Impact of Natural Compounds on Neurodegenerative Disorders: From Preclinical to Pharmacotherapeutics.

Among the major neurodegenerative disorders (NDDs), Alzheimer's disease (AD) and Parkinson's disease (PD), are a huge socioeconomic burden. Over many centuries, people have sought a cure for NDDs from the natural herbals. Many medicinal plants and their secondary metabolites are reported with the ability to alleviate the symptoms of NDDs. The major mechanisms identified, through which phytochemicals exert their neuroprotective effects and potential maintenance of neurological health in ageing, include antioxidant, anti-inflammatory, antithrombotic, antiapoptotic, acetylcholinesterase and monoamine oxidase inhibition and neurotrophic activities. This article review the mechanisms of action of some of the major herbal products with potential in the treatment of NDDs according to their molecular targets, as well as their regional sources (Asia, America and Africa). A number of studies demonstrated the beneficial properties of plant extracts or their bioactive compounds against NDDs. Herbal products may potentially offer new treatment options for patients with NDDs, which is a cheaper and culturally suitable alternative to conventional therapies for millions of people in the world with age-related NDDs.


Results and Discussion
The initial search identified 1826 publications on the topic, 28 studies were excluded at this stage, as they were not published in English. Checking the list, the human studies were excluded, that represented 535 studies, and, subsequently, 1263 potential eligible studies were considered. 41 studies based on their design and 1000 studies based on the relevance to the subject, respectively. Following abstract evaluation, 222 studies in full text, were analyzed. Of the 222 studies that were analyzed, 69 were finally included in the review. The selection procedure was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow chart [2] ( Figure 1).

Background
Man's reliance on nature for treating illness predates recorded history, and the plant kingdom is one of the most important sources of medicines [3][4][5][6][7][8][9]. The medicinal properties of plants are mostly ascribed to secondary phytochemical metabolites [10]. Secondary metabolites, also known as natural products, refer to small-molecule organic compounds that are not directly involved in growth and development, but play an adaptive role in aiding the survival of the organism [11][12][13][14][15]. Secondary

Background
Man's reliance on nature for treating illness predates recorded history, and the plant kingdom is one of the most important sources of medicines [3][4][5][6][7][8][9]. The medicinal properties of plants are mostly ascribed to secondary phytochemical metabolites [10]. Secondary metabolites, also known as natural products, refer to small-molecule organic compounds that are not directly involved in growth and development, but play an adaptive role in aiding the survival of the organism [11][12][13][14][15]. Secondary metabolites are categorized into a number of compound classes, including terpenoids, alkaloids and phenylpropanoids and allied phenolic compounds, depending on their biosynthetic origins [11], or are broadly classified as nitrogen-containing or non-nitrogen-containing metabolites [10] ( Figure 2). metabolites are categorized into a number of compound classes, including terpenoids, alkaloids and phenylpropanoids and allied phenolic compounds, depending on their biosynthetic origins [11], or are broadly classified as nitrogen-containing or non-nitrogen-containing metabolites [10] (Figure 2). Current evidence supports the applicability of natural compounds in human health, and their high diversity makes secondary metabolites a valuable source of novel drugs [16]. In fact, there is a growing interest in the potential use of secondary metabolites to prevent and manage NDDs. Some secondary metabolites may play protective roles in NDDs, including-but not limited toneuroprotection from excitotoxicity, oxidative and ER stress, neuroinflammation and the prevention of proteinopathies [17,18].

Ethnopharmacological Relevance of Natural Compounds for NDDs
Historical documents revealed that herbal therapies to treat NDDs date back to 6000 B.C. in India (Ayurvedic medicine), China, Africa and in Pre-Columbian America, especially with the Incas and the Aztecs [19]. Traditional herbal therapies still play an important role in the treatment of NDDs today. The Food and Drug Administration (FDA) consider herbal therapies as dietary supplements, rather than drugs. Complementary and alternative medicine (CAM) for NDDs have been widely used in most cultures. The National Institutes of Health National Center of Complementary and Alternative Medicine (NIH-NCCAM) defines CAM therapies as healthcare and medical practices that are not an integral part of conventional medicine as practiced in the west [20].
Herbal medicine is commonly used in Africa and up to 80% of the population uses traditional medicines as treatment [21]. In 2006, scientists predicted that the prevalence of NDDs in Sub-Saharan Africa was 2-to 3-fold higher than in developed countries [22]. In Africa, NDDs have a severe social impact, and patients face discrimination in education and employment [23]. Herbal drugs used for the treatment of NDDs included: Alchornea laxiflora, Acanthusmontanus, Ficus platyphylla, Sutherlandia Frutescens, Gladiolus dalenii, Voacanga africana [24].
In America, the pre-Columbian cultures, particularly Incas and Aztecs, have used more than 1500 plants to treat NDDs according to Spanish chroniclers [25]. The Aztec herbal textbook, "The Libellus de Medicinalibus Indorum Herbis" described the herbal treatments of NDDs and several plants were listed, such as Bidenspilosa, Plucheaodorata, Lobelia laxiflora, Cassia occidentalis, Iresinecalea, Erythrina coralloides and Luffa operculate [25,26]. In contemporary America, the herbal therapies are used in complementary or alternative medicine for many diseases and one in three patients with NDDs use herbal therapies. The most frequently used plant species for the treatment of NDDs in the Current evidence supports the applicability of natural compounds in human health, and their high diversity makes secondary metabolites a valuable source of novel drugs [16]. In fact, there is a growing interest in the potential use of secondary metabolites to prevent and manage NDDs. Some secondary metabolites may play protective roles in NDDs, including-but not limited to-neuroprotection from excitotoxicity, oxidative and ER stress, neuroinflammation and the prevention of proteinopathies [17,18].

Ethnopharmacological Relevance of Natural Compounds for NDDs
Historical documents revealed that herbal therapies to treat NDDs date back to 6000 B.C. in India (Ayurvedic medicine), China, Africa and in Pre-Columbian America, especially with the Incas and the Aztecs [19]. Traditional herbal therapies still play an important role in the treatment of NDDs today. The Food and Drug Administration (FDA) consider herbal therapies as dietary supplements, rather than drugs. Complementary and alternative medicine (CAM) for NDDs have been widely used in most cultures. The National Institutes of Health National Center of Complementary and Alternative Medicine (NIH-NCCAM) defines CAM therapies as healthcare and medical practices that are not an integral part of conventional medicine as practiced in the west [20].
Herbal medicine is commonly used in Africa and up to 80% of the population uses traditional medicines as treatment [21]. In 2006, scientists predicted that the prevalence of NDDs in Sub-Saharan Africa was 2-to 3-fold higher than in developed countries [22]. In Africa, NDDs have a severe social impact, and patients face discrimination in education and employment [23]. Herbal drugs used for the treatment of NDDs included: Alchornea laxiflora, Acanthusmontanus, Ficus platyphylla, Sutherlandia Frutescens, Gladiolus dalenii, Voacanga africana [24].
In America, the pre-Columbian cultures, particularly Incas and Aztecs, have used more than 1500 plants to treat NDDs according to Spanish chroniclers [25]. The Aztec herbal textbook, "The Libellus de Medicinalibus Indorum Herbis" described the herbal treatments of NDDs and several plants were listed, such as Bidenspilosa, Plucheaodorata, Lobelia laxiflora, Cassia occidentalis, Iresinecalea, Erythrina coralloides and Luffa operculate [25,26]. In contemporary America, the herbal therapies are used in complementary or alternative medicine for many diseases and one in three patients with NDDs use herbal therapies. The most frequently used plant species for the treatment of NDDs in the United States are St. John's wort (Hypericum perforatum), ginkgo (Ginkgo biloba), garlic (Allium sativum), black cohosh (Actaearacemosa), soy (Glycine max) and kava (Piper methysticum) [27].
In Asia, traditional Chinese medicine has a long history and recorded the use of herbal medicine in the treatment of NDDs. "The Yellow Emperor's Classic of Internal Medicine" mentioned for the first time [28]. Chinese physicians believed that the balance between specific energies of the world; Yin and Yang determine the stability of the person's health. If the balance is disturbed, NDDs will be manifested eventually [29]. For this reason, physicians worked to stabilize the balance between YIN and YANG by using herbs or acupuncture. The most preferred herbs are Ginkgo biloba, Panax, Ganoderma lucidum, Salvia miltiorrhiza, Uncaria rhynchophylla and Zingibe rofficinale [30]. The Indian medical system, Ayurveda (4500-1500 B.C.) "science of life", is the oldest medical reference in the world [31]. In the Ayurvedic system, mechanisms within the human body were categorized by physiological and physicochemical activities and related to disease, including NDDs. Various herbal formulations are mentioned, including the amount of each component and the method of preparation [32]. The contents of these preparations include gandhaka (sulfur), butter oil and plants: Ficus carica, Achythesaspena, Alstonia scholaris, Holanthena antidysenterica. Some mixtures of herbal formulations, such as Pancarnula and Triphala ahave are included [33].
These ethnopharmacological uses of plants have guided scientific investigation for a large number of plant species, and has led to the identification of thousands of secondary metabolites, with desirable biological properties, including antioxidant, antimicrobial [34,35], anticancer [36,37], antidiabetic [38], anti-inflammatory [39] and neuroprotective properties [40].

Pharmacological Activities of Plants Secondary Metabolites on Neurodegenerative Disorders (NDDs): in vitro and in vivo Studies.
Recent studies have revealed that polyphenolic compounds, including flavonoids, phenolic acids and stilbenes; alkaloids, carotenoids, catechins and terpenes have great potential in treating NDDs (Table 1). Secondary metabolites with multiple beneficial effects on neurological health deserve special attention as they demonstrate the ability to act simultaneously on various targets and may assist in treating disorders with complex pathophysiologies (Figure 3). United States are St. John's wort (Hypericum perforatum), ginkgo (Ginkgo biloba), garlic (Allium sativum), black cohosh (Actaearacemosa), soy (Glycine max) and kava (Piper methysticum) [27]. In Asia, traditional Chinese medicine has a long history and recorded the use of herbal medicine in the treatment of NDDs. "The Yellow Emperor's Classic of Internal Medicine" mentioned for the first time [28]. Chinese physicians believed that the balance between specific energies of the world; Yin and Yang determine the stability of the person's health. If the balance is disturbed, NDDs will be manifested eventually [29]. For this reason, physicians worked to stabilize the balance between YIN and YANG by using herbs or acupuncture. The most preferred herbs are Ginko biloba, Panax, Ganoderma lucidum, Salvia miltiorrhiza, Uncaria rhynchophylla and Zingibe rofficinale [30]. The Indian medical system, Ayurveda (4500-1500 B.C.) "science of life", is the oldest medical reference in the world [31]. In the Ayurvedic system, mechanisms within the human body were categorized by physiological and physicochemical activities and related to disease, including NDDs. Various herbal formulations are mentioned, including the amount of each component and the method of preparation [32]. The contents of these preparations include gandhaka (sulfur), butter oil and plants: Ficus carica, Achythesaspena, Alstonia scholaris, Holanthena antidysenterica. Some mixtures of herbal formulations, such as Pancarnula and Triphala ahave are included [33].
These ethnopharmacological uses of plants have guided scientific investigation for a large number of plant species, and has led to the identification of thousands of secondary metabolites, with desirable biological properties, including antioxidant, antimicrobial [34,35], anticancer [36,37], antidiabetic [38], anti-inflammatory [39] and neuroprotective properties [40].

Pharmacological Activities of Plants Secondary Metabolites on Neurodegenerative Disorders (NDDs): in vitro and in vivo Studies.
Recent studies have revealed that polyphenolic compounds, including flavonoids, phenolic acids and stilbenes; alkaloids, carotenoids, catechins and terpenes have great potential in treating NDDs (Table 1). Secondary metabolites with multiple beneficial effects on neurological health deserve special attention as they demonstrate the ability to act simultaneously on various targets and may assist in treating disorders with complex pathophysiologies (Figure 3).

Preventing Protein Misfolding and Aggregation
Protein misfolding is a key pathological aspect of NDDs, such as AD, Huntington's disease (HD) and PD [41] (Figure 3). In AD, the formation of extracellular senile plaques due to the accumulation of amyloid-β aggregates and neurofibrillary tangles (NFT) of tau proteins is associated with synaptic dysfunction, neuroinflammation and loss of neurons. Under normal physiological conditions, tau protein is involved in stabilizing microtubules. In AD, however, hyperphosphorylation of tau protein causes protein aggregation and the formation of intracellular NFT and the resultant degeneration of dendrites and axons [42]. Similarly, PD is characterized by the presence of the α-synuclein aggregates (Lewy bodies and Lewy neurites), the majority of which are found within the substantia nigra pars compacta (SNc) region of the midbrain. These α-synuclein aggregates acquire neurotoxic properties and compromise neuronal function and survival such as mitochondrial dysfunction, lysosome dysfunction, disruption of axonal transport and microglial activation leading to neuroinflammation [43]. Therefore, the prevention of proteinopathies is a strategy for treating NDDs.

Antioxidant Activity
The brain is highly susceptible to oxidative stress (OS) due to its high metabolic activity, elevated oxygen requirement and the presence of high levels of redox-active metals and oxidizable lipids [59]. OS is an important mechanism involved in the pathogenesis and progression of many NDDs [60] ( Figure 3). For example, mitochondrial injury and disrupted energy metabolism during cerebral ischemia and reperfusion generate nitric oxide (NO), and reactive oxygen species (ROS), subjecting the brain to an acute OS insult [61]. Aβ and cell damage induces the chronic production of ROS in the brains of AD patients. In PD, dopamine metabolism, mitochondrial dysfunction [62] and the neurotoxic effects of abnormal accumulation of α-synuclein, all promote the generation of ROS [63]. Furthermore, evidence suggests that there is reduced activity of endogenous antioxidant systems in PD patients [64]. Therefore, antioxidation is a major way by which phytochemicals exert their neuroprotective effects, which is a vital defense mechanism for neurological health.
Epileptic seizures are common underappreciated symptoms found in many NDDs, including AD. The kindling model of epilepsy is a common model for studying epileptogenesis and the cerebral effects of multiple seizures. Kindling is generally induced by repeated focal stimulation of the brain [75]. The effects of curcumin supplementation on a model of neurological disorders in rats has been reported [76]. Cortical and hippocampal neurons were protected from seizure-induced death, this being attributable to the restoration of glutathione (GSH) levels in the brain. The authors also found that curcumin prevented seizure-induced mitochondrial dysfunction and damage of the mitochondrion ultrastructure in cortical and hippocampal neurons [76]. Luteolin increased GSH levels and lowered MDA (malondialdehyde, a marker of lipid peroxidation) in the pentylenetetrazole (PTZ)-induced seizure model of mice, demonstrating neuroprotection [77]. The restoration of GSH by curcumin and luteolin signifies an increase in endogenous antioxidant defenses, which in turn prevents protein oxidation and mitochondrial swelling, by attenuating oxidative injury to mitochondrial membranes [75] D. The activation of microglia is another prominent source of ROS and reactive nitrogen species (RNS). Baicalein [45], ginsenosides [78], linalool [54] and rutin [72] have demonstrated the ability to block the activation of microglia in in vitro and in vivo models of NDDs. Naringin, a flavanone-glycoside commonly found in Citrus plants, downregulated the expression of the glial fibrillary acidic protein (GFAP), which in turn reduced microglial activation in a rodent model of PD [48].

Anti-inflammatory Activity
Neuroinflammation is a factor that plays an essential role in the increased loss of neuronal tissue and brain damage in cerebral ischemia, as well as in inflammatory diseases of the central nervous system (CNS) ( Table 1). For example, neuronal damage due to the accumulation of Aβ, tau protein and α-synuclein results in the recruitment and activation of microglia, which initiates the inflammatory response [43,79,80]. Cerebral ischemia and reperfusion injury (CI/RI) trigger the recruitment of resident microglia as well as infiltrating macrophages and neutrophils, which is followed by an enhanced inflammatory response and an over-production of inflammatory mediators (cytokines) [81,82]. The inhibition or downregulated expression of key pro-inflammatory mediators and/or the upregulation of anti-inflammatory cytokines are beneficial for preventing chronic inflammation and further cell death [83].
The neuroprotective properties of secondary metabolites can be attributed, in part, to their antioxidant capacity and anti-inflammatory potential. Genistein, a secondary metabolite of plant origin, has the structure and function similar to the primary female sex hormone, 17-beta-estradiol [84]. Genistein is capable of attaching itself to the receptive proteins of the female sex hormones and having estrogen-specific hormonal effects, even being able to replace them, triggering either an estrogenic or a regulatory hormonal impact [85]. To date, studies have shown that the anti-inflammatory activity of curcumin, genistein, resveratrol and naringenin are arbitrated via the inhibition or downregulated translocation of nuclear factor-κB (NF-κB), which regulates the transcription of cytokines [80]. Ginsenosides [49], linalool [54], quercetin [57], resveratrol [53] and sulforaphane [74] inhibit pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6 and IL-8 to reduce neuroinflammation in neurodegenerative models. In addition, quercetin also reduced GFAP in the brains of a rodent model of AD [57]. Curcumin [86] and kolaviron, a bioflavonoid complex isolated from Garcinia kola (bitter kola) [87], demonstrated neuroprotection from CI/RI by attenuating inflammation. Furthermore, secondary metabolites also attenuate neuroinflammation by preventing the activation of microglial cells [88].

Antiapoptotic and Neurotrophic Activities
AD and PD are characterized by the primary loss of cholinergic and dopaminergic neurons in the neocortex and substantia nigra of the midbrain, respectively. The variety of clinical aspects of NDDs, such as cognitive, behavioral and movement deficits are the result of neurodegeneration and loss of neurons. Therefore, preventing neuronal cell death and promoting neuron survival and regeneration are key mechanisms for reducing the impact of NDDs. In addition to the function of protecting neurons against OS and inflammation, secondary metabolites are able to prevent apoptosis induced by various neurotoxic agents, prevent excitotoxicity and promote neurogenesis via the upregulation of neurotrophic factors [17,89] (Figure 3). Acacetin [69], baicalein [45] and ginsenosides [78] inhibited dopaminergic neuron loss and preserved locomotor activity and coordination in rodent models of PD. Baicalein [45], quercetin [57] and resveratrol have been shown to attenuate 6-OHDA-induced neurotoxicity. Resveratrol also displayed neurotrophic properties in rat hippocampus by activating extracellular signal-regulated kinases (ERK)1-2/ cAMP-response element-binding protein (CREB) pathways which increase brain-derived neurotrophic factors (BDNF) and glial cell line-derived neurotrophic factor (GDNF) [40] which contribute to synaptic plasticity in key parts of the brain. Resveratrol has anti-inflammatory and antioxidant properties and can reduce the oxidation and formation of amyloid plaques in AD. Therefore, it has the potential also of reducing the pathology of PD or HD, through similar mechanisms [90,91]. Baicalein has also been shown to prevent lipopolysaccharide (LPS)-induced inflammatory-based neurotoxicity [45], while asiatic acid [70] reduced apoptosis, and resveratrol prevented neurotoxicity by activating the AMP-activated protein kinase/sirtuin 1 (AMPK-SIRT-1) autophagy pathway (crucial for the orderly degradation and recycling of cellular protein components compromised in NDD proteinopathies) in rotenone-induced models of PD [40]. The neuroprotective effect of asiatic acid was also partially mediated by activation of the extracellular-signal-regulated kinase (ERK) and phosphatidylinositol 3 kinase/protein kinase B/mammalian target of rapamycin/glycogen synthase kinase 3 beta (PI3K/Akt/mTOR/GSK-3β) pathways.
Baicalein and ginsenosides were shown to protect neurons from cerebral ischemia injury [45]. Baicalein protected rat hippocampi from glutamate-induced neurotoxicity by chelating intracellular Ca 2+ , which reduces presynaptic glutamate release [45]. Ginsenoside Rd showed beneficial effects for strokes through increased neuron survival following CI/RI, reduced infarct volume and protection of neurons against excitotoxicity by upregulating the glial glutamate transporter 1 (GLT-1), thus enhancing glutamate clearance by astrocytes [73]. Kolaviron also reduced necrotic cell death in rats subjected to bilateral common carotid artery occlusion-induced global ischemia/reperfusion injury. Prevention of excitotoxicity by reducing the release of excitatory neurotransmitters, and the preservation of Na/K/ATPase pump activity, which assists with electrolyte balance, has been proposed to be partially responsible for this neuroprotective effect [87].

Acetylcholinesterase Inhibition Activity
Acetylcholinesterase (AChE) inhibitors are a widely used class of drugs for treating early-stage dementias [94]. Acetylcholine (ACh), a neurotransmitter important for memory processing, is severely depleted in AD due to the degeneration of cholinergic neurons in the basal forebrain and, in particular, the nucleus basalis of Meynert which contributes to the cognitive impairment and memory loss seen in AD [95,96] (Figure 3). AChE is responsible for the postsynaptic degradation of ACh and, therefore, selective AChE inhibitors treat dementia by prolonging ACh activity.
Galantamine, an alkaloid extracted from Galanthus species, is a currently prescribed AChE inhibitor drug for AD and dementia [94,97]. Other promising secondary metabolites of note with AChE inhibitory activity are crocin, EGCG and naringin. In a recent study, crocin improved memory by inhibiting AChE and increasing ACh levels in the cortex and hippocampus in an AD-model mouse [68]. Naringin [92] and EGCG [18] exhibited AChE inhibitory activity and restored cognitive function and memory in rodent models of AD and dementia, respectively.

Monoamine Oxidase Inhibitors (MAOs)
Monoamine oxidases (MAO) are mitochondrial enzymes involved in the oxidative deamination of amine neurotransmitters [98,99]. In humans, two MAO isoforms are described, MAO-A and MAO-B, which share a degree of overlap between their substrate specificities. For example, both enzymes can metabolize dopamine, which makes them an important therapeutic target for PD [99,100]. MAO-A inhibitors have applications in the treatment of depression, anxiety and mood disorders as the enzyme subtype is also involved in the selective deamination of serotonin [98,100].
Molecular simulation studies have discovered chrysin, myricetin and genistein, an isoflavonoid from soybean, to possess strong inhibitory capacities versus MAO-A [99] (Figure 3). In a molecular docking study, the MAO-A-inhibitory potential of baicalein and decursin; two compounds isolated from the roots of Scutellaria baicalensis was reported [99]. In recent research, secondary metabolites, including berberine, maackiain and 3-phenyl coumarins were identified as novel MAO-B inhibitors [101].

Antithrombotic Activity
Acute cerebral ischemia is usually initiated by thrombotic or thromboembolic obstruction of a cerebral artery, which causes a sudden drop in blood flow to part of the brain. The resultant hypoxia and reduction in glucose supply to neurons causes depletion of adenosine triphosphate (ATP) and irreparable damage to surrounding neurons [102] (Figure 3). Reducing the risk of thrombosis using antithrombotic or antiplatelet agents is a preventative strategy for ischemic stroke [80,103]. In addition, preventing thrombosis of collateral arteries can potentially improve cerebral perfusion and protect the ischemic penumbra from further post-ischemic damage [104].
Studies on the antithrombotic properties of secondary metabolites appear to be limited. However, recent reviews have highlighted that carvacrol, α-cyperone and nootkatone; terpene compounds from the essential oils (Eos) of Cyperus rotundus [105], showed antiplatelet aggregation activity. On occasion, natural derivatives with a coumarin structure may have anticoagulant and antithrombotic activity, via a vitamin K antagonist mechanism, which has relevance to vascular dementias. Coumarin is well absorbed in the digestive tract, binds to plasma proteins and is metabolized by the liver [106]. The response settles slowly, is dose-dependent, within the range of interindividual variations and influenced by some associated pathologies (liver disease, thyroid disease) as well as some foods or medicines. Thus, the consumption of large quantities of green vegetables, rich in vitamin K, will mitigate the anticoagulant effects while the consumption of alcohol or the combination of non-steroidal anti-inflammatories or of anti-platelet agents may increase the risk of bleeding [107].

Future Perspectives
The strength of this comprehensive and up-to-date study is the analysis of evidence from preclinical studies from a large number of meta-analyses related to the impact of natural bioactive compounds in NDDs. All these analyses focused on highlighting the molecular and cellular mechanisms of action to open new beneficial therapeutic perspectives in the therapy of NDDs. It is difficult to attribute the pharmacological activity of a plant/or plant extract to a single compound or class of compounds as the observed beneficial properties are often the result of synergistic effects between multiple compounds on multiple targets. Many of these compounds, for example, apigenin, crocin, curcumin, EGCG, ginsenosides, hesperidin, linalool, quercetin, resveratrol, rosmarinic acid and withanolides, are either common across many plant species, present in species used in traditional medicine, and/or found in food sources, such as fruits, herbs and spices. These findings highlight the contribution of traditional medicine to modern treatments, as well as the health benefits of dietary phytochemicals.
An important aspect which limits the therapeutic applications of these natural compounds for NDD treatment is related to their poor bioavailability. For example, curcumin is a polyphenol with proven effects in the pharmacotherapy of AD, but with very low absorption and bioavailability. To increase its bioavailability, the resistance to metabolic processes and the passage through the blood-brain-barrier, new pharmaceutical technologies are required, such as liposomal nano-encapsulation, polymeric micelles, nanoparticles (nanocurcumin), cyclodextrins, nano-suspensions and nano-emulsions. Furthermore, additional properties of secondary metabolites, such as their metabolism, ability to cross the blood-brain-barrier, the dosage required for beneficial effects in humans, without toxic effects and interactions with current medications, are also important factors to be taken into consideration which need longitudinal investigations. It can be concluded that the plant secondary metabolites offer an abundant source of structurally and functionally diverse molecules for new potential preventative and therapeutic use in NDDs.