and cognitive functions The RA treatment inhibited cyclooxygenase-2 expression and lipid peroxidation, and reduced prostaglandin E2 levels The alterations in the brain tissues in the rat model of AD were prevented by the addition of RA, which was able to inhibit lipid peroxidation and the inflammatory response	2015	[100]
The outcomes of aging in a stress-induced tauopathy mouse model of chronic restraint stress and its possible effect were evaluated	The mice were placed in 50 mL tubes with holes in order to be exposed to ventilation for 30 min each day for 18 days for the repeated stress test An intraperitoneal RA (2 mg/kg) or saline injection was given to all the mice 30 min before the induction of the chronic restraint stress	RA effectively downregulated the R-tau formation caused by the CRS, especially in middle-aged mice RA could act as a potent beneficial compound for stress-derived tauopathy	2015	[101]
The study investigated whether RA is able to suppress TAC’s hepatotoxicity to slow down the progression of AD in mice	Wild-type and APP/PS1 Tg mice were randomly divided A series of experiments was carried out using open field tests, Morris water maze tests, hematoxylin–eosin (HE) and Nissl staining, as well as biochemical, immunofluorescence, and western blotting analyses	RA with TAC may inhibit AD progression in mouse brain tissues The synergistic effect of these drugs could potentially both decrease brain damage and enhance cognitive behavior in AD mice though reductions in the expression of Aβ oligomers and Aβ deposition, the inhibition of AChE’s activity, and the upregulation of ACh levels in the hippocampus	2023	[133]
This study aimed to thoroughly assess the value of RA in protecting against SCI	Male Wistar rats were divided into different groups and given an RA treatment (10 mg/kg) After the administration, the spinal tissues were assessed for possible oxidative stress by determining the levels of ROS, protein damage, and lipid peroxidation, and antioxidant enzyme efficacies To determine the activity of the selected oxidative stress factors (NF-κΒ and Nrf2), western blot analysis was used Pro-inflammatory cytokines were analyzed by ELISA	An amelioration of the antioxidant status and a downregulation of the oxidative stress conditions in Wistar rats with an SCI were observed after RA treatment Inflammatory mechanisms that suppress NF-κΒ and pro-inflammatory cytokines post SCI were improved by RA	2016	[115]
Investigation of CA’s neuroprotective effects and its effects on behavioral activity in a rat model of PD, which was induced by 6-OHDA	20 mg/kg body weight of CA was given to rats for 3 weeks before 6-OHDA exposure SH-SY5Y cells were used	An improvement in locomotor activity and a reduction in apomorphine-induced rotation was observed in all rats Pretreated rats showed improved protection against lipid peroxidation and a reduction in GSH levels Pretreatment with CA resulted in an increase in the levels of γ-glutamate-cysteine ligase catalytic and ligase modifier subunit, as well as GSH reductase and superoxide dismutase compared to 6-OHDA-treated rats The Bcl-2/Bax ratio was reduced and caspase-3 cleavage was induced In parallel, the induction of PARP cleavage by 6-OHDA was reversed by treatment of the SH-SY5Y cells with SB203580 or SP600125 CA treatment in rats reversed the 6-OHDA-mediated activation of c-Jun NH2-terminal kinase P38 decreased the Bcl-2/Bax ratio, downregulated tyrosine hydrolase protein, induced the upregulation of cleaved caspase 3/caspase 3, and increased the PARP/PARP ratio However, the activator of Bax, BAM7, attenuated CA’s effect on apoptosis in the SH-SY5Y cells	2014	[10]
Investigation of whether autophagy is correlated with CA’s neuroprotective activity against 6-OHDA-induced neurotoxicity in SH-SY5Y cells	Human SH-SY5Y neuronal cells were pretreated with 1 μΜ CA for 18 h and then incubated with 100 μΜ 6-OHDA for 12 or 18 h In the autophagy inhibition experiment, 0.5 μΜ wortmannin or 0.5 nM bafilomycin-A1 was added 1 h before CA treatment All control cells were treated with 0.3% DMSO only	The results showed higher levels of parkin protein, autophagy markers, phosphatidylinositol 3-kinase p 100, Beclin1, autophagy-related gene 7, and microtubule-associated protein 1 light chain 3-II 6-OHDA -treatment decreased these levels, but pretreatment with CA prevented these effects Tests showed that parkin–beclin1 interactions were minimized by 6-OHDA CA addition reversed such effects	2017	[79]
Investigation of whether CA is neuroprotective against a paraquat (PQ)-induced PD in terms of cellular and mitochondrial-related redox parameters	CA was used for the treatment of SH-SY5Y cells for 12 h, which were then exposed to 100 μΜ PQ (24 h)	CA protected the cells against all symptoms seen in the selected PQ model, by reducing ROS and NOS CA minimized the toxicity caused by the mitochondrial dysfunction PI3K pathway inhibition by LY294002 suppresses the expression of Nrf2, which was partially responsible for the lack of reversal of the redox dysfunction that was triggered by CA Nfr2’s activation by CA is via the modulation of the PI3K/Akt pathway, which led to high antioxidant enzyme levels and thus the neuroprotective activity of CA	2016	[17]
Study on whether R. officinalis-derived CA is able to protect against 6-OHDA-induced neurotoxicity via the upregulation of parkin both in vivo and in vitro in SH-SY5Y cells	The selected cells were incubated for 8 h with 1 mM CA Afterwards, all the cells were treated with 100 mM 6-OHDA for 18 h 6-OHDA was administered as a single injection into the right striatum of male Wistar rats	CA was able to reverse the upregulation of ubiquitinated protein, which was observed using immunoblots Also, CA was responsible for a reduction in PINK1 and parkin protein levels in the cells and rats that were treated with 6-OHDA CA produced an obvious reduction in the aggregation of α-syn in muscle cells of roundworms and in transgenic OW13 Caenorhabditis elegans	2016	[16]
The established mechanism used by CA in the modulation of the neurotoxic impact of 6-OHDA in SH-SY5Y cells was observed	CA was given to cells for 12 h as a pretreatment, followed by treatment with 100 μM 6-OHDA for 12 or 24 h	Immunoblots showed that the phosphorylation of the c-Jun NH2-terminal kinase, JNK, and p38 caused by 6-OHDA was minimized by pretreatment with CA The levels of GSH, γ-glutamate–cysteine ligase catalytic subunit, and γ-glutamate–cysteine ligase modifier subunit were increased in the presence of CA An increase in Nfr2 activation, ARE–luciferase reporter activity, and amount of DNA binding to AREs were mentioned	2012	[15]
The determination of whether CA can protect hippocampal neurons by reversing neurodegeneration in rats was this study’s main aim	Every group of rats received 10 mg/kg CA by an intraperitoneal injection one hour before surgery and then 3-4 h after receiving 3 mg/kg of CA The process was repeated for 12 days 4 μL of Aβ protein (1.5 nmol/μL) was injected bilaterally into the hippocampus After 14 days, the rats’ brains were histologically examined	CA pretreatment was able to diminish cellular death in the cornu ammonis 1 (CA1) region located in the hippocampus	2011	[86]
The study assessed whether CA’s administration owns a protective effect against memory loss induced by β-amyloid toxicity in rats	Injection of Aβ (1-40) into the CA1 region of the rats’ hippocampus was performed CA was administered intraperitoneally, both before and after surgery The evaluation included the shuttle box and Y-maze tests Fluoro-jade b staining was used to detect degenerating hippocampal neurons	Aβ(1-40) caused potent neurodegeneration in the CA1 hippocampus region The conducted behavioral tests revealed higher test scores in the Aβ+CA group compared to the Aβ control group The spatial and learning memory deficits induced by Aβ in the rat hippocampus may be improved with CA	2013	[87]
The study in vitro examined the protective abilities of CA on primary neurons that were treated with oligomeric Aβ. In vivo on mouse models of AD after the delivery of CA, investigated learning and memory ability as well as synaptic damage	CA was utilized in vitro on primary neurons treated with oligomeric Aβ In the in vivo studies, two transgenic mouse models of AD ((hAPP)-J20 and triple transgenic (3xTg AD) mice) were used Trans-nasal administration of CA twice a week for over 3 months in mice was also conducted Histological and neurobehavioral assessments were performed	In vitro, CA diminished dendritic spine loss In vivo, CA treatment of hAPP-J20 mice models ameliorated the mice’s learning and memory abilities in the Morris water maze test CA was able to increase dendritic and synaptic markers and decrease astrogliosis, Ab plaque number, and phospho-tau staining in the hippocampus	2016	[85]
This study investigated the possible use of CA to prevent MG-induced neurotoxicity	The SH-SY5Y cell line was used Dopaminergic toxicity was induced by methylglyoxal at 500 mM CA was used at concentrations of 0.1–2 mM for different periods of time	CA pretreatment (1 mM for 12 h), proved cytoprotective abilities and tackled the damage caused by MG in SH-SY5Y cells CA prevented the loss of the mitochondrial membrane polarity and the cytochrome’s c release by the inhibition of pro-apoptotic caspase enzyme’s activation CA aided vitally against oxidative and nitrosative damage, while neurotoxicity was combated by the activation of the PI3K/Akt/Nfr2 signaling pathway and the antioxidant enzymes transcribed by the Nrf2 factor	2015	[81]
The effect of CA on the production of Aβ1-42 peptides (Aβ42) and on the expressed genes in human neuroblastoma SH-SY5Y cells were explored	Human neuroblastoma SH-SY5Y cells were pretreated with the inhibitor 1 h prior to the addition of 30 mM CA RNA interference, real-time quantitative PCR, ELISA, and immunoblot analysis techniques were utilized	Treatment of SH-SY5Y cells with CA was observed to diminish A42 secretion (61% at 30 M) The mRNA expression of secretases RACE (tumor necrosis factor-converting enzyme, ADAM17) and ADAM10 was enhanced by the CA treatment CA did not impact the expression of the secretase BACE1	2012	[82]
Investigation of CA’s impact on the apoptosis induced by A42 or A43 peptides in cultured SH-SY5Y human neuroblastoma cells	Cells were treated with Aβ42 or Aβ43 (10 μM)	The apoptosis induced by Aβ42 or Aβ43 peptides was alleviated by a pretreatment of the cells with 10 M CA; the results were confirmed by the observed cleavage of PARP and AIF Furthermore, Aβ42 and Aβ43 levels were diminished in the presence of CA Overall, CA reduced the activation of the Casp cascades induced by Aβ through the downregulation of the intracellular oligomerization of Aβ42/43 monomers	2014	[83]
This study investigated the effects of CA on NLRP3 activation using in in vitro and in vivo experiments	8–10-week-old male WT C57BL /6 mice were utilized Primary peritoneal macrophages were collected Cell viability, inflammasome activation, ASC oligomerization, immuno-precipitation, western blot, ELISA, and histological analyses were used	CA displayed potent inhibition of the NLRP3 inflammasome both in vitro and in vivo NLRP3 expression was downregulated by CA via its blockage of NF-κΒ CA also affected NLRP3 inflammasome formation and activation by reducing mitochondrial ROS and by halting NLRP3–NEK7 interactions In the in vivo experiments using mouse models, CA prevented lipopolysaccharide-induced acute systemic inflammation and MSU-induced peritonitis (NLRP3 pathway)	2023	[120]
This study compared the phytochemical content and the biological properties of R. officinalis samples	Eight Rosmarinus officinalis populations were collected RA and CA were measured using the NMR technique Non-polar constituents were analyzed through the utilization of GC-MS Antioxidant properties and activity were assessed using in vitro assays	The CA content was greater than that of RA The isolated extracts could inhibit AChE and BChE	2013	[80]
The impact of carnosol on rotenone-induced neurotoxicity in cultured SN4741 dopaminergic cells was studied	Cells were first treated with rotenone When it was indicated, CA was added an hour before rotenone treatment and maintained for the reminder of the incubation period	Cell viability was improved by inhibiting caspase-3 Moreover, CS increases TH levels, Nurrl, and extracellular signal-regulated kinase ½	2006	[11]
The effect of eugenol in a mouse model induced with MPTP was studied	The mice were treated with eugenol before and after MPTP induction	MPTP led to motor inability, glutathione decrease, and lipid peroxidation, while treatment with the phenylpropanoid reversed those complications	2022	[103]
The effect of eugenol along with levodopa in 6-OHDA-stimulated Wistar rats was studied	Rats were induced with 6-OHDA and then with eugenol, levodopa, or their combination	The combination increased the neuroprotection against PD-associated symptoms, in contrast to L-dopa alone GSH synthesis was induced	2020	[104]
The efficacy of eugenol on AD pathologies was explored using a 5X familiar AD mouse model (5XFAD)	8-month-old 5X FAD and WT mice were treated with 10 or 30 mg/kg/day p.o. of eugenol for over 2 months The Morris water maze and Y-maze tests were used to determine cognitive function Biochemical analysis was used to study the underlying mechanism of eugenol	Eugenol treatment could combat cognitive deterioration in mice This result was correlated with aiding AD pathologies (neuronal apoptosis and Aβ fibrillization) Eugenol upregulated microglial phagocytosis	2023	[111]
This study assessed the effect of eugenol on the amyloid plaques present in AD rat models	Aβ fibrils were administered into the rats’ hippocampus Then, after a week, 0.01 or 0.02 mg/kg of eugenol was given to the rats for 2 weeks Both passive avoidance learning and memory performance were assessed The amyloid plaques were assessed and analyzed using ANOVA	0.01 mg/kg of eugenol ameliorated memory and suppressed positively amyloid plague’s formation	2019	[112]
This study aimed to explore the anti-amnesic effect of eugenol in scopolamine-treated AD rodents	3 mg/kg/day i.p. scopolamine and 12.5, 25.0, and 50.0 mg/kg eugenol were administered to male rats for 14 consecutive days at a time lag of 30 min	Doses of 25.0 and 50.0 mg/kg of eugenol alleviated scopolamine-induced deterioration in the learning ability and memory function of mice Eugenol diminished hippocampal cholinergic dysfunction (acetylcholine levels), glutamate neurotoxicity, and mitochondrial dysfunction	2019	[113]
The activity of luteolin in 6-OHDA-treated PC12 cells	The cells were pretreated with luteolin before their exposure to the ROS	Pretreatment of cells with luteolin reduced ROS production induced by 6-OHDA and downregulated the p53, UPR, and Nrf2-ARE pathways, making it a potential PD neuroprotective agent	2014	[105]
Effect of 1,8 cineole and a-pinene as neuroprotective in H2O2-treated cells	The cells were pretreated with the two terpenes before exposure to ROS species	An increase in cell survival, inhibition of intracellular ROS production, and enhancement of antioxidant enzyme activity were observed Low levels of caspase-3 revealed minimum apoptosis Elimination of ROS and activation of the Nrf2 factor through induction proved that the two terpenes had antioxidant effects and could protect against diseases associated with oxidative stress, including PD	2016	[107]
The potent pharmacological connection between 1,8-cineole, mood, and cognitive performance after exposure to R. officinalis aroma was assessed	Twenty healthy volunteers were tested for subtraction and visual information processing, while exposed to rosemary aroma Venous blood was drawn from all participating subjects Mood assessments were made before and after testing Levels of 1,8-cineole, cognitive performance, and mood changes were assessed	Performance in cognitive tasks was adequately linked to the concentration of 1,8-cineole, with ameliorated results at higher concentrations The link between 1,8-cineole levels and mood was less profound	2012	[118]
This study experimented on AGE-induced neuronal injury and intracerebroventricular AGE animals, as candidate AD models. Additionally, the impact of CIN on AD and the mechanisms both in vitro and in vivo were also investigated	SH-SY5Y cells were incubated for 48 h with different AGE conc. (100, 200, 300, 400, and 500 μg/mL) MTT assays were used to estimate the cell viability	CIN alleviated the expected tau phosphorylation through the suppression of efficient GSK-3β and tau phosphorylation CIN also diminished Aβ excretion by affecting BACE-1 activity, in vivo and in vitro CIN was concluded to have therapeutic potential for AD treatment	2022	[110]
RA isolated from an R. officinalis extract and EO was evaluated for its AChE and BChE inhibition activity	The Ellman method using an ELISA microplate reader using 0.2, 0.5 and 1.0 mg/mL concentrations of RA was chosen HPLC and GC-MS were used	The major monoterpenes in this R. officinalis EO were 1,8-cineole and α-pinene The AChE activity of the RO EO is suspected to exist due to a synergistic interaction between all the different oil components	2007	[90]
UA’s effect on rotenone-treated rats was studied	Rats were given stereotaxic bilateral injections of rotenone into their SN Then, they were treated orally with UA for 30 days	Treatment with UA protected TH-positive cells, enhanced cognitive function in the Barnes maze (BMT), and minimized the oxidative stress and inflammation caused by rotenone infusion It also mitigated the complex I inhibition and facilitated the promotion of mitochondrial biogenesis (MB)	2020	[108]
Camphor’s ability to treat depression in rats was studied	Depression was induced with ciproflaxin The rats were divided into five groups	An increase in catalase and Nrf2 action, downregulation of NO, MDA, TNF-α, TLR4 serum levels, and rise in the levels of serotonin, DA, GABA (gamma-amino butyric acid), and P190-RHO GTP protein in normal neuronal cells in the frontal cortex of the brain were observed	2021	[123]
The study assessed the potency of different diterpenes that were isolated from rosemary to function as AChE inhibitors	The use of in silico and molecular docking techniques helped in exploring how these molecules interact with the active site of AChE	Rosmanol was proposed as the candidate with the most potential for further clinical trials and research to validate the molecule’s potency	2024	[109]

¹ In vitro and in vivo studies on the major R. officinalis compounds for treating NDs.

3.9. Rosemary Extracts and EOs for Treating NDs

Rosemary has been utilized in vitro on human SH-SY5Y dopaminergic cells treated with H₂O₂, a type of ROS that is responsible for causing oxidative stress and subsequent apoptosis to the human cells in PD. The R. officinalis treatment was suggested to suppress the H₂O₂-induced cytotoxicity in the SH-SY5Y cells. Furthermore, the herb extract effectively mitigated the disruption to the mitochondrial membrane composition and the apoptosis attributed to ROS. It also attenuated the increase in the expression of Bax, Bac, caspase-3, and caspase-9 while preventing the downregulation of Bcl-2. Lastly, RO inhibited the reduction in the levels of TH and aromatic amino acid decarboxylase (AADC) in SH-SY5Y cells [129].

The inhalation of rosemary EOs has been adequately studied as a treatment for Alzheimer’s. Studies using model mice (scopolamine-induced AD) have proven that the nasal administrative method of rosemary EO can improve cognitive function [130]. Aromatherapy (EO) has been studied in older adults with Alzheimer-type dementia. After therapy, all the patients displayed noteworthy alterations in cognitive function regarding personal orientation using the GBSS-J and TDAS (dementia test assessments). Overall, AD patients improved in their total TDAS scores. The biochemical analysis indicated no noteworthy deteriorations, meaning no adverse effects were present after using the aromatherapy [131]. In middle-aged healthy subjects, a double-blind, placebo-controlled pilot study investigated the impact of a mixture of rosemary and two other herbs on verbal recall and their clinical value for memory and brain function. This pioneering study demonstrated that treatment with SRM orally showed a more fruitful outcome than a placebo in terms of verbal episodic memory in the “under 63 years” age group. The study provided an effective trial protocol and noted no side effects [132].

4. Limitations and Future Perspectives

Despite the proposed benefits, several considerations must be taken into account when proposing the use of naturally grown herbs like rosemary for pharmaceutical and therapeutic uses. And, whilst the evidence suggests that rosemary has undeniable potential in this field, particularly for AD and PD [9,131], the consistency and validity of the results are the primary factors in need of optimization before establishing its use. A significant gap in the literature on this topic seems to stem from the fact that most of the experimental studies have been performed on animal models or in vitro [10,79,129,130]. So, there is an undeniable need for larger-scale clinical trials that perform a much more thorough investigation of the extracts’ results. Another gray area that needs to be addressed is the composition of the extract. Understanding that different cultivating conditions can produce many variables in compounds, it is safe to say that with the aid of biotechnology, further research should be conducted in order to by-pass this drawback [7]. More specifically, the mechanisms of action of other key components of RO, apart from CA and RA, should be fully evaluated in order to determine the correct dose of the extract as well as of each of its components. One solution may be the use of genetically modified rosemary, with a more “fixed” and better regulated consistency of compounds, which may also ameliorate sustainability issues and its future widespread use. Lastly, apart from its beneficial synergistic action alongside drugs, a definite area of interest in need of exploration is rosemary’s interactions with other treatments in order to minimize the possibilities of adverse reactions or the aggravation of any pre-existing side effects [133].

As far as the future perspective on functional foods and dietary implementations are concerned, it is widely supported by scientists that food antioxidants can diminish the symptoms of AD. This is in agreement with the hypothesis that oxidative stress might be associated with NDs [134]. For instance, a meal with rosemary or its extract as an ingredient contains several bioactive compounds, which can act synergistically and have been investigated for their health benefits. This concept can be intentionally used to improve fortified bio-functional foods or it can be incorporated into supplements or nutraceuticals [135]. In the cosmetic field, rosemary extracts have displayed more substantial antimicrobial effects on Gram-positive and Gram-negative bacteria and molds. In contrast, their impact on yeasts is weaker.

Nevertheless, the antimicrobial properties of rosemary extracts allow for their implementation as ingredients in a series of cosmetic products [136]. Lastly, in terms of pharmaceuticals, a break-through idea still in the making is the conceptualization of RA complexed or encapsulated with nanotechnology-based delivery systems that could improve its solubility, safeguard it from damage, permit its access to tissues that are difficult to enter, and consequently ameliorate its bioavailability. These systems could be of a polymer or lipid-based nature, whose production is optimized to contain a significant but safe amount of RA. Even though this system could face cardinal limitations, nasal delivery could act as a solution concerning the delivery route, providing direct access to the CNS [137]. Moreover, bioinspired compounds are also eligible candidates in the pharmaceutical industry. In the following paradigm, terpenes, to which rosemary attributes many of its beneficial effects, were isolated from microbial metabolites as novel meroterpenoid AChE inhibitors. Solid-state fermentation of Aspergillus terreus allowed for the extraction of terreulactones A and D. Terreulactone A and D belong to meroterpenoids and display AChE inhibition abilities. Isomers of terreulactone A were found to be 10 times weaker AChEIs than terreulactones. These novel inhibitors have a heterocycle, which interacts with the active site of the enzyme, and new substituents connected to the nitrogen atom N 20, which were found to be involved in adhering to the peripheral site of the enzyme [138]. RA combined with TAC and the first generation AChEI drug tacrine can enter the brain tissues of AD mice. The synergistic action of these drugs can enhance cognitive behavior and the level of AChE in the hippocampus, downregulate Aβ expression, and counteract Aβ aggregation. Both in vivo and in vitro experiments have suggested that RA is able to reverse the hepatotoxicity or liver injury caused by TAC. RA, in combination with TAC, can halt the cell death caused by Bcl-2/Bax, minimize the apoptosis attributed to caspase-3, inhibit the development of liver apoptosis by alleviating the hepatotoxicity of TAC, and inhibit the phosphorylation of JNK [133], which are vital processes and are summarized in Figure 6.

Figure 6. Graphical illustration of the mechanism of tacrine (TAC) and rosmarinic acid (RA)’s synergistic action in reducing hepatotoxicity and enhancing anti-AD effects. RA combined with TAC is able to enter the brain tissues of the tested AD mice. This enhances cognitive behavior and AChE levels in the hippocampus, downregulates Aβ expression, and counteracts Aβ aggregation. The RA/TAC combination may halt the cell death induced by Bcl-2/Bax, minimize the apoptosis attributed to caspase-3, inhibit the development of liver apoptosis by alleviating the hepatotoxicity of TAC, and inhibit the phosphorylation of JNK.

5. Conclusions

It is widely apparent that rosemary holds excellent potential for use in neuroprotection, not only for Parkinson’s and Alzheimer’s patients but also in improving health in general. Although further studies are essential to verify the activity of drug interactions, evaluate the adverse effects, and determine the proper dosage that leads to a neuroprotective effect, this herb can be considered to have an important part in advancing medical interventions. More examinations of different signaling pathways that can be regulated by rosemary EOs, extracts, and components must be conducted in vivo and in vitro in brain cells to completely elucidate their great potential. Moreover, the clarification of whether this herb elicits neurotoxicity in human cells through laboratory experiments must be further studied. The synergistic effect of its compounds is also a potential factor that must be extensively investigated to maximize the positive influence of rosemary’s components. Lastly, it is crucial to investigate the possible correlation between the regulation of some mechanisms and rosemary’s effects on the homeostasis of redox or immune-related functions in vivo and in vitro in brain cells.