Next Article in Journal
How to Target Small-Molecule Fluorescent Imaging Probes to the Plasma Membrane—The Influence and QSAR Modelling of Amphiphilicity, Lipophilicity, and Flip-Flop
Previous Article in Journal
The Synthesis, Structure, and Dielectric Properties of a One-Dimensional Hydrogen-Bonded DL-α-Phenylglycine Supramolecular Crown-Ether-Based Inclusion Compound
Previous Article in Special Issue
Ethanolic Extract of Polygonum minus Protects Differentiated Human Neuroblastoma Cells (SH-SY5Y) against H2O2-Induced Oxidative Stress
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Emerging Role of Plant-Based Bioactive Compounds as Therapeutics in Parkinson’s Disease

1
Department of Biotechnology, School of Applied Sciences, REVA University, Bengaluru 560064, Karnataka, India
2
Institute of Pharmaceutical Research, GLA University, Mathura 281406, Uttar Pradesh, India
3
Drug Testing Laboratory Avam Anusandhan Kendra, Raipur 492010, Chhattisgarh, India
4
Faculty of Pharmacy, School of Pharmaceutical and Populations Health Informatics, DIT University, Dehradun 248009, Uttarakhand, India
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(22), 7588; https://doi.org/10.3390/molecules28227588
Submission received: 11 September 2023 / Revised: 6 November 2023 / Accepted: 9 November 2023 / Published: 14 November 2023

Abstract

:
Neurological ailments, including stroke, Alzheimer’s disease (AD), epilepsy, Parkinson’s disease (PD), and other related diseases, have affected around 1 billion people globally to date. PD stands second among the common neurodegenerative diseases caused as a result of dopaminergic neuron loss in the midbrain’s substantia nigra regions. It affects cognitive and motor activities, resulting in tremors during rest, slow movement, and muscle stiffness. There are various traditional approaches for the management of PD, but they provide only symptomatic relief. Thus, a survey for finding new biomolecules or substances exhibiting the therapeutic potential to patients with PD is the main focus of present-day research. Medicinal plants, herbal formulations, and natural bioactive molecules have been gaining much more attention in recent years as synthetic molecules orchestrate a number of undesired effects. Several in vitro, in vivo, and in silico studies in the recent past have demonstrated the therapeutic potential of medicinal plants, herbal formulations, and plant-based bioactives. Among the plant-based bioactives, polyphenols, terpenes, and alkaloids are of particular interest due to their potent anti-inflammatory, antioxidant, and brain-health-promoting properties. Further, there are no concise, elaborated articles comprising updated mechanism-of-action-based reviews of the published literature on potent, recently investigated (2019–2023) medicinal plants, herbal formulations, and plant based-bioactive molecules, including polyphenols, terpenes, and alkaloids, as a method for the management of PD. Therefore, we designed the current review to provide an illustration of the efficacious role of various medicinal plants, herbal formulations, and bioactives (polyphenols, terpenes, and alkaloids) that can become potential therapeutics against PD with greater specificity, target approachability, bioavailability, and safety to the host. This information can be further utilized in the future to develop several value-added formulations and nutraceutical products to achieve the desired safety and efficacy for the management of PD.

Graphical Abstract

1. Introduction

The brain is the most complicated organ of the body consisting of a complex network of neurons, and functions as a site of intelligence, memory, and cognition, the initiator of body movement, the interpreter of the senses, and the manager of behaviors. It mainly consists of billions of nerves, which are in regular communication through trillions of connections called synapses [1,2]. The brain is subjected to various forms of stresses, including oxidative stress (OS) resulting from the body’s oxygen requirements/utilization and high content of unsaturated fatty acids [3,4]. Nerve cells in the mid-brain degrade slowly, leading to movement- and coordination-related problems, ultimately resulting in neuropathophysiology. Neurodegeneration is associated with the progressive damage of neuronal tissue that causes the irrecoverable loss of neuronal function, subsequent decline in cognitive function, and motor activity [5,6,7]. Among the neurodegenerative diseases, Parkinson’s disease (PD), mild cognitive impairment (MCI), Alzheimer’s disease (AD), epilepsy, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD) are of primary importance with distinguished pathological etiologies and clinical management [8,9].
PD is the second common chronic neurodegenerative disorder after AD seen mostly in the aging population [10,11]. It is characterized by synucleipathy, wherein neurons in specific part of the brain undergo damage, resulting in motor signs of muscle stiffness, tremor, and postural instability. Additionally, synucleipathy more specifically refers to a class of neurodegenerative disorders that are characterized by a prion-like spread through interconnected neuronal networks and the abnormal aggregation of α-syn inside glial or neuronal cells. However, the complete etiologies of PD still remain unclear [12,13,14]. The disease’s progression has been pointed out as being related to the depletion of dopamine in the nigrostriatal pathway. Further, intracytoplasmic inclusions of dopamine called Lewy bodies have been identified in patients with PD [12,13]. The deterioration of dopamine-producing neurons inside the substantia nigra (SN), with reduced dopamine release in the striatum, is a major cause of the disease. The SN is located in the midbrain, posterior to the crus cerebri fibers of the cerebral peduncle. It consists of two regions: the substantia nigra pars compacta (SNpc), which harbors dopaminergic neurons, and the substantia nigra pars reticulata (SNpr), comprising gamma-aminobutyric acid-responsive (or GABAergic) neuronal cells. The putamen, striatum, and caudate nuclei are well connected with dopaminergic projections from the SNpc. Each side of an adult SNpc has 400–500 thousand dopaminergic cells, constituting a negligible fraction of total brain mass. As evident in PD, these tiny clusters of cells have a disproportionate impact on motor output and behavior. When compared to other neurons, dopaminergic neurons in the SNpc are more vulnerable to oxidative stress. In the ventral midbrain, these neurons extend to the striatum and play a crucial role in regulating motor behavior in mammals. The SNpc comprises a cluster of cells that releases the neurotransmitter dopamine in the striatum connected to the basal ganglia. The basal ganglion in turn is linked to the thalamus and motor cortex, which are associated with controlling motor output. PD is predominantly attributed to the loss of the majority of cells in the SNpc region [15,16,17]. The factors that are involved in the progression of PD includes ROS, neuroinflammation, mitochondrial dysfunction, the misfolding of proteins, and protein agglomeration, along with several other environmental factors and biological processes [11].
Many drugs are available to treat PD, such as L-dopa, COMT inhibitor, MAO-B inhibitor, and dopamine agonists, but these drugs simply compensate for dopamine loss in PD and therefore cannot completely suppress its symptoms or progression. Drugs that are currently available for PD do not result in the much-expected permanent therapeutic benefits to patients, and as such scientists have now focused their attention towards natural compounds, which may have a more promising antiparkinsonian potential [18,19]. Several studies have documented that varieties of medicinal plants and natural bioactive compounds exhibit healing properties with negligible side effects via extraordinary antioxidant and anti-inflammatory action, which make them suitable candidates for antiparkinsonian activity [20,21].
Specifically, phytochemicals execute their effect against PD by several mechanisms, such as suppressing apoptosis (minimizing the level of caspase-3, -8, and -9, Bax/Bcl-2), synuclein deposition, reducing the loss of dopaminergic neurons, expression of proinflammatory cytokines (like interleukin-1β, nuclear factor-κB, prostaglandin E2, and interleukin-6), dopamine depletion, cellular inflammatory signaling, augmenting antioxidant status, and neurotrophic factors, respectively [20,22,23]. To date, different types of bioactive molecules have been extracted and recognized from plants including polyphenols, terpenes, and alkaloids. Surprisingly, there are no concise elaborated articles comprising updated reviews of published literature towards emerging trends in potent natural bioactive compounds for the management of PD. Therefore, we designed the current review to provides an illustration of the efficacious role of various medicinal plants and bioactive compounds (polyphenols, terpenes, and alkaloids) that can become potential therapeutics against PD with greater specificity, target approachability, bioavailability, and safety to the host.

2. Pathophysiology of Parkinson’s Disease (PD)

PD is defined as a neurodegenerative disorder showcasing different types of pathophysiological symptoms owing to A9 dopaminergic (DA) neuron loss in the SNpc selectively and formation of an intracellular aggregate called a Lewy body [12,24]. In pathological inclusions, α-synuclein (α-syn) shortened at the carboxy terminal congregates, thereby leading to its accumulation. Hemoglobin (Hb) expression is not only limited to erythrocytes but also evident in neurons. It is particularly concentrated in PD-susceptible mesencephalic dopaminergic neurons rather than resistant neurons. In physiological condition, the neuronal Hb has been found to be extensively restricted to cell bodies, including the nucleus, mitochondria, and the cytoplasm. However, it has been reported that when dopaminergic neurons were challenged with α-syn, Hb-α-syn complex formation was initiated in the mitochondria and cytoplasm, together with reduced transport of Hb from cytoplasm to the mitochondria, low levels of free mitochondrial Hb, and Hb aggregation in the nucleus, contributing to neuronal cell damage and pathological progression of PD. Research findings have shown that, due to the overexpression of Hb, cells’ vulnerability increases in an in vitro PD model and creates nucleolar and cytoplasmic aggregates in mice [12,25,26]. The dysfunctionality of the nerves becomes evident with a very broad range of non-motor symptoms, such as autonomic dysfunction, sleep disturbances, sensory abnormalities, and cognitive impairment together with neuropsychiatric symptoms. Figure 1 shows that PD is a multifaceted disorder influencing both motor as well as non-motor symptoms during the development of the disease [12,25,26,27,28,29]. In relation to the advent of various symptoms, PD can be categorized into three stages including preclinical, prodromal, and, clinical, respectively. In the preclinical stage, a fixed neurodegeneration is initiated in the SN, with no noticeable clinical symptoms. It is followed by a more than 10 years of a prodromal stage having unceasing neuronal loss but also showing some non-motor symptoms. Subsequently, a stage at which 40–60% of dopaminergic cells become non-functional followed by motor symptoms (tremors, rigidity, and bradykinesia) are characterized as the initial stage of PD to the patients. As evidence from various studies the genetic, environmental, and life-style components are some of the major influential factors for the pre-clinical stage. At stage 2, the promising biomarkers for early detection and diagnosis of PD include α-synuclein measurements in the cerebrospinal fluid, blood, and peripheral tissue and dopamine transporter scanning, respectively. Finally, during clinical stages, the evidence related to Lewy bodies’ development and multiple system atrophy are identified as a biomarker [30]. Further, several toxicological models, which have been established for pharmacological screening of several medicinal plants, bioactive compounds, and pharmaceutical drugs are herewith incorporated in Figure 2.

3. Medicinal Plants, Herbal Formulations and Plant-Based Bioactives (Polyphenols, Terpenes, and Alkaloids) as a Potent Therapeutics for PD Management

Medicinal plants possessing high concentrations of additional nutritional elements provide both health advantages and increased nutritional value due to their potency to influence metabolic processes. In the recent decade, medicinal plants and bioactive constituents with diverse structures have shown to be promising resources for PD drug research. The efficacy of some notable medicinal plants and herbal formulations investigated in the last five years (2019–2023) with a mechanism of action for the management of PD has been incorporated in Table 1. The information on earlier published studies before 2019 has been already reviewed by many scholars [33,34,35,36,37,38,39]. Similarly, many polyphenols, terpenoids, and alkaloids manifest their possible beneficial properties in an in vitro and in vivo models of neurodegenerative disorders, specifically PD, as represented in Table 2.

3.1. Polyphenolic Compounds

Polyphenols are a class of significant natural bioactive molecule has been found to be broadly distributed in dietary vegetation and display potential neuroprotective properties against neuroinflammation and neuronal death as evidenced from both in vitro and in vivo experimentation. They have been further classified as flavonoids and non-flavonoids consisting of bioactive compounds including stilbenes, lignans, phenolic acids, curcuminoids, and coumarins.
Polyphenols are secondary metabolites synthesized in plants by the polyketide or shikimate pathway and commonly found in vegetables, fruits, nuts, and seeds. They possess multiple phenol units (C6H5OH) with hydroxyl groups (OH) linked to the aromatic benzene ring. Polyphenols have been found to exhibit potential therapeutic properties. A polyphenols-rich diet has demonstrated significant modulatory effects on the pathophysiological mechanisms of many underlying chronic diseases, especially in diabetes and cardiovascular and neurodegenerative diseases as evidenced from several experimental and clinical studies, indicating their significant prophylactic and therapeutic potential [82]. A growing body of evidence has demonstrated that the supplementation of polyphenolic compounds limits the risk for neurodegenerative disorders. Several of these compounds have been found to have cell-protective abilities against oxysterols (e.g., 7-ketocholesterol),mitigate mitochondrial dysfunction and cell injury. Polyphenols, namely resveratrol, quercetin, and apigenin, have shown potential scavenging activity against reactive oxygen species (ROS) induced by oxysterols and thereby counteracting ROS [83]. They possess influential antioxidant properties owing to their free radical scavenging potential and iron chelating action. Additionally, these have been further documented to display antiviral, antibacterial, anti-inflammatory, anticarcinogenic, and neuroprotective properties [84]. Recently, it has been established that plant polyphenols orchestrate neuroprotective abilities such as the capacity to combat misfolded protein gathering, the probability to endorse cognition, memory, ROS, neuroinflammation, neurotrophin secretion, and the capability to shield nerve cells after neurotoxins exposure [85]. These compounds possess at least one OH group existing over the aromatic side chain with its backbone having a simple moiety to a multifaceted polymer [86].
  • Structure activity relationship
Polyphenolic compounds contain an OH group at an ortho or para position acting as a hydrogen donor and reductant during redox reactions [87]. Antioxidant activity increases with the higher number of total OH groups present. Therefore, polyphenols counteract the oxidation of biomolecules by donating protons rapidly to radicals or by reacting with them to form products that block them from reacting with other biological molecules. Moreover, polyphenols also have the ability to interact with enzymes or receptors in signal transduction, thus modulating cellular oxidation and enhancing the antioxidant status [88]. Preclinical and clinical studies strongly support the protective action of polyphenols in neurodegenerative diseases owing to their high antioxidant activity orchestrated by the presence of OH groups in their structure [89].
  • In vitro and in vivo studies
Recent studies have demonstrated that dietary polyphenols reduce the breakdown of monoamine oxidase A (MAO-A)- and monoamine oxidase B (MAO-B)-dependent monoaminergic neurotransmitters, maintaining the levels of dopamine and serotonin in animal brain tissue [90]. More specifically, MAO-A is responsible for the metabolism of tyramine, norepinephrine (NE), serotonin (5-HT), and dopamine (DA). However, MAO-B mainly metabolizes DA and some less clinically relevant chemicals [91]. In this context, the supplementation of polyphenols to rats after post-fluid percussion injury demonstrated a promising neuroprotective action [92]. Further, research findings have also revealed that a polyphenol-rich diet normalizes brain-derived neurotrophic factor (BDNF) levels and synapsin 1-dependent synaptic plasticity. These studies support the role of polyphenols in the enhancement of memory, learning abilities, and hippocampal neurogenesis. Thus, polyphenols maintains normal brain health by directly influencing the central nervous system and the underlying machinery [93,94].
Polyphenols have been chiefly divided into two categories, namely flavonoids and non-flavonoids in accordance with current recognized classifications [95]. On the basis of the oxidation state and hydroxylation mode, the flavonoids have been further subdivided into flavanones, anthocyanins, flavanols, isoflavones, and flavones, whereas the non-flavonoids are further classified as stilbenes, phenolic acids, phenolic alcohols, lignans, coumarins, and curcuminoids [96,97,98].

3.1.1. Flavonoids

Flavonoids have a common 1,2-diphenylpropane or 1,3-diphenylpropane (C6-C3-C6) basic structure [99]. Various biological properties of flavonoids include antithrombotic, anticancer, anti-inflammatory, antimicrobial, antiviral, and immunomodulation. Flavonoids have been reported in a wide variety of vegetables (tomatoes, onion, cabbage, cauliflower) and fruits (apple, grapes, berries, banana). Li et al. have revealed that these compounds are beneficial to skeletal muscles, liver, pancreas, adipocytes, and neuronal cells [100]. The results of the randomized clinical trials have demonstrated the enhancement of cognitive abilities resulting from the dietary intake of flavonoids-rich foods, irrespective of age and health status [21]. According to structure activity relationship studies, it has been documented that the double bond between the second and third carbon atoms, the 3′,4′-catechol, the ketone group, and the hydroxyl group at the third position present in the flavonoid backbone are responsible for the free radical scavenging and antioxidant properties of flavonoids. Because the double bond between C2–C3 is conjugated to the carbonyl group present in the C ring, unsaturated flavonoids have a higher capacity to scavenge free radicals in relation to saturated compounds like flavanones [101,102]. Mittal et al. mentioned that the extract of Ginkgo biloba rich in flavonoids orchestrates a protective impact on dopaminergic neurons in animal models of PD [21]. In vitro and in vivo findings suggest that flavonoids intake (with supplements or with normal diet) could be a promising intervention for the attenuation and/or prevention of the deterioration effects of cognitive decline associated with various neuronal disorders [22]. Flavonoids consists of potent bioactive compounds including genistein, baicalein, epigallocatechin-3-gallate (EGCG), and hesperidin (Figure 3).
Acacetin is a flavone found naturally in plants including Linaria spp., Chrysanthemum morifolium, Calaminth spp., Carthamus tinctorius, Turnera diffusa (known as damiana), and Robiniapseudo acacia (also called black locust) [103,104]. Findings of various studies have reported that neuroinflammation is not only involved in inflammatory diseases but also in neurodegenerative diseases, including PD. Neuroinflammation in PD is associated with microglial and T-lymphocyte activation with an upregulation of pro-inflammatory cytokines like prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and nitric oxide (NO). Experiments conducted in rodent PD models have suggested that neuroinflammation is prominently implicated in neuronal cell death. Acacetin displays antiparkinsonian activities by diminishing the inflammatory factors associated with the inflammation. It also helps in tumbling dopamine-producing nerve cells, cyclooxygenase-2 (COX-2) glial stimulation, intensifying DA levels and inducible NO synthase (iNOS) [105,106].
Baicalein is one of the main flavonoids and has been reported to be found in roots of the Chinese medicinal herb Scutellaria baicalensis [107]. It has a wide array of biological functions, namely anti-inflammatory, antioxidant, antiviral, anticancer, and cardioprotection [108]. It also inhibits acetylcholinesterase and has neuroprotective ability. Baicalein exhibits antiparkinsonian activity by defending PD through caspase-mediated cell death inhibition and by increasing the feasibility of the SHSY5Y cell line. Specific proteins are also suppressed by this flavonoid, via controlling the neuronal cell damage and the ratio of Bcl-2-associated X protein linked with X protein/B-cell lymphoma (Bax/Bcl-2). It was further reported that baicalein potentially reduces the ROS generation, ATP deficit, apoptosis, and mitochondrial transmembrane breach in PC12 cells, when subjected to rotenone-induced neurotoxicity. Treatment with baicalein increases and maintains basal ganglia dopamine and 5-hydroxytryptamine levels. Additionally, it also decreases the oligomerization and aggregation of α-syn in SH-SY5Y and Hela cells [109,110,111].
Epigallocatechin-3-gallate (EGCG), an essential polyphenolic compound from green tea, has been found to function as an important therapeutic for the treatment of PD [112]. The antiparkinsonian outcome from EGCG is controlled through a rise in reactivators including coactivator-(PGC-1α), peroxisome proliferator-activated receptor, and SIRT1 protein expression. Hence, these are amongst the important metabolic supervisory transcriptase agents which are destined to have an input displaying the inflection in the cellular performance of cells in the anxiety state of PD [113,114].
Theaflavin (TF), is a major constituent of black tea, consisting of three vital compounds, namely TF-3,3′-digallate, TF-3′-gallate, and TF-3-gallate, responsible for lessening the adverse effect in SN TH-positive neurons and employing anti-apoptotic action via suppressing the activities of caspase-9, -8, and -3 in SN [115]. Various scientific studies have been carried out which demonstrated TF to possess excellent neuroprotective role against PD. TF has also been reported to eradicate toxic amyloid deposits. When compared to EGCG, TF3 was less susceptible to air oxidation and had an increased efficacy under oxidizing conditions. Interestingly, TF has been found equal in efficiency to EGCG at inhibiting β-amyloid and α-synuclein-induced neurotoxicity due to its potential antioxidant properties [116,117].
Fustin is a flavanonol extracted from Rhus verniciflua (heartwood). The flavanonol fustin orchestrates its neuroprotective ability by suppressing cell apoptosis, which is further facilitated by the drop in p38 phosphorylation, ROS generation, caspase-3 activation, and the Bax/Bcl-2 ratio [118].
Hesperidin, a flavanone glycoside, has also been found to be associated with multiple neuroprotective activities including the suppression of neuroinflammation, inhibition of oxidative damage, and anti-apoptosis [119]. It diminishes iron-induced death, mitochondrial dysfunction, OS, and reinstates levels of dopamine in the Drosophila melanogaster model of PD. Furthermore, hesperidin also prevents neuroinflammation which was attributed by the augmented synthesis of transforming growth factor-(TGF-) β and IL-10 in an MS mouse model. It possesses the ability to cross the blood–brain barrier (BBB) which can offer its application as a capable therapeutic towards the treatment and management of neurodegenerative diseases [120,121,122].
Anthocyanins are water-soluble flavonoids extensively found in numerous vegetables, as well as fruits such as purple grapes, blackcurrants, blueberries, cherries, and raspberries, respectively. Several studies conducted on cell lines, animal models, and humans have indicated that anthocyanins orchestrate anti-carcinogenic, anti-diabetic, cardiovascular disease prevention, and brain homeostasis [123]. Research findings have documented that anthocyanins exhibits neuroprotective potential through Aβ-inhibition, suppression of inflammatory responses, and reduction in oxidative damage [124,125].
Genistein, an isoflavone derived from Glycine max, has been explored for its implications in various diseases. This compound has attracted attention owing to its pharmacological roles, such as neuroprotection, cardioprotection, anti-cancer, antioxidant activity, anti-inflammatory effects, and obesity prevention. Recently, the synergistic effect of galantamine and genistein was evaluated to explore its neuroprotective ability against Aβ1–42-triggered toxicity in AD. The results of the study demonstrated decreased genotoxicity and cell death by influencing the RAGE/LRP-1 pathway in Wistar rats. Genistein has been extensively studied for its neuroprotective potential in numerous neurodegenerative disorders including PD [126,127,128].

3.1.2. Non-Flavonoids

Non-flavonoids are also polyphenolic compounds exhibiting various types of neuroprotective effects in PD by different mechanisms of action. This group of compounds comprises phenolic acids, phenolic alcohols, stilbenes, and curcumin.

Phenolic Acids

Phenolic acids are secondary metabolites produced by plants. They exist as acidic complexes in the form of hydroxycinnamic and hydroxybenzoic acids (Figure 4A,B) [129]. They possess important biological and pharmacological properties including anti-inflammatory, anticarcinogenic, anticancer, antioxidant, and antimutagenic. Due to the presence of the phenol group and resonance-stabilized conformation, phenolic acids stand out among other chemicals of natural origin for their potent antioxidant and anti-inflammatory activity, which is achieved by a radical scavenging mechanism. Studies carried out using PC12 cells have demonstrated that phenolic acids mitigate 1-methyl-4-phenylpyridinium (MPP+)-induced cell death by boosting the neurite network and triggering the production of proteins essential for synaptogenesis (synaptophysin and synapsin I) and axonal growth (GAP-43). Findings of studies have also demonstrated that phenolic acid reduces the sickness behavior and neuroinflammation induced by lipopolysaccharide (LPS) in mice. TNF-α, a measure of inflammation, has been found to be decreased in the serum in a dose-dependent way, when phenolic acids were administered orally (30 mg/kg) one hour before LPS exposure (1.5 mg/kg) [130]. Phenolic acids are composed of a wide array of bioactive compounds including gallic acid, coumaric acid, ellagic acid (EA), salvianic acid, and rosmarinic acid.
Gallic acid (GA) is a phenolic acid widely distributed in grapes, berries, nuts, honey, tea, and vegetables, either in the bound or free form as a derivative. It has been utilized in a variety of healthcare conditions and has been shown to be effective in preventing stroke, cardiovascular problems, Parkinson’s disease, and Alzheimer’s disease. GA’s capacity to cross the BBB, scavenge abnormal levels of ROS and RNS, and bind transition metal ions are the underlying machinery for orchestrating its neuroprotective actions. GA has been demonstrated to end the vicious cycle of OS and tissue injury as a result of its scavenging capacity and the activation of important antioxidant enzymes in the brain. It was further shown that GA reduces neurobehavioral activities by lowering interleukin-1, nitric oxide, myeloperoxidase activity, and TNF-α, and increasing glutathione levels, antioxidant activities, lowering OS, and caspase-3 levels. It also checks apoptosis by bringing down the levels of caspase 3. GA supplementation further enhances the neuromotor abilities that deteriorate during psychosis. It has been found to be promising in reducing lipid peroxidation, controlling dopamine levels, and inflammatory signals [131,132,133].
A polyphenolic compound, para-coumaric acid (p-CA), is a plant-derived secondary metabolite. p-CA is a dietary polyphenol distributed in several natural food sources, such as tomato, carrot, green pepper, and strawberry, functioning majorly as an antioxidant [134,135]. However, a growing body of evidence has reported its beneficial effects including anti-inflammation, antihyperlipidemia, antihyperglycemia, antineurodegeneration, anticancer, anticardiac infarction, and antimicrobial. Research findings have demonstrated the potent neuroprotective potential of p-CA. In vivo findings have shown that p-CA supplementation diminishes the degeneration of axon in sciatic nerves of rat and OS, followed by ischemia or reperfusion [136]. p-CA has also exhibited neuroprotective potential in models of global and local cerebral ischemia by preventing apoptosis and ROS generation [137].
Ellagic acid (EA) is a phenolic compound extensively distributed in dicotyledonous plants possessing robust antioxidant and anti-inflammatory properties. Research also revealed that it improves neural feasibility, lessens neuronic faults, and decreases injury associated with neurodegenerative diseases [138]. EA has also been found to mitigate oxidative damage by controlling the pathways like Nrf2 and NF-κB and also by refining the antioxidants, as well as antioxidant enzymes’ action. Further, findings have revealed that EA could promisingly reduce malondialdehyde heights and amplify proceedings of total GSH, catalase, and superoxide dismutase (SOD) in a PD animal model [139,140].
Salvianolic acid B is obtained from Salvia miltiorrhiza plant. Research findings have suggested that this compound is potentially capable in amending the rate of cell death. Further, it orchestrates its bioactive role through various ways including maintenance of ROS levels, releasing alteration of cells nuclear morphology protecting matrix metalloproteases, tempering cell’s apoptotic and antiapoptotic mediators, and dropping Bax/Bcl-2 ratio, thereby lowering caspase-3 enzyme activity [141,142,143].
Syringic acid is a naturally occurring derivative of benzoic acid distributed widely in edible plants and fruits. It exhibits antiparkinsonian potential by reducing lipid peroxidation, refining the GSH level, and conquering the pro-inflammatory expression of cytokines including COX-2 enzyme, interleukin (IL)-β1, and TNF-α. Motor dysfunction is prevented by means of striatal DA damage and also their metabolites in MPTP-induced experimental model and consequently, the expression level of VMAT-2 and TH inside the SN is amended [144,145,146].
Rosmarinic acid, an important phenolic compound derived from cinnamate is reported in several naturally occurring plants, namely Melissa officinalis, Ocimum basilicum, Salvia officinalis, Origanum majorana, and Rosmarinus officinalis. It has displayed an outstanding antiparkinsonian action by improving the viability of cells, shielding matrix metalloproteases through intracellular ROS production hindrance, elevating DA levels, and controlling the ratio of Bcl-2/Bax. Rosmarinic acid has also been demonstrated to positively influence cell nuclear condensation, the mitochondrial respiratory chain, and several cell morphological fluctuations. In addition, it also helps in the deactivation of caspase-3 which in turn helps in re-establishing the activity of complex I in the mitochondrial electron transport chain [147,148,149].

Phenolic Alcohols

Phenolic alcohols reported in various plants are also polyphenolic compounds containing an OH group linked to an aromatic hydrocarbon. Plants synthesize this class of compounds in order to combat environmental stresses including pathogens or insects that attack plants [150,151]. Phenolic alcohols orchestrate antioxidant and anti-inflammatory activities by rescuing nerve terminals in the striatum and dopaminergic neurons in the SNpc area and restoring SOD, CAT, and glutamate levels, preventing lipid oxidation, reducing the level of ionized calcium binding adaptor molecule (Iba-1), GFAP hyperactivity, pro-inflammatory cytokines, iNOS, and COX-2 activities, respectively. They contain an OH moiety linked to an aromatic hydrocarbon which helps to scavenge free radicals and protect the neuronal damage. In vitro and in vivo studies have shown that phenolic alcohols have significant levels of anti-inflammatory and antioxidant properties due to which they play a very important role in managing PD symptoms [152]. The major phenolic alcohols found predominantly in plants are 6-Shogaol and sesamol.
6-Shogaol (6S) is a pungent ingredient extracted from ginger. It exhibits a wide range of pharmacological properties including neuroprotective potential by overpowering neuroinflammatory factors including TNF-α, NO, COX-2, and iNOS. In addition to these, it also acts through the activation of microglia in the SNpc. Several investigations have documented its neuropharmacological effects for neurodegenerative disorders. In an AD transgenic mice model, 6S prevented aberrant buildup of the Aβ-peptide in the hippocampus and cortical areas and improved memory impairment. Additionally, it has been documented to reduce memory loss, neuronal damage, and neuroinflammatory effects in mice. In studies on 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-induced PD models, the anti-PD effects of 6S have been investigated. These studies revealed that 6S remarkably prevents dopaminergic neuronal damage, MPTP-induced motor impairment, and striatal dopamine depletion. In MPTP-induced PD mice, 6S prevents gliosis, dopaminergic neuronal degeneration, and motor impairment. Further, it prevents nuclear factor B’s increased nuclear translocation, as well as apoptotic cell death [153,154,155,156].
Sesamol, a lignin obtained from the shrub Sesamum indicum, holds a wide range of defined neuroprotective potential, and remains utilized as therapeutics against PD. Owing to high metabolic activity, brain requires a lot of energy inputs for physiological functions. The brain also features a high membrane surface to cytoplasm ratio, a low repair capability, a non-replicating nature of neurons, and a comparatively low antioxidant machinery. Due to an imbalance between pro-oxidant and antioxidant agents in the brain, increased free radicals, which are mostly created through oxidative phosphorylation, play a significant role in neurological illnesses. This supports the need to target antioxidant systems in order to combat OS and the resulting brain disorders. By encouraging antioxidative defense systems for neutralizing free radicals and by limiting transcription, the antioxidant system is crucial for saving neuronal cells from OS and maintaining the proper redox balance in the brain tissue. Sesamol has been found to boost the action of various antioxidant enzymes, namely glutathione reductase, CAT, SOD, GPx, and also non-enzymatic antioxidants (vitamin E, GSH, and vitamin C), thereby reducing the levels of the lipid peroxidation and nitrites [157,158,159,160].

Stilbenes

Stilbenes are polyphenolic compounds found in various plant species. They have been shown to have anti-inflammatory properties, estrogen receptor agonist qualities, and effects on cell proliferation, cell signaling pathways, and apoptosis. Stilbenes also exhibit antifungal, antiviral, and antibacterial properties. They possess numerous beneficial attributes for the inhibition of abundant pathophysiological issues, namely age-linked ailments (example: type 2 diabetes mellitus, and obesity), OS, and neurodegenerative disorders including PD [161,162]. In addition, an oligostilbene compound, Amurensin G, found in Vitis amurensis (a type of wild grape) root was revealed to maintain the survivability of SH-SY5Y cells by downregulating α-syn and ubiquitinated proteins [163,164].
A stilbene compound, resveratrol, occurring naturally in several plants including Polygonum cuspidatum has demonstrated protective potential in the animal and cellular models of PD (Figure 5). Heme oxygenase-1 (HOX-1) is a 32 kDa stress response protein implicated in the prevention of PD. HOX-1 functions in response to stress and eventually becomes downregulated. Resveratrol exhibits neuroprotection against paraquat-induced PC12 cells via HOX upregulation. Supplementation of resveratrol has been found to upregulate the SOD enzyme activity [165]. The in vitro findings on antiparkinsonian activity of this compound have revealed the capability of resveratrol to downregulate the level of caspase-3 enzyme activity and the lactate dehydrogenase (LDH) leakage. On a similar line, its hydroxylated derivative oxy-resveratrol also has reported neuroprotective potential through the decrease in ROS generation inside the cell, reduction in phospho-JNK-1 and 2, and cytosolic SIRT1. Due to its hydroxyl group and competing with coenzyme Q, resveratrol decreases the activity of complex III, hence lowering the formation of ROS. Resveratrol has also been demonstrated to protect oxygen glucose deprivation and reperfusion (OGD/R), at least in part, according to a study on the PC12 cell line. It exerts neuroprotective effects by reducing OGD/R-induced OS and maintaining mitochondrial function through PINK1/Parkin-mediated mitophagy [103]. Studies carried out using two-month-old male rats with middle cerebral artery occlusion (MCAO) treated with rehabilitation training and resveratrol indicated that resveratrol enhanced neurological and motor function in MCAO rats via activating the brain-derived neurotrophic factor/tyrosine kinase receptor B (BDNF/TrkB) signaling pathways and SIRT1 signaling network. In both in vivo and in vitro experimental models of neurodegeneration, studies have shown that resveratrol moderates mitochondrial activity, maintains redox homeostasis, and cellular dynamics [166].

Curcumin

Curcumin, also known as diferuloylmethane is a polyphenolic compound obtained from the plant rhizome Curcuma longa. Curcumin exhibits, a broad array of pharmacological properties owing to its hydroxy (antioxidant activity) and methoxy (antitumor and anti-inflammatory activities) groups (Figure 6). It has been established to possess various health benefits. Curcumin’s therapeutic and prophylactic efficacy has been demonstrated in many neurodegenerative, oncological, inflammatory, and autoimmune diseases. Studies carried out on an antiparkinsonian rat model revealed that curcumin treatment potentially controls the PD complications via the dopaminergic neuronal damage and depletion of DA. Moreover, iron chelating activity in addition to condensed iron-positive cells in SN has also been mitigated by curcumin. Research findings have shown that curcumin has the ability to downregulate the level of the caspase-3 enzyme, besides amplifying the LRRK2 mRNA and protein expression in vitro. Accumulated evidence showed that curcumin exhibits various neuroprotective properties, including chelating metal ions’ antioxidation, inhibition of the aggregation of misfolded proteins, and attenuating neuroinflammation [167,168]. According to Jin et al., curcumin was found to alleviate PD by energizing the BDNF/PI3k/Akt transduction pathway [169]. Additionally, a nanoformulation of this medication plus levodopa was recently suggested for the treatment of PD [170]. In a PD model, curcumin also offers protective effects on the cerebellum [171]. Earlier biochemical findings established that curcumin proficiently blocked aggregation of α-syn in vitro. Various improved equivalents of curcumin having enhanced constancy have also been confirmed to be effective in preventing depolymerizing α-syn fibrils and α-syn amyloid aggregation. In vivo studies have demonstrated that curcumin has no effect on how α-syn condensates develop or their initial shape. It does however effectively prevent α-syn from amyloid genesis by reducing its fluidity within the condensates. Additionally, it prevents α-syn E46K and H50Q mutants that are linked to PD illness from aggregating amyloid under phase separation. Curcumin can also weaken α-syn amyloid aggregates that have already developed in the condensates [167,168].

3.2. Terpenes

Terpenes are one among the most widely distributed compounds in the plant kingdom. They possess the utmost molecular dissimilarity amongst the secondary metabolites. Terpenes are mainly obtained from coniferous plants, namely juniperus, abies, pinus, and picea. They are mainly hydrocarbons constituting the main bioactive components of natural products including essential oil, wax, rubber, and resin. Terpenoids have biological and pharmacological potential including anticancer, antiviral, anti-inflammatory, antifungal, antihyperglycemic, antiparasitic, and antimicrobial [172,173,174,175]. Some of the important terpenes includes carnosic acid, ginkgolide B, and celastrol (Figure 7).
Carnosic acid, reported in the herb rosemary, is a phenolic diterpene. It amplifies neural cell capability by enhancing the antioxidant presentation in cellular models of cell apoptosis, and also through interacting with the γ-glutamyl cysteine ligase catalytic subunit, SOD, and GSR stimulation of nuclear factor-E2-linked factor 2 (Nrf2) pathways, brain-derived neurotrophic factor (BDNF) release, and γ-glutamyl cysteine ligase modifier subunit [176,177,178].
One of the important diterpenes, Ginkgolide B, extracted from Ginkgo biloba shields against neuronal damage by lowering the calcium concentration within the cell, declining the action of caspase-3 enzyme and cell death. The calcium-binding protein calbindin D28K encourages neuronal process extension in dopaminergic neurons, thereby possessing the potential to defend dopaminergic neurons against uncontrolled PD. The terpene ginkgolide B holds an outstanding capability of restoring the protein calbindin D28K mRNA, as evidenced by in vitro studies [179,180,181,182,183,184].
A triterpene celastrol found in Tripterygium wilfordii lessens the loss of dopaminergic neurons, thereby minimizing the DA and DOPAC level exhaustion indicating its antiparkinsonian potential. It is associated with the synthesis of various noteworthy intermediates in the inflammation like NF-κβ and TNF-α. Celastrol also orchestrates neuroprotective activity through the attenuation of the loss in the SNpc and dropping reduction in its levels in the striatum. In addition to this, it has also been found to augment the expression of HSP70 in the SNpc. Celastrol is reported to be involved in the nuclear translocation of cytoplasmic HSP70 facilitating HSP70 expression. After inducing expression of HSP70, inflammation is documented to be reduced through the prevention of TNF-α and NF-κB stimulation [185,186,187,188].
  • Structure Activity Relationship
Terpenes are a subclass of hydrocarbons that make up the majority of natural products like rubber, resin, wax, and essential oils. Structurally, terpenes are made up of isoprene units. The fundamental structure of terpenes, isoprene (2-methyl-1,3 butadiene), is made up of short carbon units with two double bonds and five carbon atoms. Terpenes have been classified based on the number of isoprene units. These units arrange themselves in the form of head–tail to form compounds with straight chains or rings. Due to the presence of isoprene in their structure, terpenes have been demonstrated to have antiparkinsonian, antimutagenic, antioxidant, and anticarcinogenic potential. As a result, they are frequently utilized in aromatherapy and phytotherapy. Terpenes have been employed in a variety of industries including food, medicine, cosmetics, pharmacy, and cleaning because of their multifaceted properties. Additionally, in recent years, it has been advised to use several terpenes derived from plants as supplements to enhance overall health [172,189,190].
  • In vitro and in vivo studies
In vitro investigation has showed that the terpene ginkgolide B has a remarkable capacity for repairing the protein calbindin D28K mRNA [170]. Investigations carried out in PC-12 and SH-SY-5Y cell lines demonstrated that ginkgolide B can promote antioxidant mechanisms via the Akt/Nrf2/ARE pathways. In vitro and in vivo studies have demonstrated that terpenes prevent demyelination and work with astrocytes to orchestrate a neuroprotective effect [191,192,193,194].

3.3. Alkaloids

Alkaloids are secondary metabolites, consisting of nitrogen, which at the beginning have been considered as the principal group of bioactive natural compounds isolated from plants (Figure 8). Additionally, alkaloids exhibit much structural diversity including in the chemical skeleton such as tetra-hydro-isoquinoline, indole, pyrrolizidine, tropane, piperidine, quinolizidine, indolizidine, pyridine, pyridinone, quinoline, quinazoline, xanthine, steroid, terpenoid, chromone, and flavoalkaloids, respectively [195]. A wide variety of biological roles such as antidepressant, emetic, diuretic, antimicrobial, antiviral, antihypertensive, anti-inflammatory, antitumor, anticholinergic, myorelaxant, hypoalgesia, and sympathomimetic have been displayed by alkaloids [196]. Various studies have shown that numerous alkaloid components possess a promising relaxing ability for a diverse neuron-related disorders including PD [197]. Thus, natural product-based alkaloids having polypharmacology variation characteristics are very beneficial in the progress of drug development in managing PD [198,199,200]. Zingerone and acetylcorynoline are among the important alkaloids possessing diverse pharmacological functions.
Zingerone, an alkaloid component found in the rhizome of ginger has been established to possess an outstanding antiparkinsonian potential. By lowering the expression of glial fibrillary acidic protein and IL-1ß in the hippocampus, it inhibits the overactivation of astrocytes and attenuates LPS-induced neuronal cell death. Low antioxidant levels lead to the creation of free radicals (ROS/RNS) and the consequent inflammation is considered to be the major cause for neurodegeneration in PD. Zingerone potentially inhibits the inflammatory cascade components including TNF-α, NO, COX-2, and iNOS that may contribute to lowering memory impairment in animal models of dementia by limiting glial cell activation. It modulates the depletion of dopamine and their metabolic products, namely homovanillic acid and DOPAC. In addition, it also boosts the antioxidative defense like superoxide scavenging and hydroxyl action, with the suppression of OS. Zingerone pretreatment has been found to upregulate the dopamine levels in the nigrostriatal region, which clearly suggests its protective role in the management of PD and its associated symptoms [201,202,203,204,205].
Acetylcorynoline, an alkaloid obtained from Corydalis bungeana, has also been revealed several neuroprotective abilities including inhibition of dopaminergic neuron loss, augmented levels of α-syn, and exhaustion of DA level. Programmed cell death has been documented to be suppressed by dropping the abnormal-1 (egl-1) expression levels, an apoptosis regulator, exhibiting its antiparkinsonian potential. It is well reported that acetylcorynoline is able to prevent pathogenesis in PD via increasing protein breakdown by proteasomes. Acetylcorynoline has been found to facilitate the increased expression of rpn-5, a proteasome-governing subunit, suggesting its antiparkinsonian activity [206].
  • Structure Activity relationship
The alkaloids’ nucleus contains a benzene ring linked to several (three to four) ether bonds having the capacity to generate hydroxyl groups. However, as there are not many hydroxyl groups present on these compounds, they have a low degree of polarity, which makes it easier for them to cross the BBB. Multiple ether bonds are transformed into hydroxyl groups attached to the benzene ring, which makes these aromatic hydroxyl groups powerful antioxidant structures for crossing the BBB. Based on the structural perspectives, alkaloids may act primarily as antioxidants, with anti-inflammatory, autophagy modulation, and suppression of calcium overload effects [207,208,209,210].
  • In vitro and in vivo studies
Several studies have demonstrated a neuroprotective effect of alkaloids against H2O2-induced oxidative damage in SH-SY5Y cell lines and AChE inhibitory activity [211,212]. Studies conducted in vivo subjected to aluminum-induced neuroinflammation and excitotoxicity have revealed that alkaloid therapy was successful in controlling glutamate and acetylcholinesterase levels, which were otherwise raised by aluminum. The findings of this study also been demonstrated to reduce the excitotoxic harm induced by aluminum, as well as the level of expression of the inflammatory markers IL-6 and TNF-α. The increased expression of inflammatory markers in the groups that received alkaloid treatment is suggestive of the neuroprotective ability of alkaloids in the recovery of neuroplasticity. The neuroprotective ability of alkaloid is further supported by histopathology, wherein the therapy greatly reduced neuronal loss and degeneration while restoring healthy and viable neurons. The study’s findings support the hypothesis that alkaloid has neuroprotective properties against neuroinflammation and excitotoxicity brought on by aluminum [213,214,215].

4. Conclusions

PD stands second among the long-lasting neurological diseases which disturb both cognitive performance and motor skills. Different types of healing methods have been actively involved in the managing PD to date, but they only provide symptomatic relief. Therefore, exploration for achieving the innovative natural moieties from plant sources can be very helpful in lessening the psychological antagonistic properties, and can also recover efficiency through healing aids, common in the patients with PD: this is the emphasis of the current review. The present assessment demands that bioactive natural compounds of plants origin be taken into consideration, which can play a vital role in PD treatment and management.

Author Contributions

Conceptualization, S.A. and N.K.; methodology, N.K. and M.S.; investigation, S.A. and N.S.C.; writing—original draft preparation, S.A., M.S. and N.K.; writing—review and editing, S.A., K.S., N.K.S. and N.S.C.; supervision, S.A. and N.K.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Acknowledgments

The authors acknowledge the department of Biotechnology, School of Applied Sciences, REVA University, for providing the necessary facilities.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Bassett, D.S.; Gazzaniga, M.S. Understanding complexity in the human brain. Trends Cogn. Sci. 2011, 15, 200–209. [Google Scholar] [CrossRef] [PubMed]
  2. Colom, R.; Karama, S.; Jung, R.E.; Haier, R.J. Human intelligence and brain networks. Dialogues Clin. Neurosci. 2010, 12, 489–501. [Google Scholar] [CrossRef] [PubMed]
  3. Salim, S. Oxidative Stress and the Central Nervous System. J. Pharmacol. Exp. Ther. 2017, 360, 201–205. [Google Scholar] [CrossRef] [PubMed]
  4. Singh, A.; Kukreti, R.; Saso, L.; Kukreti, S. Oxidative Stress: A Key Modulator in Neurodegenerative Diseases. Molecules 2019, 24, 1583. [Google Scholar] [CrossRef]
  5. Vasic, V.; Barth, K.; Schmidt, M.H.H. Neurodegeneration and Neuro-Regeneration-Alzheimer’s Disease and Stem Cell Therapy. Int. J. Mol. Sci. 2019, 20, 4272. [Google Scholar] [CrossRef]
  6. Gao, H.; Hong, J. Why neurodegenerative diseases are progressive: Uncontrolled inflammation drives disease progression. Trends Immunol. 2008, 29, 357–365. [Google Scholar] [CrossRef]
  7. Zia, A.; Pourbagher-Shahri, A.M.; Farkhondeh, T. Saeed Samarghandian Molecular and cellular pathways contributing to brain aging. Behav. Brain Funct. 2021, 17, 6. [Google Scholar] [CrossRef]
  8. Rauf, A.; Badoni, H.; Abu-Izneid, T.; Olatunde, A.; Rahman, M.M.; Painuli, S.; Semwal, P.; Wilairatana, P.; Mubarak, M.S. Neuroinflammatory Markers: Key Indicators in the Pathology of Neurodegenerative Diseases. Molecules 2022, 27, 3194. [Google Scholar] [CrossRef]
  9. Choonara, Y.E.; Pillay, V.; Toit, L.C.; Modi, G.; Naidoo, D.; Ndesendo, V.M.K.; Sibambo1, S.R. Trends in the Molecular Pathogenesis and Clinical Therapeutics of Common Neurodegenerative Disorders. Int. J. Mol. Sci. 2009, 10, 2510–2557. [Google Scholar] [CrossRef]
  10. Reeve, A.; Simcox, E.; Turnbulla, D. Ageing and Parkinson’s disease: Why is advancing age the biggest risk factor? Ageing Res. Rev. 2014, 14, 19–30. [Google Scholar] [CrossRef]
  11. Pang, S.Y.Y.; Ho, P.W.L.; Liu, H.F.; Leung, C.; Li, L.; Chang, E.E.S.; Ramsden, D.B.; Ho, S. The interplay of aging, genetics and environmental factors in the pathogenesis of Parkinson’s disease. Transl. Neurodegener. 2019, 8, 23. [Google Scholar] [CrossRef] [PubMed]
  12. Kouli, A.; Torsney, K.M.; Kuan, W.L. Parkinson’s Disease: Etiology, Neuropathology, and Pathogenesis. In Parkinson’s Disease: Pathogenesis and Clinical Aspects [Internet]; Stoker, T.B., Greenland, J.C., Eds.; Codon Publications: Brisbane, Australia, 21 December 2018; Chapter 1. Available online: https://www.ncbi.nlm.nih.gov/books/NBK536722/ (accessed on 13 November 2023).
  13. Ma, J.; Gao, J.; Wang, J.; Xie, A. Prion-Like Mechanisms in Parkinson’s Disease. Front. Neurosci. 2019, 13, 552. [Google Scholar] [CrossRef] [PubMed]
  14. Calabresi, P.; Mechelli, A.; Natale, G.; Volpicelli-Daley, L.; Lazzaro, G.D.; Ghiglieri, V. Alpha-synuclein in Parkinson’s disease and other synucleinopathies: From overt neurodegeneration back to early synaptic dysfunction. Cell Death Dis. 2023, 14, 176. [Google Scholar] [CrossRef] [PubMed]
  15. Ni, A.; Ernst, C. Evidence That Substantia Nigra Pars Compacta Dopaminergic Neurons Are Selectively Vulnerable to Oxidative Stress Because They Are Highly Metabolically Active. Front. Cell. Neurosci. 2022, 16, 826193. [Google Scholar] [CrossRef]
  16. González-Hernández, T.; Rodríguez, M. Compartmental organization and chemical profile of dopaminergic and GABAergic neurons in the substantia nigra of the rat. J. Comp. Neurol. 2000, 421, 107–135. [Google Scholar] [CrossRef]
  17. Gröger, A.; Kolb, R.; Schäfer, R.; Klose, U. Dopamine Reduction in the Substantia Nigra of Parkinson’s Disease Patients Confirmed by In Vivo Magnetic Resonance Spectroscopic Imaging. PLoS ONE 2014, 9, e84081. [Google Scholar] [CrossRef]
  18. Jankovic, J.; Aguilar, L.G. Current approaches to the treatment of Parkinson’s disease. Neuropsychiatr. Dis. Treat. 2008, 4, 743–757. [Google Scholar] [CrossRef]
  19. Sarkar, S.; Raymick, J.; Imam, S. Neuroprotective and Therapeutic Strategies against Parkinson’s Disease: Recent Perspectives. Int. J. Mol. Sci. 2016, 17, 904. [Google Scholar] [CrossRef]
  20. Balakrishnan, R.; Azam, S.; Cho, D.; Su-Kim, I.; Choi, D. Natural Phytochemicals as Novel Therapeutic Strategies to Prevent and Treat Parkinson’s Disease: Current Knowledge and Future Perspectives. Oxid. Med. Cell. Longev. 2021, 2021, 6680935. [Google Scholar] [CrossRef]
  21. Mittal, P.; Dhankhar, S.; Chauhan, S.; Garg, N.; Bhattacharya, T.; Ali, M.; Chaudhary, A.A.; Rudayni, H.A.; Al-Zharani, M.; Ahmad, W. A Review on Natural Antioxidants for Their Role in the Treatment of Parkinson’s Disease. Pharmaceuticals 2023, 16, 908. [Google Scholar] [CrossRef]
  22. Shahpiri, Z.; Bahramsoltani, R.; Farzaei, M.H.; Farzaei, F.; Rahimi, R. Phytochemicals as future drugs for Parkinson’s disease: A comprehensive review. Rev. Neurosci. 2016, 27, 651–668. [Google Scholar] [CrossRef]
  23. Khan, A.; Jahan, S.; Imtiyaz, Z.; Alshahrani, S.; Makeen, H.A.; Alshehri, B.M.; Kumar, A.; Arafah, A.; Rehman, M.U. Neuroprotection: Targeting Multiple Pathways by Naturally Occurring Phytochemicals. Biomedicines 2020, 8, 284. [Google Scholar] [CrossRef]
  24. Varadi, C. Clinical Features of Parkinson’s Disease: The Evolution of Critical Symptoms. Biology 2020, 9, 103. [Google Scholar] [CrossRef]
  25. Pyatha, S.; Kim, H.; Lee, D.; Kim, K. Association between Heavy Metal Exposure and Parkinson’s Disease: A Review of the Mechanisms Related to Oxidative Stress. Antioxidants 2022, 11, 2467. [Google Scholar] [CrossRef] [PubMed]
  26. Zhou, S.; Zhou, X.; Jiang, Z.; Ma, J.; Li, Y.; Qian, Z.; Li, H. The Mechanism of SNHG8/Microrna-421-3p/Sorting Nexin 8 Axis on Dopaminergic Neurons in Substantia Nigra in a Mouse Model of Parkinson’s Disease. Neurochem. Res. 2023, 48, 942–945. [Google Scholar] [CrossRef] [PubMed]
  27. Sharma, S.; Rabbani, S.A.; Agarwal, T.; Baboota, S.; Pottoo, F.H.; Kadian, R. Nanotechnology Driven Approaches for the Management of Parkinson’s Disease: Current Status and Future Perspectives. Curr. Drug Metab. 2021, 22, 287–298. [Google Scholar] [CrossRef] [PubMed]
  28. Scott-Massey, A.; Boag, M.K.; Magnier, A.; Bispo, D.P.C.F.; Khoo, T.K.; Pountney, D.L. Glymphatic System Dysfunction and Sleep Disturbance May Contribute to the Pathogenesis and Progression of Parkinson’s Disease. Int. J. Mol. Sci. 2022, 23, 12928. [Google Scholar] [CrossRef]
  29. Poewe, W.; Seppi, K.; Tanner, C.M.; Halliday, G.M.; Brundin, P.; Volkmann, J.; Schrag, A.E.; Lang, A.E. Parkinson disease. Nat. Rev. Dis. Primers 2017, 3, 17013. [Google Scholar] [CrossRef]
  30. Mallet, D.; Dufourd, T.; Decourt, M.; Carcenac, C.; Bossù, P.; Verlin, L.; Fernagut, P.; Benoit-Marand, M.; Spalletta, G.; Barbier, E.L.; et al. A metabolic biomarker predicts Parkinson’s disease at the early stages in patients and animal models. J. Clin. Investig. 2022, 132, e146400. [Google Scholar] [CrossRef]
  31. Chia, S.J.; Tan, E.K.; Chao, Y.X. Historical Perspective: Models of Parkinson’s Disease. Int. J. Mol. Sci. 2020, 21, 2464. [Google Scholar] [CrossRef]
  32. Pang, M.; Peng, R.; Wang, Y.; Zhu, Y.; Wang, P.; Moussian, B.; Su, Y.; Liu, X.; Ming, D. Molecular understanding of the translational models and the therapeutic potential natural products of Parkinson’s disease. Biomed. Pharmacother. 2022, 155, 113718. [Google Scholar] [CrossRef] [PubMed]
  33. Rabiei, Z.; Solati, K.; Amini-Khoei, H. Phytotherapy in treatment of Parkinson’s disease: A review. Pharm. Biol. 2019, 57, 355–362. [Google Scholar] [CrossRef] [PubMed]
  34. Corona, J.C. Natural Compounds for the Management of Parkinson’s Disease and Attention-Deficit/Hyperactivity Disorder. BioMed Res. Int. 2018, 2018, 4067597. [Google Scholar] [CrossRef] [PubMed]
  35. Cho, B.; Kim, T.; Huh, Y.; Lee, J.; Lee, Y. Amelioration of Mitochondrial Quality Control and Proteostasis by Natural Compounds in Parkinson’s Disease Models. Int. J. Mol. Sci. 2019, 20, 5208. [Google Scholar] [CrossRef] [PubMed]
  36. Khazdair, M.R.; Kianmehr, M.; Anaeigoudari, A. Effects of Medicinal Plants and Flavonoids on Parkinson’s Disease: A Review on Basic and Clinical Evidences. Adv. Pharm. Bull. 2021, 11, 224–232. [Google Scholar] [CrossRef]
  37. Carrera, I.; Cacabelos, R. Current Drugs and Potential Future Neuroprotective Compounds for Parkinson’s Disease. Curr. Neuropharmacol. 2019, 17, 295–306. [Google Scholar] [CrossRef]
  38. Yin, R.; Xue, J.; Tan, Y.; Fang, C.; Hu, C.; Yang, Q.; Mei, X.; Qi, D. The Positive Role and Mechanism of Herbal Medicine in Parkinson’s Disease. Oxid. Med. Cell. Longev. 2021, 2021, 9923331. [Google Scholar] [CrossRef]
  39. Sethiya, N.K.; Dube, B.; Mishra, S.H. Herbs in Metal Health; LAP Lambert Academic Publishing: Saarbrücken, Germany, 2012; Volume 1, pp. 1–75. [Google Scholar]
  40. Li, J.; He, Y.; Fu, J.; Wang, Y.; Fan, X.; Zhong, T.; Zhou, H. Dietary supplementation of Acanthopanax senticosus extract alleviates motor deficits in MPTP-induced Parkinson’s disease mice and its underlying mechanism. Front. Nutr. 2023, 9, 1121789. [Google Scholar] [CrossRef]
  41. Han, C.; Guo, L.; Yang, Y.; Li, W.; Sheng, Y.; Wang, J.; Guan, Q.; Zhang, X. Study on antrodia camphorata polysaccharide in alleviating the neuroethology of PD mice by decreasing the expression of NLRP3 inflammasome. Phytother. Res. 2019, 33, 2288–2297. [Google Scholar] [CrossRef]
  42. Han, C.; Shen, H.; Yang, Y.; Sheng, Y.; Wang, J.; Li, W.; Zhou, X.; Guo, L.; Zhai, L.; Guan, Q. Antrodia camphorata polysaccharide resists 6-OHDA-induced dopaminergic neuronal damage by inhibiting ROS-NLRP3 activation. Brain Behav. 2020, 10, 01824. [Google Scholar] [CrossRef]
  43. Wang, C.; Nguyen, T.; Yang, X.; Mellick, G.D.; Feng, Y. Phytochemical investigation of Asarum sieboldii var. seoulense and the phenotypic profiles of its constituents against a Parkinson’s Disease olfactory cell line. Bioorg. Med. Chem. Lett. 2023, 92, 129386. [Google Scholar] [CrossRef]
  44. Liu, Y.; Li, H.; Li, Y.; Yang, M.; Wang, X.; Peng, Y. Velvet Antler Methanol Extracts Ameliorate Parkinson’s Disease by Inhibiting Oxidative Stress and Neuroinflammation: From, C. elegans to Mice. Oxid. Med. Cell. Longev. 2021, 2021, 8864395. [Google Scholar] [CrossRef]
  45. Silva, J.; Martins, A.; Alves, C.; Pinteus, S.; Gaspar, H.; Alfonso, A.; Pedrosa, R. Natural Approaches for Neurological Disorders-The Neuroprotective Potential of Codium tomentosum. Molecules 2020, 25, 5478. [Google Scholar] [CrossRef] [PubMed]
  46. Omoruyi, S.I.; Ibrakaw, A.S.; Ekpo, O.E.; Boatwright, J.S.; Cupido, C.N.; Hussein, A.A. Neuroprotective Activities of Crossyne flava Bulbs and Amaryllidaceae Alkaloids: Implications for Parkinson’s Disease. Molecules 2021, 26, 3990. [Google Scholar] [CrossRef]
  47. Ren, Z.; Wang, C.; Wang, T.; Ding, H.; Zhou, M.; Yang, N.; Liu, Y.; Chan, P. Ganoderma lucidum extract ameliorates MPTP-induced parkinsonism and protects dopaminergic neurons from oxidative stress via regulating mitochondrial function, autophagy, and apoptosis. Acta Pharmacol. Sin. 2019, 40, 441–450. [Google Scholar] [CrossRef] [PubMed]
  48. Arslan, M.E.; Yılmaz, A. Neuroprotective effects of Geranium robertianum L. Aqueous extract on the cellular Parkinson’s disease model. Eur. Rev. Med. Pharmacol. Sci. 2023, 27, 570–579. [Google Scholar] [CrossRef] [PubMed]
  49. Siracusa, R.; Scuto, M.; Fusco, R.; Trovato, A.; Ontario, M.L.; Crea, R.; Paola, R.D.; Cuzzocrea, S.; Calabrese, V. Anti-inflammatory and Anti-Oxidant Activity of Hidrox® in Rotenone-Induced Parkinson’s Disease in Mice. Antioxidants 2020, 9, 824. [Google Scholar] [CrossRef]
  50. Lin, D.; Zeng, Y.; Tang, D.; Cai, Y. Study on the Mechanism of Liuwei Dihuang Pills in Treating Parkinson’s Disease Based on Network Pharmacology. BioMed Res. Int. 2021, 2021, 4490081. [Google Scholar] [CrossRef]
  51. Kabra, A.; Baghel, U.S.; Hano, C.; Martins, N.; Khalid, M.; Sharma, R. Neuroprotective potential of Myrica esulenta in Haloperidol induced Parkinson’s disease. J. Ayurveda Integr. Med. 2020, 11, 448–454. [Google Scholar] [CrossRef]
  52. Ly, H.T.; Nguyen, T.T.H.; Le, V.M.; Lam, B.T.; Mai, T.T.T.; Dang, T.P.T. Therapeutic Potential of Polyscias fruticosa (L.) Harms Leaf Extract for Parkinson’s Disease Treatment by Drosophila melanogaster Model. Oxid. Med. Cell. Longev. 2022, 2022, 5262677. [Google Scholar] [CrossRef]
  53. Nghi, N.B.T.; Uyen, T.T.; Anh, H.M.; Linh, D.M.; Thao, D.T.P. Rumdul (Sphaerocoryne affinis) Antioxidant Activity and Its Potential for Parkinson’s Disease Treatment. Oxid. Med. Cell. Longev. 2022, 2022, 8918966. [Google Scholar] [CrossRef]
  54. Sanad, S.M.; Farouk, R.; Nassar, S.E.; Alshahrani, M.Y.; Suliman, M.; Ahmed, A.E.; Elesawi, I.E. The neuroprotective effect of quercetin nanoparticles in the therapy of neuronal damage stimulated by acrolein. Saudi J. Biol. Sci. 2023, 30, 103792. [Google Scholar] [CrossRef] [PubMed]
  55. Yarim, G.F.; Kazak, F.; Yarim, M.; Sozmen, M.; Genc, B.; Ertekin, A.; Gokceoglu, A. Apigenin alleviates neuroinflammation in a mouse model of Parkinson’s disease. Int. J. Neurosci. 2022, 26, 1–10. [Google Scholar] [CrossRef] [PubMed]
  56. Sharma, N.; Soni, R.; Sharma, M.; Chatterjee, S.; Parihar, N.; Mukarram, M.; Kale, R.; Sayyed, A.A.; Behera, S.K.; Khairnar, A. Chlorogenic Acid: A Polyphenol from Coffee Rendered Neuroprotection Against Rotenone-Induced Parkinson’s Disease by GLP-1 Secretion. Mol. Neurobiol. 2022, 59, 6834–6856. [Google Scholar] [CrossRef] [PubMed]
  57. Gao, X.; Zhang, B.; Zheng, Y.; Liu, X.; Rostyslav, P.; Finiuk, N.; Sik, A.; Stoika, R.; Liu, K.; Jin, M. Neuroprotective effect of chlorogenic acid on Parkinson’s disease like symptoms through boosting the autophagy in zebrafish. Eur. J. Pharmacol. 2023, 956, 175950. [Google Scholar] [CrossRef]
  58. Brunetti, G.; Rosa, G.D.; Scuto, M.; Leri, M.; Stefani, M.; Schmitz-Linneweber, C.; Calabrese, V.; Saul, N. Healthspan Maintenance and Prevention of Parkinson’s-like Phenotypes with Hydroxytyrosol and Oleuropein Aglycone in C. elegans. Int. J. Mol. Sci. 2020, 21, 2588. [Google Scholar] [CrossRef]
  59. Gallardo-Fernández, M.; Hornedo-Ortega, R.; Alonso-Bellido, I.M.; Rodríguez-Gómez, J.A.; Troncoso, A.M.; García-Parrilla, M.C.; Venero, J.L.; Espinosa-Oliva, A.M.; de Pablos, R.M. Hydroxytyrosol Decreases LPS- and α-Synuclein-Induced Microglial Activation in Vitro. Antioxidants 2020, 9, 36. [Google Scholar] [CrossRef]
  60. Pathania, A.; Kumar, R.; Sandhir, R. Hydroxytyrosol as anti-parkinsonian molecule: Assessment using in-silico and MPTP-induced Parkinson’s disease model. Biomed. Pharmacother. 2021, 139, 111525. [Google Scholar] [CrossRef]
  61. Perez-Barron, G.; Montes, S.; Aguirre-Vidal, Y.; Santiago, M.; Gallardo, E.; Espartero, J.L.; Ríos, C.; Monroy-Noyola, A. Antioxidant Effect of Hydroxytyrosol, Hydroxytyrosol Acetate and Nitrohydroxytyrosol in a Rat MPP+ Model of Parkinson’s Disease. Neurochem. Res. 2021, 46, 2923–2935. [Google Scholar] [CrossRef]
  62. Mursaleen, L.; Noble, B.; Somavarapu, S.; Zariwala, M.G. Micellar Nanocarriers of Hydroxytyrosol Are Protective against Parkinson’s Related Oxidative Stress in an in Vitro hCMEC/D3-SH-SY5Y Co-Culture System. Antioxidants 2021, 10, 887. [Google Scholar] [CrossRef]
  63. Ba, Q.; Cui, C.; Wen, L.; Feng, S.; Zhou, J.; Yang, K. Schisandrin B shows neuroprotective effect in 6-OHDA-induced Parkinson’s disease via inhibiting the negative modulation of miR-34a on Nrf2 pathway. Biomed. Pharmacother. 2015, 75, 165–172. [Google Scholar] [CrossRef] [PubMed]
  64. Vijayakumaran, S.; Nakamura, Y.; Henley, J.M.; Pountney, D.L. Ginkgolic acid promotes autophagy-dependent clearance of intracellular alpha-synuclein aggregates. Mol. Cell. Neurosci. 2019, 101, 103416. [Google Scholar] [CrossRef] [PubMed]
  65. Zou, Z.C.; Fu, J.J.; Dang, Y.Y.; Zhang, Q.; Wang, X.F.; Chen, H.B.; Jia, X.J.; Lee, S.M.; Li, C.W. Pinocembrin-7-Methylether Protects SH-SY5Y Cells Against 6-Hydroxydopamine-Induced Neurotoxicity via Modulating Nrf2 Induction Through AKT and ERK Pathways. Neurotox. Res. 2021, 39, 1323–1337. [Google Scholar] [CrossRef] [PubMed]
  66. Mishra, A.; Mishra, P.S.; Bandopadhyay, R.; Khurana, N.; Angelopoulou, E.; Paudel, Y.N.; Piperi, C. Neuroprotective Potential of Chrysin: Mechanistic Insights and Therapeutic Potential for Neurological Disorders. Molecules 2021, 26, 6456. [Google Scholar] [CrossRef] [PubMed]
  67. Yan, X.; Liu, D.; Zhang, X.; Liu, D.; Xu, S.; Chen, G.; Huang, B.; Ren, W.; Wang, W.; Fu, S.; et al. Vanillin Protects Dopaminergic Neurons against Inflammation-Mediated Cell Death by Inhibiting ERK1/2, P38 and the NF-κB Signaling Pathway. Int. J. Mol. Sci. 2017, 18, 389. [Google Scholar] [CrossRef]
  68. Long, T.; Wu, Q.; Wei, J.; Tang, Y.; He, Y.; He, C.; Chen, X.; Yu, L.; Yu, C.; Law, B.Y.; et al. Ferulic Acid Exerts Neuroprotective Effects via Autophagy Induction in C. elegans and Cellular Models of Parkinson’s Disease. Oxid. Med. Cell. Longev. 2022, 2022, 3723567. [Google Scholar] [CrossRef]
  69. Varshney, M.; Kumar, B.; Rana, V.S.; Sethiya, N.K. An Overview on Therapeutic and Medicinal Potential of Poly-hydroxy Flavone viz. Heptamethoxyflavone, Kaempferitrin, Vitexin and Amentoflavone for Management of Alzheimer’s and Parkinson’s Diseases: A critical analysis on mechanistic insight. Crit. Rev. Food Sci. Nutr. 2023, 63, 2749–2772. [Google Scholar] [CrossRef]
  70. Walia, V.; Chaudhary, S.K.; Sethiya, N.K. Therapeutic potential of mangiferin in the treatment of various neuropsychiatric and neurodegenerative disorders. Neurochem. Int. 2021, 143, 104939. [Google Scholar] [CrossRef]
  71. Sethiya, N.K.; Ghiloria, N.; Srivastav, A.; Bisht, D.; Chaudhary, S.K.; Walia, V.; Alam, M.S. Therapeutic Potential of Myricetin in the Treatment of Neurological, Neuropsychiatric, and Neurodegenerative Disorders. CNS Neurol. Disord. Drug Targets 2023. online ahead of print. [Google Scholar] [CrossRef]
  72. Chen, D.; Zhang, X.; Sun, J.; Cong, Q.; Chen, W.; Ahsan, H.M.; Gao, J.; Qian, J. Asiatic Acid Protects Dopaminergic Neurons from Neuroinflammation by Suppressing Mitochondrial ROS Production. Biomol. Ther. 2019, 27, 442–449. [Google Scholar] [CrossRef]
  73. He, Z.; Huan, P.; Wang, L.; He, J. Paeoniflorin ameliorates cognitive impairment in Parkinson’s disease via JNK/p53 signaling. Metab. Brain Dis. 2022, 37, 1057–1070. [Google Scholar] [CrossRef] [PubMed]
  74. Xu, C.; Qu, R.; Zhang, J.; Li, L.; Ma, S. Neuroprotective effects of Madecassoside in early stage of Parkinson’s disease induced by MPTP in rats. Fitoterapia 2013, 90, 112–118. [Google Scholar] [CrossRef] [PubMed]
  75. Xu, Y.; Cui, C.; Sun, M.; Zhu, Y.; Chu, M.; Shi, Y.; Lin, S.L.; Yang, X.; Shen, Y. Neuroprotective Effects of Loganin on MPTP-Induced Parkinson’s Disease Mice: Neurochemistry, Glial Reaction and Autophagy Studies. J. Cell. Biochem. 2017, 118, 3495–3510. [Google Scholar] [CrossRef] [PubMed]
  76. Ahmed, S.; Panda, S.R.; Kwatra, M.; Sahu, B.D.; Naidu, V. Perillyl Alcohol Attenuates NLRP3 Inflammasome Activation and Rescues Dopaminergic Neurons in Experimental In Vitro and In Vivo Models of Parkinson’s Disease. ACS Chem. Neurosci. 2022, 13, 53–68. [Google Scholar] [CrossRef] [PubMed]
  77. Lee, T.; Yang, W.; Cha, D.S.; Han, Y.T. Synthesis of a natural quinoline alkaloid isolated from the deep-sea-derived fungus and its potential as a therapeutic for Parkinson’s disease. J. Asian Nat. Prod. Res. 2023, 25, 446–455. [Google Scholar] [CrossRef]
  78. Li, Y.J.; Li, J.; Xie, L.; Zhou, J.Y.; Li, Q.X.; Yang, R.Y.; Liu, Y.P.; Fu, Y.H. Monoterpenoids indole alkaloids with potential neuroprotective activities from the stems and leaves of Melodinus cochinchinensis. Nat. Prod. Res. 2022, 36, 5181–5188. [Google Scholar] [CrossRef]
  79. Wang, Y.; Tong, Q.; Ma, S.R.; Zhao, Z.; Pan, L.; Cong, L.; Han, P.; Peng, R.; Yu, H.; Lin, Y.; et al. Oral berberine improves brain dopa/dopamine levels to ameliorate Parkinson’s disease by regulating gut microbiota. Signal Transduct. Target. Ther. 2021, 6, 77. [Google Scholar] [CrossRef]
  80. Schepici, G.; Silvestro, S.; Bramanti, P.; Mazzon, E. Caffeine: An Overview of Its Beneficial Effects in Experimental Models and Clinical Trials of Parkinson’s Disease. Int. J. Mol. Sci. 2020, 21, 4766. [Google Scholar] [CrossRef]
  81. Jayaraj, R.L.; Beiram, R.; Azimullah, S.; Meeran, M.F.N.; Ojha, S.K.; Adem, A.; Jalal, F.Y. Lycopodium Attenuates Loss of Dopaminergic Neurons by Suppressing Oxidative Stress and Neuroinflammation in a Rat Model of Parkinson’s Disease. Molecules 2019, 24, 2182. [Google Scholar] [CrossRef]
  82. Singh, A.K.; Singla, R.K.; Pandey, A.K. Chlorogenic Acid: A Dietary Phenolic Acid with Promising Pharmacotherapeutic Potential. Curr. Med. Chem. 2023, 30, 3905–3926. [Google Scholar] [CrossRef]
  83. Uddin, M.S.; Al Mamun, A.; Kabir, M.T.; Ahmad, J.; Jeandet, P.; Sarwar, M.S.; Ashraf, G.M.; Aleya, L. Neuroprotective role of polyphenols against oxidative stress-mediated neurodegeneration. Eur. J. Pharmacol. 2020, 886, 173412. [Google Scholar] [CrossRef] [PubMed]
  84. Arias-Sánchez, R.A.; Torner, L.; Fenton Navarro, B. Polyphenols and Neurodegenerative Diseases: Potential Effects and Mechanisms of Neuroprotection. Molecules 2023, 28, 5415. [Google Scholar] [CrossRef] [PubMed]
  85. Efimova, S.S.; Ostroumova, O.S. Modulation of the Dipole Potential of Model Lipid Membranes with Phytochemicals: Molecular Mechanisms, Structure-Activity Relationships, and Implications in Reconstituted Ion Channels. Membranes 2023, 13, 453. [Google Scholar] [CrossRef] [PubMed]
  86. Anand, S.; Sowbhagya, R.; Ansari, M.A.; Alzohairy, M.A.; Alomary, M.N.; Almalik, A.I.; Ahmad, W.; Tripathi, T.; Elderdery, A.Y. Polyphenols and Their Nanoformulations: Protective Effects against Human Diseases. Life 2022, 12, 1639. [Google Scholar] [CrossRef]
  87. Liu, S.; Cheng, L.; Liu, Y.; Zhan, S.; Wu, Z.; Zhang, X. Relationship between Dietary Polyphenols and Gut Microbiota: New Clues to Improve Cognitive Disorders, Mood Disorders and Circadian Rhythms. Foods 2023, 12, 1309. [Google Scholar] [CrossRef]
  88. Platzer, M.; Kiese, S.; Tybussek, T.; Herfellner, T.; Schneider, F.; Schweiggert-Weisz, U.; Eisner, P. Radical Scavenging Mechanisms of Phenolic Compounds: A Quantitative Structure-Property Relationship (QSPR) Study. Front. Nutr. 2022, 9, 882458. [Google Scholar] [CrossRef]
  89. Lopez-Corona, A.V.; Valencia-Espinosa, I.; González-Sánchez, F.A.; Sánchez-López, A.L.; Garcia-Amezquita, L.E.; Garcia-Varela, R. Antioxidant, Anti-Inflammatory and Cytotoxic Activity of Phenolic Compound Family Extracted from Raspberries (Rubus idaeus): A General Review. Antioxidants 2022, 11, 1192. [Google Scholar] [CrossRef]
  90. Zhang, Z.; Hamada, H.; Gerk, P.M. Selectivity of Dietary Phenolics for Inhibition of Human Monoamine Oxidases A and B. BioMed Res. Int. 2019, 2019, 8361858. [Google Scholar] [CrossRef]
  91. Shih, J.C.; Chen, K.; Ridd, M.J. MONOAMINE OXIDASE: From Genes to Behavior. Annu. Rev. Neurosci. 1999, 22, 197–217. [Google Scholar] [CrossRef]
  92. Carecho, R.; Carregosa, D.; Ratilal, B.O.; Figueira, I.; Ávila-Gálvez, M.A.; Santos, C.N.; Loncarevic-Vasiljkovic, N. Dietary (Poly)phenols in Traumatic Brain Injury. Int. J. Mol. Sci. 2023, 24, 8908. [Google Scholar] [CrossRef]
  93. Grabska-Kobyłecka, I.; Szpakowski, P.; Król, A.; Książek-Winiarek, D.; Kobyłecki, A.; Głąbiński, A.; Nowak, D. Polyphenols and Their Impact on the Prevention of Neurodegenerative Diseases and Development. Nutrients 2023, 15, 3454. [Google Scholar] [CrossRef] [PubMed]
  94. Vauzour, D. Dietary Polyphenols as Modulators of Brain Functions: Biological Actions and Molecular Mechanisms Underpinning Their Beneficial Effects. Oxid. Med. Cell. Longev. 2012, 2012, 914273. [Google Scholar] [CrossRef]
  95. Shahidi, F.; Ambigaipalan, P. Phenolics and polyphenolics in foods, beverages and spices: Antioxidant activity and health effects—A review. J. Funct. Foods 2015, 18, 820–897. [Google Scholar] [CrossRef]
  96. Li, M.; Qian, M.; Jiang, Q.; Tan, B.; Yin, Y.; Han, X. Evidence of Flavonoids on Disease Prevention. Antioxidants 2023, 12, 527. [Google Scholar] [CrossRef] [PubMed]
  97. Sun, W.; Shahrajabian, M.H. Therapeutic Potential of Phenolic Compounds in Medicinal Plants—Natural Health Products for Human Health. Molecules 2023, 28, 1845. [Google Scholar] [CrossRef]
  98. Yan, L.; Guo, M.; Zhang, Y.; Yu, L.; Wu, J.; Tang, Y.; Ai, W.; Zhu, F.; Law, B.Y.; Chen, Q.; et al. Dietary Plant Polyphenols as the Potential Drugs in Neurodegenerative Diseases: Current Evidence, Advances, and Opportunities. Oxid. Med. Cell. Longev. 2022, 2022, 5288698. [Google Scholar] [CrossRef]
  99. Chen, S.; Wang, X.; Cheng, Y.; Gao, H.; Chen, X. A Review of Classification, Biosynthesis, Biological Activities and Potential Applications of Flavonoids. Molecules 2023, 28, 4982. [Google Scholar] [CrossRef]
  100. Bellavite, P. Neuroprotective Potentials of Flavonoids: Experimental Studies and Mechanisms of Action. Antioxidants 2023, 12, 280. [Google Scholar] [CrossRef]
  101. Spiegel, M.; Andruniów, T.; Sroka, Z. Flavones’ and Flavonols’ Antiradical Structure–Activity Relationship—A Quantum Chemical Study. Antioxidants 2020, 9, 461. [Google Scholar] [CrossRef]
  102. Kumar, S.; Pandey, A.K. Chemistry and Biological Activities of Flavonoids: An Overview. Sci. World J. 2013, 2013, 162750. [Google Scholar] [CrossRef]
  103. Devi, S.; Kumar, V.; Singh, S.K.; Dubey, A.K.; Kim, J.J. Flavonoids: Potential Candidates for the Treatment of Neurodegenerative Disorders. Biomedicines 2021, 9, 99. [Google Scholar] [CrossRef]
  104. Singh, S.; Gupta, P.; Meena, A.; Luqman, S. Acacetin, a flavone with diverse therapeutic potential in cancer, inflammation, infections and other metabolic disorders. Food Chem. Toxicol. 2020, 145, 111708. [Google Scholar] [CrossRef] [PubMed]
  105. Kim, H.G.; Ju, M.S.; Ha, S.K.; Lee, H.; Lee, H.; Kim, S.Y.; Oh, M.S. Acacetin protects dopaminergic cells against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neuroinflammation in vitro and in vivo. Biol. Pharm. Bull. 2012, 35, 1287–1294. [Google Scholar] [CrossRef] [PubMed]
  106. Kim, S.M.; Park, Y.J.; Shin, M.; Kim, H.; Kim, M.J.; Lee, S.H.; Yun, S.P.; Kwon, S. Acacetin inhibits neuronal cell death induced by 6-hydroxydopamine in cellular Parkinson’s disease model. Bioorg. Med. Chem. Lett. 2017, 27, 5207–5212. [Google Scholar] [CrossRef] [PubMed]
  107. Zhao, Q.; Chen, X.; Martin, C. Scutellaria baicalensis, the golden herb from the garden of Chinese medicinal plants. Sci. Bull. 2016, 61, 1391–1398. [Google Scholar] [CrossRef]
  108. Jadhav, R.; Kulkarni, Y.A. Effects of baicalein with memantine on aluminium chloride-induced neurotoxicity in Wistar rats. Front. Pharmacol. 2023, 14, 1034620. [Google Scholar] [CrossRef]
  109. Li, Y.; Zhao, J.; Hölscher, C. Therapeutic Potential of Baicalein in Alzheimer’s Disease and Parkinson’s Disease. CNS Drugs 2017, 31, 639–652. [Google Scholar] [CrossRef]
  110. Wang, Y.; Wei, N.; Li, X. Preclinical Evidence and Possible Mechanisms of Baicalein for Rats and Mice with Parkinson’s Disease: A Systematic Review and Meta-Analysis. Front. Aging Neurosci. 2020, 12, 277. [Google Scholar] [CrossRef]
  111. Chen, M.; Peng, L.; Gong, P.; Zheng, X.; Sun, T.; Zhang, X.; Huo, J. Baicalein Induces Mitochondrial Autophagy to Prevent Parkinson’s Disease in Rats via miR-30b and the SIRT1/AMPK/mTOR Pathway. Front. Neurol. 2021, 12, 646817. [Google Scholar] [CrossRef]
  112. Wang, Y.; Wu, S.; Li, Q.; Lang, W.; Li, W.; Jiang, X.; Wan, Z.; Chen, J.; Wang, H. Epigallocatechin-3-gallate: A phytochemical as a promising drug candidate for the treatment of Parkinson’s disease. Front. Pharmacol. 2022, 13, 977521. [Google Scholar] [CrossRef]
  113. Sergi, C.M. Epigallocatechin gallate for Parkinson’s disease. Clin. Exp. Pharmacol. Physiol. 2022, 49, 1029–1041. [Google Scholar] [CrossRef]
  114. Xu, Y.; Xie, M.; Xue, J.; Xiang, L.; Li, Y.; Xiao, J.; Xiao, G.; Wang, H. EGCG ameliorates neuronal and behavioral defects by remodeling gut microbiota and TotM expression in Drosophila models of Parkinson’s disease. FASEB J. 2020, 34, 5931–5950. [Google Scholar] [CrossRef]
  115. Caruana, M.; Vassallo, N. Tea Polyphenols in Parkinson’s Disease. Adv. Exp. Med. Biol. 2015, 863, 117–137. [Google Scholar] [CrossRef] [PubMed]
  116. Anandhan, A.; Tamilselvam, K.; Radhiga, T.; Rao, S.; Essa, M.M.E.; Manivasagam, T. Theaflavin, a black tea polyphenol, protects nigral dopaminergic neurons against chronic MPTP/probenecid induced Parkinson’s disease. Brain Res. 2012, 1433, 104–113. [Google Scholar] [CrossRef] [PubMed]
  117. Grelle, G.; Otto, A.; Lorenz, M.; Frank, R.F.; Wanker, E.E.; Bieschke, J. Black tea theaflavins inhibit formation of toxic amyloid-β and α-synuclein fibrils. Biochemistry 2011, 50, 10624–10636. [Google Scholar] [CrossRef] [PubMed]
  118. Park, B.C.; Lee, Y.S.; Park, H.; Kwak, M.; Yoo, B.K.; Kim, J.Y.; Kim, J. Protective effects of fustin, a flavonoid from Rhus verniciflua Stokes, on 6-hydroxydopamine-induced neuronal cell death. Exp. Mol. Med. 2007, 39, 316–326. [Google Scholar] [CrossRef] [PubMed]
  119. Hajialyani, M.; Farzaei, M.H.; Echeverría, J.; Nabavi, S.M.; Uriarte, E.; Sobarzo-Sánchez, E. Hesperidin as a Neuroprotective Agent: A Review of Animal and Clinical Evidence. Molecules 2019, 24, 648. [Google Scholar] [CrossRef] [PubMed]
  120. Atoki, A.V.; Aja, P.M.; Shinkafi, T.S.; Ondari, E.N.; Awuchi, C.G. Hesperidin plays beneficial roles in disorders associated with the central nervous system: A review. Int. J. Food Prop. 2023, 26, 1867–1884. [Google Scholar] [CrossRef]
  121. Tamilselvam, K.; Braidy, N.; Manivasagam, T.; Essa, M.M.; Prasad, N.R.; Karthikeyan, S.; Thenmozhi, A.J.; Selvaraju, S.; Guillemin, G.J. Neuroprotective Effects of Hesperidin, a Plant Flavanone, on Rotenone-Induced Oxidative Stress and Apoptosis in a Cellular Model for Parkinson’s Disease. Oxid. Med. Cell. Longev. 2013, 2013, 102741. [Google Scholar] [CrossRef]
  122. Antunes, M.S.; Goes, A.T.R.; Boeira, S.P.; Prigol, M.; Jesse, C.R. Protective effect of hesperidin in a model of Parkinson’s disease induced by 6-hydroxydopamine in aged mice. Nutrition 2014, 30, 1415–1422. [Google Scholar] [CrossRef]
  123. Li, P.; Feng, D.; Yang, D.; Li, X.; Sun, J.; Wang, G.; Tian, L.; Jiang, X.; Bai, W. Protective effects of anthocyanins on neurodegenerative diseases. Trends Food Sci. Technol. 2021, 117, 205–217. [Google Scholar] [CrossRef]
  124. Winter, A.N.; Bickford, P.C. Anthocyanins and Their Metabolites as Therapeutic Agents for Neurodegenerative Disease. Antioxidants 2019, 8, 333. [Google Scholar] [CrossRef]
  125. Strathearn, K.E.; Yousef, G.G.; Grace, M.H.; Roy, S.L.; Tambe, M.A.; Ferruzzi, M.G.; Wu, Q.; Simon, J.E.; Lila, M.A.; Rochet, J. Neuroprotective effects of anthocyanin- and proanthocyanidin-rich extracts in cellular models of Parkinsons disease. Brain Res. 2014, 1555, 60–77. [Google Scholar] [CrossRef] [PubMed]
  126. Li, R.; Robinson, M.; Ding, X.; Geetha, T.; Al-Nakkash, L.; Broderick, T.L.; Babu, J.R. Genistein: A focus on several neurodegenerative diseases. J. Food Biochem. 2022, 46, e14155. [Google Scholar] [CrossRef] [PubMed]
  127. Siddique, Y.H.; Naz, F.; Jyoti, S.; Ali, F.; Rahul. Effect of Genistein on the Transgenic Drosophila Model of Parkinson’s Disease. J. Diet. Suppl. 2019, 16, 550–563. [Google Scholar] [CrossRef] [PubMed]
  128. Liu, L.; Chen, W.; Xie, J.; Wong, M. Neuroprotective effects of genistein on dopaminergic neurons in the mice model of Parkinson’s disease. Neurosci. Res. 2008, 60, 156–161. [Google Scholar] [CrossRef] [PubMed]
  129. Khoddami, A.; Wilkes, M.A.; Roberts, T.H. Techniques for Analysis of Plant Phenolic Compounds. Molecules 2013, 18, 2328–2375. [Google Scholar] [CrossRef] [PubMed]
  130. Caruso, G.; Godos, J.; Privitera, A.; Lanza, G.; Castellano, S.; Chillemi, A.; Bruni, O.; Ferri, R.; Caraci, F.; Grosso, G. Phenolic Acids and Prevention of Cognitive Decline: Polyphenols with a Neuroprotective Role in Cognitive Disorders and Alzheimer’s Disease. Nutrients 2022, 14, 819. [Google Scholar] [CrossRef]
  131. Shabani, S.; Rabiei, Z.; Amini-Khoei, H. Exploring the multifaceted neuroprotective actions of gallic acid: A review. Int. J. Food Prop. 2020, 23, 736–752. [Google Scholar] [CrossRef]
  132. Chandrasekhar, Y.; Kumar, G.P.; Ramya, E.M.; Anilakumar, K.R. Gallic Acid Protects 6-OHDA Induced Neurotoxicity by Attenuating Oxidative Stress in Human Dopaminergic Cell Line. Neurochem. Res. 2018, 43, 1150–1160. [Google Scholar] [CrossRef] [PubMed]
  133. Abdelsalam, S.A.; Renu, K.; Zahra, H.A.; Abdallah, B.M.; Ali, E.M.; Veeraraghavan, V.P.; Sivalingam, K.; Ronsard, L.; Ammar, R.B.; Vidya, D.S.; et al. Polyphenols Mediate Neuroprotection in Cerebral Ischemic Stroke-An Update. Nutrients 2023, 15, 1107. [Google Scholar] [CrossRef]
  134. Pathan, A.S.; Jain, P.G.; Kumawat, V.S.; Katolkar, U.N.; Surana, S.J. Neuroprotective Effects of P-Coumaric Acid on Haloperidol-Induced Catalepsy Through Ameliorating Oxidative Stress and Brain Dopamine Level. J. Pharmacol. Pharmacother. 2022, 13, 364–374. [Google Scholar] [CrossRef]
  135. Dolrahman, N.; Mukkhaphrom, W.; Sutirek, J.; Thong-Asa, W. Benefits of p-coumaric acid in mice with rotenone-induced neurodegeneration. Metab. Brain Dis. 2023, 38, 373–382. [Google Scholar] [CrossRef] [PubMed]
  136. Guven, M.; Yuksel, Y.; Sehitoglu, M.H.; Tokmak, M.; Aras, A.B.; Akman, T.; Golge, U.H.; Goksel, F.; Karavelioglu, E.; Cosar, M. The Effect of Coumaric Acid on Ischemia-Reperfusion Injury of Sciatic Nerve in Rats. Inflammation 2015, 38, 2124–2132. [Google Scholar] [CrossRef]
  137. Pluta, R.; Miziak, B.; Czuczwar, S.J. Apitherapy in Post-Ischemic Brain Neurodegeneration of Alzheimer’s Disease Proteinopathy: Focus on Honey and Its Flavonoids and Phenolic Acids. Molecules 2023, 28, 5624. [Google Scholar] [CrossRef] [PubMed]
  138. Sharifi-Rad, J.; Quispe, C.; Castillo, C.M.S.; Caroca, R.; Lazo-Vélez, M.A.; Antonyak, H.; Polishchuk, A.; Lysiuk, R.; Oliinyk, P.; Masi, L.D.; et al. Ellagic Acid: A Review on Its Natural Sources, Chemical Stability, and Therapeutic Potential. Oxid. Med. Cell. Longev. 2022, 2022, 3848084. [Google Scholar] [CrossRef]
  139. Ardah, M.T.; Bharathan, G.; Kitada, T.; Haque, M.E. Ellagic Acid Prevents Dopamine Neuron Degeneration from Oxidative Stress and Neuroinflammation in MPTP Model of Parkinson’s Disease. Biomolecules 2020, 10, 1519. [Google Scholar] [CrossRef]
  140. Sarkaki, A.; Farbood, Y.; Dolatshahi, M.; Mansouri, S.M.T.; Khodadadi, A. Neuroprotective Effects of Ellagic Acid in a Rat Model of Parkinson’s Disease. Acta Med. Iran. 2016, 54, 494–502. [Google Scholar]
  141. Tian, L.; Wang, X.; Sun, Y.; Li, C.; Xing, Y.; Zhao, H.; Duan, M.; Zhou, Z.; Wang, S. Salvianolic acid B, an antioxidant from Salvia miltiorrhiza, prevents 6-hydroxydopamine induced apoptosis in SH-SY5Y cells. Int. J. Biochem. Cell Biol. 2008, 40, 409–422. [Google Scholar] [CrossRef]
  142. Zhou, J.; Qu, X.; Li, Z.; Ji, W.; Liu, Q.; Ma, Y.; He, J. Salvianolic Acid B Attenuates Toxin-Induced Neuronal Damage via Nrf2-Dependent Glial Cells-Mediated Protective Activity in Parkinson’s Disease Models. PLoS ONE 2014, 9, e101668. [Google Scholar] [CrossRef]
  143. Zhao, R.; Liu, X.; Zhang, L.; Yang, H.; Zhang, Q. Current Progress of Research on Neurodegenerative Diseases of Salvianolic Acid B. Oxid. Med. Cell. Longev. 2019, 2019, 3281260. [Google Scholar] [CrossRef] [PubMed]
  144. Güzelad, O.; Özkan, A.; Parlak, H.; Sinen, O.; Afşar, E.; Öğüt, E.; Yıldırım, F.B.; Bülbül, M.; Ağar, A.; Aslan, M. Protective mechanism of Syringic acid in an experimental model of Parkinson’s disease. Metab. Brain Dis. 2021, 36, 1003–1014. [Google Scholar] [CrossRef] [PubMed]
  145. Ogut, E.; Armagan, K.; Gül, Z. The role of syringic acid as a neuroprotective agent for neurodegenerative disorders and future expectations. Metab. Brain Dis. 2022, 37, 859–880. [Google Scholar] [CrossRef] [PubMed]
  146. Cheemanapalli, S.; Mopuri, R.; Golla, R.; Anuradha, C.M.; Chitta, S.K. Syringic acid (SA)—A Review of Its Occurrence, Biosynthesis, Pharmacological and Industrial Importance. Biomed. Pharmacother. 2018, 108, 547–557. [Google Scholar] [CrossRef]
  147. Presti-Silva, S.M.; Herlinger, A.L.; Martins-Silva, C.; Pires, R.G.W. Biochemical and behavioral effects of rosmarinic acid treatment in an animal model of Parkinson’s disease induced by MPTP. Behav. Brain Res. 2023, 440, 114257. [Google Scholar] [CrossRef] [PubMed]
  148. Lv, R.; Du, L.; Liu, X.; Zhou, F.; Zhang, Z.; Zhang, L. Rosmarinic acid attenuates inflammatory responses through inhibiting HMGB1/TLR4/NF-κB signaling pathway in a mouse model of Parkinson’s disease. Life Sci. 2019, 223, 158–165. [Google Scholar] [CrossRef]
  149. Cai, G.; Lin, F.; Wu, D.; Lin, C.; Chen, H.; Wei, Y.; Weng, H.; Chen, Z.; Wu, M.; Huang, E.; et al. Rosmarinic Acid Inhibits Mitochondrial Damage by Alleviating Unfolded Protein Response. Front. Pharmacol. 2022, 13, 859978. [Google Scholar] [CrossRef]
  150. War, A.R.; Paulraj, M.G.; Ahmad, T.; Buhroo, A.A.; Hussain, B.; Ignacimuthu, S.; Sharma, H.C. Mechanisms of plant defense against insect herbivores. Plant Signal. Behav. 2012, 7, 1306–1320. [Google Scholar] [CrossRef]
  151. Dehghanian, Z.; Habibi, K.; Dehghanian, M.; Aliyar, S.; Asgari Lajayer, B.; Astatkie, T.; Minkina, T.; Keswani, C. Reinforcing the bulwark: Unravelling the efficient applications of plant phenolics and tannins against environmental stresses. Heliyon 2022, 8, e09094. [Google Scholar] [CrossRef]
  152. Giuliano, C.; Cerri, S.; Blandini, F. Potential therapeutic effects of polyphenols in Parkinson’s disease: In vivo and in vitro pre-clinical studies. Neural Regen. Res. 2021, 16, 234–241. [Google Scholar] [CrossRef]
  153. Huh, E.; Choi, J.G.; Choi, Y.; Ju, I.G.; Noh, D.; Shin, D.; Kim, D.H.; Park, H.; Oh, M.S. 6-Shogaol, an Active Ingredient of Ginger, Improves Intestinal and Brain Abnormalities in Proteus Mirabilis-Induced Parkinson’s Disease Mouse Model. Biomol. Ther. 2023, 31, 417–424. [Google Scholar] [CrossRef] [PubMed]
  154. Ha, S.K.; Moon, E.; Ju, M.S.; Kim, D.H.; Ryu, J.H.; Oh, M.S.; Kim, S.Y. 6-Shogaol, a ginger product, modulates neuroinflammation: A new approach to neuroprotection. Neuropharmacology 2012, 63, 211–223. [Google Scholar] [CrossRef] [PubMed]
  155. Gwon, M.G.; Gu, H.; Leem, J.; Park, K.K. Protective Effects of 6-Shogaol, an Active Compound of Ginger, in a Murine Model of Cisplatin-Induced Acute Kidney Injury. Molecules 2021, 26, 5931. [Google Scholar] [CrossRef] [PubMed]
  156. Sandoval-Avila, S.; Diaz, N.F.; Gómez-Pinedo, U.; Canales-Aguirre, A.A.; Gutiérrez-Mercado, Y.K.; Padilla-Camberos, E.; Marquez-Aguirre, A.L.; Díaz-Martínez, N.E. Neuroprotective effects of phytochemicals on dopaminergic neuron cultures. Neurologia 2019, 34, 114–124. [Google Scholar] [CrossRef]
  157. Angeline, M.S.; Sarkar, A.; Anand, K.; Ambasta, R.K.; Kumar, P. Sesamol and naringenin reverse the effect of rotenone-induced PD rat model. Neuroscience 2013, 254, 379–394. [Google Scholar] [CrossRef]
  158. Singh, N.; Vishwas, S.; Kaur, A.; Kaur, H.; Kakoty, V.; Khursheed, R.; Chaitanya, M.V.N.L.; Babu, M.R.; Awasthi, A.; Corrie, L.; et al. Harnessing role of sesamol and its nanoformulations against neurodegenerative diseases. Biomed. Pharmacother. 2023, 167, 115512. [Google Scholar] [CrossRef]
  159. Bosebabu, B.; Cheruku, S.P.; Chamallamudi, M.R.; Nampoothiri, M.; Shenoy, R.R.; Nandakumar, K.; Parihar, V.K.; Kumar, N. An Appraisal of Current Pharmacological Perspectives of Sesamol: A Review. Mini Rev. Med. Chem. 2020, 20, 988–1000. [Google Scholar] [CrossRef]
  160. Shah, A.; Lobo, R.; Krishnadas, N.; Surubhotla, R. Sesamol and Health—A Comprehensive Review. Indian J. Pharm. Educ. 2019, 53, S28–S42. [Google Scholar] [CrossRef]
  161. Teka, T.; Zhang, L.; Ge, X.; Li, Y.; Han, L.; Yan, X. Stilbenes: Source plants, chemistry, biosynthesis, pharmacology, application and problems related to their clinical Application—A comprehensive review. Phytochemistry 2022, 197, 113128. [Google Scholar] [CrossRef]
  162. El Khawand, T.; Courtois, A.; Valls, J.; Richard, T.; Krisa, S. A review of dietary stilbenes: Sources and bioavailability. Phytochem. Rev. 2018, 17, 1007–1029. [Google Scholar] [CrossRef]
  163. Huang, K.S.; Lin, M. Oligostilbenes from the roots of Vitis amurensis. J. Asian Nat. Prod. Res. 1999, 2, 21–28. [Google Scholar] [CrossRef] [PubMed]
  164. Ryu, H.; Oh, W.K.; Jang, I.; Park, J. Amurensin G induces autophagy and attenuates cellular toxicities in a rotenone model of Parkinson’s disease. Biochem. Biophys. Res. Commun. 2013, 433, 121–126. [Google Scholar] [CrossRef] [PubMed]
  165. Zhang, L.; Dong, M.; Deng, J.; Zhang, C.; Liu, M. Resveratrol exhibits neuroprotection against paraquat-induced PC12 cells via heme oxygenase 1 upregulation by decreasing MiR-136-5p expression. Bioengineered 2022, 13, 7065–7081. [Google Scholar] [CrossRef] [PubMed]
  166. Santos, M.G.D.; Schimith, L.E.; André-Miral, C.; Muccillo-Baisch, A.L.; Arbo, B.D.; Hort, M.A. Neuroprotective Effects of Resveratrol in In vivo and In vitro Experimental Models of Parkinson’s Disease: A Systematic Review. Neurotox. Res. 2022, 40, 319–345. [Google Scholar] [CrossRef]
  167. Nebrisi, E.E. Neuroprotective Activities of Curcumin in Parkinson’s Disease: A Review of the Literature. Int. J. Mol. Sci. 2021, 22, 11248. [Google Scholar] [CrossRef]
  168. Patel, A.; Olang, C.A.; Lewis, G.; Mandalaneni, K.; Anand, N.; Gorantla, V.R. An Overview of Parkinson’s Disease: Curcumin as a Possible Alternative Treatment. Cureus 2022, 14, e25032. [Google Scholar] [CrossRef]
  169. Jin, T.; Zhang, Y.; Botchway, B.O.A.; Zhang, J.; Fan, R.; Zhang, Y.; Liu, X. Curcumin can improve Parkinson’s disease via activating BDNF/PI3k/Akt signaling pathways. Food Chem. Toxicol. 2022, 164, 113091. [Google Scholar] [CrossRef]
  170. Mogharbel, B.F.; Cardoso, M.A.; Irioda, A.C.; Stricker, P.E.F.; Slompo, R.C.; Appel, J.M.; Oliveira, N.B.; Perussolo, M.C.; Saçaki, C.S.; Rosa, N.N.; et al. Biodegradable Nanoparticles Loaded with Levodopa and Curcumin for Treatment of Parkinson’s Disease. Molecules 2022, 27, 2811. [Google Scholar] [CrossRef]
  171. Fikry, H.; Saleh, L.A.; Gawad, S.A. Neuroprotective effects of curcumin on the cerebellum in a rotenone- induced Parkinson’s Disease Model. CNS Neurosci. Ther. 2022, 28, 732–748. [Google Scholar] [CrossRef]
  172. Xu, Y.; Wei, H.; Gao, J. Natural Terpenoids as Neuroinflammatory Inhibitors in LPS-stimulated BV-2 Microglia. Mini Rev. Med. Chem. 2021, 21, 520–534. [Google Scholar] [CrossRef]
  173. Del Prado-Audelo, M.L.; Cortés, H.; Caballero-Florán, I.H.; González-Torres, M.; Escutia-Guadarrama, L.; Bernal-Chávez, S.A.; Giraldo-Gomez, D.M.; Magaña, J.J.; Leyva-Gómez, G. Therapeutic Applications of Terpenes on Inflammatory Diseases. Front. Pharmacol. 2021, 12, 704197. [Google Scholar] [CrossRef] [PubMed]
  174. González-Burgos, E.; Gómez-Serranillos, M.P. Terpene compounds in nature: A review of their potential antioxidant activity. Curr. Med. Chem. 2012, 19, 5319–5341. [Google Scholar] [CrossRef] [PubMed]
  175. Masyita, A.; Sari, R.M.; Astuti, A.D.; Yasir, B.; Rumata, N.R.; Emran, T.B.; Nainu, F.; Simal-Gandaraf, J. Terpenes and terpenoids as main bioactive compounds of essential oils, their roles in human health and potential application as natural food preservatives. Food Chem. X 2022, 13, 100217. [Google Scholar] [CrossRef] [PubMed]
  176. Wu, C.; Tsai, C.; Chang, S.; Lin, C.; Huang, L.; Tsai, C. Carnosic acid protects against 6-hydroxydopamine-induced neurotoxicity in in vivo and in vitro model of Parkinson’s disease: Involvement of antioxidative enzymes induction. Chem. Biol. Interact. 2015, 225, 40–46. [Google Scholar] [CrossRef] [PubMed]
  177. Lai, C.Y.; Lin, C.Y.; Wu, C.R.; Tsai, C.H.; Tsai, C.W. Carnosic Acid Alleviates Levodopa-Induced Dyskinesia and Cell Death in 6-Hydroxydopamine-lesioned Rats and in SH-SY5Y Cells. Front. Pharmacol. 2021, 12, 703894. [Google Scholar] [CrossRef]
  178. Mirza, F.J.; Zahid, S.; Holsinger, R.M.D. Neuroprotective Effects of Carnosic Acid: Insight into Its Mechanisms of Action. Molecules 2023, 28, 2306. [Google Scholar] [CrossRef]
  179. Jiang, Y.; Liu, Y.; Ding, C.; Feng, X. Protective Effect of Ginkgolide B on Dopaminergic Neurons and Expression of Neuroinflammatory Factors in 6-OHDA-Induced Parkinson’s Disease Mice. J. Biomater. Tissue Eng. 2020, 10, 1312–1317. [Google Scholar] [CrossRef]
  180. Yin, J.; Miao, Q.; Wang, Q.; Huang, J.; Xiao, B.; Ma, C. The protective effect of Ginkgolide B on MPTP-induced Parkinson mice. J. Neurol. Sci. 2021, 429, 119481. [Google Scholar] [CrossRef]
  181. Zhao, Y.; Xiong, S.; Liu, P.; Liu, W.; Wang, Q.; Liu, Y.; Tan, H.; Chen, X.; Shi, X.; Wang, Q.; et al. Polymeric Nanoparticles-Based Brain Delivery with Improved Therapeutic Efficacy of Ginkgolide B in Parkinson’s Disease. Int. J. Nanomed. 2020, 15, 10453–10467. [Google Scholar] [CrossRef]
  182. Nabavi, S.M.; Habtemariam, S.; Daglia, M.; Braidy, N.; Loizzo, M.R.; Tundis, R.; Nabavi, S.F. Neuroprotective Effects of Ginkgolide B Against Ischemic Stroke: A Review of Current Literature. Curr. Top. Med. Chem. 2015, 15, 2222–2232. [Google Scholar] [CrossRef]
  183. Gachowska, M.; Szlasa, W.; Saczko, J.; Kulbacka, J. Neuroregulatory role of ginkgolides. Mol. Biol. Rep. 2021, 48, 5689–5697. [Google Scholar] [CrossRef] [PubMed]
  184. Xia, S.; Fang, D. Pharmacological action and mechanisms of ginkgolide B. Chin. Med. J. 2007, 120, 922–928. [Google Scholar] [CrossRef] [PubMed]
  185. Shi, J.; Li, J.; Xu, Z.; Chen, L.; Luo, R.; Zhang, C.; Gao, F.; Zhang, J.; Fu, C. Celastrol: A Review of Useful Strategies Overcoming its Limitation in Anticancer Application. Front. Pharmacol. 2020, 11, 558741. [Google Scholar] [CrossRef] [PubMed]
  186. Lin, M.; Lin, C.C.; Chen, Y.; Yang, H.; Hung, S. Celastrol Inhibits Dopaminergic Neuronal Death of Parkinson’s Disease through Activating Mitophagy. Antioxidants 2019, 9, 37. [Google Scholar] [CrossRef] [PubMed]
  187. Cui, Y.; Jiang, X.; Feng, J. The therapeutic potential of triptolide and celastrol in neurological diseases. Front. Pharmacol. 2022, 13, 1024955. [Google Scholar] [CrossRef]
  188. Bai, X.; Fu, R.; Zhang, S.; Yue, S.; Chen, Y.; Xu, D.; Tang, Y. Potential medicinal value of celastrol and its synthesized analogues for central nervous system diseases. Biomed. Pharmacother. 2021, 139, 111551. [Google Scholar] [CrossRef]
  189. Mosquera, M.E.G.; Jiménez, G.; Tabernero, V.; Vinueza-Vaca, J.; García-Estrada, C.; Kosalková, K.; Sola-Landa, A.; Monje, B.; Acosta, C.; Alonso, R.; et al. Terpenes and Terpenoids: Building Blocks to Produce Biopolymers. Sustain. Chem. 2021, 2, 467–492. [Google Scholar] [CrossRef]
  190. Souza, M.T.S.; Almeida, J.R.G.S.; Araujo, A.A.S.; Duarte, M.C.; Gelain, D.P.; Moreira, J.C.F.; Santos, M.R.V.; Quintans-Júnior, L.J. Structure–activity relationship of terpenes with anti-inflammatory profile- a systematic review. Basic Clin. Pharmacol. Toxicol. 2014, 115, 244–256. [Google Scholar] [CrossRef]
  191. Zhang, W.; Song, J.; Yan, R.; Li, L.; Xiao, Z.; Zhou, W.; Wang, Z.; Xiao, W.; Du, G. Diterpene ginkgolides protect against cerebral ischemia/reperfusion damage in rats by activating Nrf2 and CREB through PI3K/Akt signaling. Acta Pharmacol. Sin. 2018, 39, 1259–1272. [Google Scholar] [CrossRef]
  192. Moratilla-Rivera, I.; Sánchez, M.; Valdés-González, J.A.; Gómez-Serranillos, M.P. Natural Products as Modulators of Nrf2 Signaling Pathway in Neuroprotection. Int. J. Mol. Sci. 2023, 24, 3748. [Google Scholar] [CrossRef]
  193. Wang, L.; Lei, Q.; Zhao, S.; Xu, W.J.; Dong, W.; Ran, J.H.; Shi, Q.H.; Fu, J.F. Ginkgolide B Maintains Calcium Homeostasis in Hypoxic Hippocampal Neurons by Inhibiting Calcium Influx and Intracellular Calcium Release. Front. Cell. Neurosci. 2021, 14, 627846. [Google Scholar] [CrossRef] [PubMed]
  194. Akkol, E.K.; Çankaya, I.T.; Karatoprak, G.S.; Carpar, E.; Sobarzo-Sánchez, E.; Capasso, R. Natural Compounds as Medical Strategies in the Prevention and Treatment of Psychiatric Disorders Seen in Neurological Diseases. Front. Pharmacol. 2021, 12, 669638. [Google Scholar] [CrossRef] [PubMed]
  195. Bhambhani, S.; Kondhare, K.R.; Giri, A.P. Diversity in Chemical Structures and Biological Properties of Plant Alkaloids. Molecules 2021, 26, 3374. [Google Scholar] [CrossRef]
  196. Omar, F.; Tareq, A.M.; Alqahtani, A.M.; Dhama, K.; Sayeed, M.A.; Emran, T.B.; Simal-Gandara, J. Plant-Based Indole Alkaloids: A Comprehensive Overview from a Pharmacological Perspective. Molecules 2021, 26, 2297. [Google Scholar] [CrossRef] [PubMed]
  197. Hussain, G.; Rasul, A.; Anwar, H.; Aziz, N.; Razzaq, A.; Wei, W.; Ali, M.; Li, J.; Li, X. Role of Plant Derived Alkaloids and Their Mechanism in Neurodegenerative Disorders. Int. J. Biol. Sci. 2018, 14, 341–357. [Google Scholar] [CrossRef] [PubMed]
  198. Kempste, P.; Ma, A. Parkinson’s disease, dopaminergic drugs and the plant world. Front. Pharmacol. 2022, 13, 970714. [Google Scholar] [CrossRef] [PubMed]
  199. Aryal, B.; Raut, B.K.; Bhattarai, S.; Bhandari, S.; Tandan, P.; Gyawali, K.; Sharma, K.; Ranabhat, D.; Thapa, R.; Aryal, D.; et al. Potential Therapeutic Applications of Plant-Derived Alkaloids against Inflammatory and Neurodegenerative Diseases. Evid.-Based Complement. Altern. Med. 2022, 2022, 7299778. [Google Scholar] [CrossRef]
  200. Kong, Y.R.; Tay, K.C.; Su, Y.X.; Wong, C.K.; Tan, W.N.; Khaw, K.Y. Potential of Naturally Derived Alkaloids as Multi-Targeted Therapeutic Agents for Neurodegenerative Diseases. Molecules 2021, 26, 728. [Google Scholar] [CrossRef]
  201. Kabuto, H.; Yamanushi, T.T. Effects of zingerone [4-(4-hydroxy-3-methoxyphenyl)-2-butanone] and eugenol [2-methoxy-4-(2-propenyl) phenol] on the pathological progress in the 6-hydroxydopamine-induced Parkinson’s disease mouse model. Neurochem. Res. 2011, 36, 2244–2249. [Google Scholar] [CrossRef]
  202. Kabuto, H.; Nishizawa, M.; Tada, M.; Higashio, C.; Shishibori, T.; Kohno, M. Zingerone [4-(4-hydroxy-3-methoxyphenyl)-2-butanone] prevents 6-hydroxydopamine-induced dopamine depression in mouse striatum and increases superoxide scavenging activity in serum. Neurochem. Res. 2005, 30, 325–332. [Google Scholar] [CrossRef]
  203. Saraiva, A.A.; Silva, J.P.O.D.; Sousa, J.V.M.; Brandim, A.D. Molecular Docking of Zingerone and Gamma-Mangostin to Inhibit MAO-B and Catechol-O-Methyltransferase (COMT) in the Treatment of Parkinson’s Disease. Res. Soc. Dev. 2022, 11, e189111637853. [Google Scholar] [CrossRef]
  204. Rashid, S.; Wali, A.F.; Rashid, S.M.; Alsaffar, R.M.; Ahmad, A.; Jan, B.L.; Paray, B.A.; Alqahtani, S.M.A.; Arafah, A.; Rehman, M.U. Zingerone Targets Status Epilepticus by Blocking Hippocampal Neurodegeneration via Regulation of Redox Imbalance, Inflammation and Apoptosis. Pharmaceuticals 2021, 14, 146. [Google Scholar] [CrossRef] [PubMed]
  205. Ahmad, B.; Rehman, M.U.; Amin, I.; Arif, A.; Rasool, S.; Bhat, S.A.; Afzal, I.; Hussain, I.; Bilal, S.; Mir, M.R. A Review on Pharmacological Properties of Zingerone (4-(4-Hydroxy-3-methoxyphenyl)-2-butanone). Sci. World J. 2015, 2015, 816364. [Google Scholar] [CrossRef]
  206. Fu, R.; Wang, Y.; Chen, C.; Tsai, R.; Liu, S.; Chang, W.; Lin, H.; Lu, C.; Wei, J.; Wang, Z.; et al. Acetylcorynoline attenuates dopaminergic neuron degeneration and α-synuclein aggregation in animal models of Parkinson’s disease. Neuropharmacology 2014, 82, 108–120. [Google Scholar] [CrossRef] [PubMed]
  207. Han, N.; Yang, Z.; Liu, Z.; Liu, H.; Yin, J. Research Progress on Natural Benzophenanthridine Alkaloids and their Pharmacological Functions: A Review. Nat. Prod. Commun. 2016, 11, 1181–1188. [Google Scholar] [CrossRef]
  208. Charlton, N.C.; Mastyugin, M.; Török, B.; Török, M. Structural Features of Small Molecule Antioxidants and Strategic Modifications to Improve Potential Bioactivity. Molecules 2023, 28, 1057. [Google Scholar] [CrossRef]
  209. Zhang, Y.; Yang, Y.; Yang, X. Blood-brain barrier permeability and neuroprotective effects of three main alkaloids from the fruits of Euodia rutaecarpa with MDCK-pHaMDR cell monolayer and PC12 cell line. Biomed. Pharmacother. 2018, 98, 82–87. [Google Scholar] [CrossRef]
  210. Li, J.; Wu, Y.; Dong, S.; Yu, Y.; Wu, Y.; Xiang, B.; Li, Q. Research Progress on Neuroprotective Effects of Isoquinoline Alkaloids. Molecules 2023, 28, 4797. [Google Scholar] [CrossRef]
  211. Xiao, X.; Tong, Z.; Zhang, Y.; Zhou, H.; Luo, M.; Hu, T.; Hu, P.; Kong, L.; Liu, Z.; Yu, C.; et al. Novel Prenylated Indole Alkaloids with Neuroprotection on SH-SY5Y Cells against Oxidative Stress Targeting Keap1–Nrf2. Mar. Drugs 2022, 20, 191. [Google Scholar] [CrossRef]
  212. Kongkiatpaiboon, S.; Duangdee, N.; Prateeptongkum, S.; Chaijaroenkul, W. Acetylcholinesterase Inhibitory Activity of Alkaloids Isolated from Stephania venosa. Nat. Prod. Commun. 2016, 11, 1805–1806. [Google Scholar] [CrossRef]
  213. Nishal, S.; Phaugat, P.; Bazaad, J.; Dhaka, R.; Khatkar, S.; Khatkar, A.; Khayatkashani, M.; Alizadeh, P.; Haghighi, S.M.; Mehri, M.; et al. A Concise Review of Common Plant-derived Compounds as a Potential Therapy for Alzheimer’s Disease and Parkinson’s Disease: Insight into Structure-Activity-Relationship. CNS Neurol. Disord. Drug Targets 2023, 22, 1057–1069. [Google Scholar] [CrossRef] [PubMed]
  214. Bhusal, C.K.; Uti, D.E.; Mukherjee, D.; Alqahtani, T.; Alqahtani, S.; Bhattacharya, A.; Akash, S. Unveiling Nature’s potential: Promising natural compounds in Parkinson’s disease management. Park. Relat. Disord. 2023, 10, 105799. [Google Scholar] [CrossRef] [PubMed]
  215. Baburaj, R.; Kuntal, D.A. Neuroprotective role of a protoberberine alkaloid against aluminium-induced neuroinflammation and excitotoxicity. Not. Sci. Biol. 2023, 15, 11488. [Google Scholar] [CrossRef]
Figure 1. The diverse nature of various motor and non-motor symptoms affecting Parkinson’s disease (PD) patients (adapted from [24,27]).
Figure 1. The diverse nature of various motor and non-motor symptoms affecting Parkinson’s disease (PD) patients (adapted from [24,27]).
Molecules 28 07588 g001
Figure 2. Toxicological model for pharmacological screening of investigated molecules against PD [31,32].
Figure 2. Toxicological model for pharmacological screening of investigated molecules against PD [31,32].
Molecules 28 07588 g002
Figure 3. Different types of flavonoids.
Figure 3. Different types of flavonoids.
Molecules 28 07588 g003
Figure 4. (A) Phenolic acids—hydroxycinnamic acid. (B) Phenolic acids—hydroxybenzoic acid.
Figure 4. (A) Phenolic acids—hydroxycinnamic acid. (B) Phenolic acids—hydroxybenzoic acid.
Molecules 28 07588 g004aMolecules 28 07588 g004b
Figure 5. Natural stilbene—resveratrol.
Figure 5. Natural stilbene—resveratrol.
Molecules 28 07588 g005
Figure 6. Curcumin.
Figure 6. Curcumin.
Molecules 28 07588 g006
Figure 7. Structures of various terpenes.
Figure 7. Structures of various terpenes.
Molecules 28 07588 g007
Figure 8. Zingerone.
Figure 8. Zingerone.
Molecules 28 07588 g008
Table 1. Notable medicinal plants or herbal formulation investigated for management of PD in the last five years (2019–2023).
Table 1. Notable medicinal plants or herbal formulation investigated for management of PD in the last five years (2019–2023).
Name of Extract or FormulationDoseStudy ModelMechanism of Action
Acanthopanax senticosus extract4.5 g/kgMPTP-induced miceRegulated multiple targets to improve motor deficits [40].
Antrodia comphorata10–50 mmol/L (in vitro); 10, 50, and 100 mg/kg (in vivo)6-OHDA induced MES23.5 cells and C57BL/6 miceDownregulate NLRP3, ASC, IL-1β, caspase-1, and ROS and upregulate dopaminergic neuron protection [41,42].
Asarum sieboldii5 μMOlfactory cell line (hONS)Induced significant perturbation on biological organelles [43].
Cervus nippon (Velvet antler from sika deer)20–40 μg/mL and 30 mg/kgIn vitro (BV2 cells), Caenorhabditis elegans, and MPTP-treated miceDecreased aggregation of α-synuclein and protect from oxidative stress-induced DAergic neuron degeneration [44].
Codium tomentosum enriched fractions100 µg/mL6-OHDA-induced SH-SY5Y human cellsMitigation of ROS generation, mitochondrial dysfunctions, and DNA damage followed by reduction in Caspase-3 activity [45].
Crossyne flava2.5, 5, and 10 µg/mLMPP+-induced SH-SY5Y cells.Inhibited ROS and ATP depletion followed by induction of apoptosis [46].
Ganoderma lucidum extract800 μg/mL and 400 mg/kg Neuro-2a cells and mouse modelRegulating autophagy, mitochondrial function, and apoptosis [47].
Geranium robertianum aqueous extract0–200 µg/mLMPP+-induced SH-SY5Y Antioxidant and apoptosis inhibitory properties [48].
Hidrox® with Hydroxytyrosol10 mg/kg, i.p.Rotenone induced miceImproves neuroinflammation, oxidative stress, and apoptosis [49].
Liuwei Dihuang Pills (enriched with quercetin, stigmasterol, kaempferol, and β-sitosterol)Not availableNetwork pharmacology (in silico)Regulates AKT1, VEGFA, and IL6, G protein-coupled amine receptor activity, ROS, membrane raft, MAPK signaling pathway, and cellular senescence [50].
Myrica esculenta leaves methanol extract50, 100, and 200 mg/kg, orally for one weekHaloperidol-induced ratsEscalation of cellular antioxidants [51].
Polyscias fruticosa leaves extract1, 2, 4, 8, and 16 mg/mLDrosophila melanogaster model (dUCH knockdown)Ameliorate dopaminergic neuron degeneration [52].
Sphaerocoryne affinis fruit water extract3, 6, 12, and 18 mg/mL.DPPH and fly modelAmeliorate the locomotor disabilities and degeneration of dopaminergic neurons [53].
Table 2. Plant-based bioactives (polyphenols, terpenes, and alkaloids) in the management of PD.
Table 2. Plant-based bioactives (polyphenols, terpenes, and alkaloids) in the management of PD.
CompoundsBotanical SourcesDoseStudy ModelMechanism of Action
Polyphenols
QuercetinOnions, apples, tea, brassica vegetables, and nuts30 mg/kg for 30 daysAcrolein (3 mg/kg for 30 days) induced ratsProtects cerebellum tissues from neurotoxicity and oxidative stress [54].
ApigeninGrape fruit, parsley, celery, and oranges50 mg/kg apigenin, 5 daysMPTP (25 mg/kg for 5 days) induced mouse Reverses the expressions and concentrations of TNF-α, IL-1β, IL-6, IL-10, and TGF-β [55].
Chlorogenic acidCoffee (Coffea arabica)1, 5, 10, 20, 40, and 100 µg/mL (in vitro); 50 mg/kg, orally for 13 weeks (in vivo).In silico, in vitro (GLUTag cell line), and in vivo (rotenone-induced PD mice).Acts as GLP-1 secretagogue [56].
Coffee, honeysuckle, and Eucommia75, 150, and 300 μMMPTP zebrafish (6-OHDA-treated SHSY5Y cells).Boosting the autophagy in neuronal cells [57].
HydroxytyrosolExtra virgin olive oil 250 µg/mLC. elegans models Improvements in locomotive behavior and the attenuation of autofluorescence [58].
Virgin olive oil1, 10, 25, and 50 μMMurine microglial BV2 cell lineMicroglial activation, expression of NADPH oxidase, MAPKs, and production of ROS [59].
Extra virgin olive oil 0.1–200 µM (in vitro) and 50 mg/kg (in vivo).In silico, in vitro (platelet MAO-B activity) and MPTP-induced mouse modelMAO-B inhibition (IC50: 7.78 μM), improved DA and motor impairments [60].
Methanol extract of Buddleja cordata and extra virgin olive oil1.5 mg/kgMPP+ induced ratsInhibitory effect on the MAO isoforms (MAO A and MAO B) [61].
Micellar nanocarriers10–200 μMIn vitro (hCMEC/D3-SH-SY5Y) cells (rotenone)Improves oxidative stress by 12% and 9%, respectively, compared to the corresponding free drug [62].
Schisandrin BSchisandra chinensis100 μM6-OHDA-induced SH-SY5Y cells and miceInhibitis the negative modulation of miR-34a on Nrf2 pathway [63].
Ginkgolic acidGinkgo biloba leaves10, 40, and 80 μMKCl-induced SH-SY5Y cellsPromotes autophagy-dependent clearance of α-syn aggregates [64].
Pinocembrin-7-methyletherPigeon pea, thai ginger, honey, and propolisUp to 200 μM6-OHDA-induced SH-SY5Y cells and zebrafshActivation of Nrf2/ARE/HO-1 signaling cascades [65].
ChrysinPassion flowers (Oroxylum indicum, Passiflora incarnata and Passiflora caerulea), Scutellaria baicalensis, mushrooms, bee propolis, and honeyUp to 500 mg/kgIn various in vitro and in vivo modelsIncreasing the expression of Nrf2, activates MEF2D, suppresses the MPP-induced upregulation of c-caspase and Bax, as well as the downregulation of anti-apoptotic protein Bcl 2. Additionally, enhances the production of neurotrophic factors and increase dopamine levels in the striatum via MAO-B [66].
VanillinNatural vanilla 100, 200, 300, 400, and 500 nM (in vitro) and 5, 10, or 20 mg/kg (in vivo)LPS-induced murine microglial BV-2 cells and ratsReduces over expression of iNOS, COX-2, IL-1β, and IL-6 through regulating ERK1/2, p38 and NF-κB signaling [67].
Ferulic acidRhizoma Ligustici wallichii, Angelica sinensis, and Asafoetida giantfennel50 μM6-OHDA-induced C. elegans modelsAutophagy induction [68].
HeptamethoxyflavoneOrange and grapefruit3–10 µM (in vitro) and 1.2–100 mg/kg (in vivo)In various in vitro and in vivo modelsRegulates IL-1β expression and suppresses MK-801-induced locomotive hyperactivity [69].
Kaempferitrin Cinnamomum osmophloeum25 µM (in vitro) and 2–5 mg/kg (in vivo)In various in vitro and in vivo modelsPrevents H2O2-induced oxidative stress [69].
Vitexin Hawthorn, pearl millet, mung bean, pigeon pea, mosses and tartary buckwheat sprouts10–50 µM (in vitro) and 1–100 mg/kg (in vivo)In various in vitro and in vivo modelsRegulates PI3/AKT, mTOR pathway; enhanced effect of TPv1 and NR2B pathway, suppresses CDPK II, prevents lipid peroxidation by TBHP; and inhibits effect of CYP2C11 and CYP3A1 [69].
AmentoflavoneCnestis ferruginea, Hypericum perforatum, Viburnum and Ginkgo species.0.1–60 µM (in vitro) and 0.1–100 µg/mL (in vivo)In various in vitro and in vivo modelsInhibits COX and phospholipase A2, activate p38-AKT signaling pathway and inhibits production of prostaglandins E2 [69].
MangiferinSwertia minor and Mangifera pajangUp to 100 mg/kgIn various in vitro and in vivo modelsCounteracts the neurotoxic effect of MPTP, rotenone, and 6-OHDA, etc. [70].
MyricetinMyrica nagiUp to 100 mg/kgIn various in vitro and in vivo modelsProtective effect against amyloid-beta, MPTP, rotenone, and 6-OHDA, etc. [71].
Terpenes
Asiatic acidCentella asiatica10–100 nMLPS-induced BV2 microglia cells and MPP+-induced SH-SY5Y cells,Protects dopaminergic neurons from neuroinflammation by suppressing NLRP3 inflammasome activation in microglia cells as well as protecting dopaminergic neurons directly [72].
PaeoniflorinHerbaceous peony30 mg/kgNetwork pharmacology and MPTP-induced mice Inhibits apoptosis in hippocampal neurons of the CA1 and CA3, and upregulates PSD-95 as well as SYN protein levels. Similar protective effects were observed upon JNK/p53 pathway inhibition using SP600125 [73].
MadecassosideCentella asiatica15, 30, 60 mg/kgMPTP-induced ratsReversing the depletion of DA, antioxidant activity, increasing ratio of Bcl-2/Bax, increasing protein expression of BDNF [74].
LoganinCornus officinalis fruits50 mg/kgMPTP-induced miceReduce inflammation, autophagy, and apoptosis [75].
Perillyl alcoholMentha haplocalyx200 µMLPS and MPTP induced in vitro and in vivo studyAttenuates NLRP3 inflammasome activation and rescues dopaminergic neurons [76].
Alkaloids
2-(Quinoline-8-carboxamido) benzoic acidAspergillus sp.Various doseMPP+-induced Caenorhabditis elegansModulates the formation of neurotoxic α-synuclein ameliorated induced dopaminergic neurodegeneration [77].
Melodicochine AStems and leaves of Melodinus cochinchinensis0.72 to 17.89 μM6-hydroxydopamine-induced SH-SY5Y cells Neuroprotection [78].
BerberineCoptis chinensis and Berberis vulgaris100–200 mg/kgMice and bacteriaImproves brain dopa/dopamine levels [79].
Caffeine (1,3,7-trimethylxanthin)Seeds and leaves of coffee (Coffea arabica), tea (Camellia sinensis) and cocoa (Theobroma cacao L.)20 mg/kg (varied dose)In various in vitro and in vivo modelsExhibits antioxidant properties and inhibits lipid peroxidation [80].
LycopodiumLycopodiaceae plants50 mg/kgRotenone-induced ratReduction in pro-inflammatory response and α-synuclein expression. Also, synergistically enhances antioxidant defense via multimodal action [81].
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Kumari, N.; Anand, S.; Shah, K.; Chauhan, N.S.; Sethiya, N.K.; Singhal, M. Emerging Role of Plant-Based Bioactive Compounds as Therapeutics in Parkinson’s Disease. Molecules 2023, 28, 7588. https://doi.org/10.3390/molecules28227588

AMA Style

Kumari N, Anand S, Shah K, Chauhan NS, Sethiya NK, Singhal M. Emerging Role of Plant-Based Bioactive Compounds as Therapeutics in Parkinson’s Disease. Molecules. 2023; 28(22):7588. https://doi.org/10.3390/molecules28227588

Chicago/Turabian Style

Kumari, Nitu, Santosh Anand, Kamal Shah, Nagendra Singh Chauhan, Neeraj K. Sethiya, and Manmohan Singhal. 2023. "Emerging Role of Plant-Based Bioactive Compounds as Therapeutics in Parkinson’s Disease" Molecules 28, no. 22: 7588. https://doi.org/10.3390/molecules28227588

Article Metrics

Back to TopTop