Therapeutic Implications of Some Natural Products for Neuroimmune Diseases: A Narrative of Clinical Studies Review

Neuroimmune diseases are a group of disorders that occur due to the dysregulation of both the nervous and immune systems, and these illnesses impact tens of millions of people worldwide. However, patients who suffer from these debilitating conditions have very few FDA-approved treatment options. Neuroimmune crosstalk is important for controlling the immune system both centrally and peripherally to maintain tissue homeostasis. This review aims to provide readers with information on how natural products modulate neuroimmune crosstalk and the therapeutic implications of natural products, including curcumin, epigallocatechin-3-gallate (EGCG), ginkgo special extract, ashwagandha, Centella asiatica, Bacopa monnieri, ginseng, and cannabis to mitigate the progression of neuroimmune diseases, such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, depression, and anxiety disorders. The majority of the natural products based clinical studies mentioned in this study have yielded positive results. To achieve the expected results from natural products based clinical studies, researchers should focus on enhancing bioavailability and determining the synergistic mechanisms of herbal compounds and extracts, which will lead to the discovery of more effective phytomedicines while averting the probable negative effects of natural product extracts. Therefore, future studies developing nutraceuticals to mitigate neuroimmune diseases that incorporate phytochemicals to produce synergistic effects must analyse efficacy, bioavailability, gut-brain axis function safety, chemical modifications, and encapsulation with nanoparticles.


Introduction
Neuroimmune disorders are multifactorial and include neuroinfectious, autoimmune, paraneoplastic, neurodegenerative, and neuropsychiatric conditions that are primarily characterized by infammatory responses in the central nervous system (CNS). Even though neuroimmune disorders predominantly manifest as an exaggerated immune response, the underlying pathogenesis involves different immunological mechanisms such as those that are cell-mediated, humoral mediated, or triggered by infection, which is characterized by genetically defned mechanisms for each disorder [1].
Neuroinfammation is a hallmark responsible for the occurrence of neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and multiple sclerosis (MS) [2]. T and B lymphocytes, as well as infammatory cells in the nervous system such as microglia, oligodendrocytes, and astrocytes, are stimulated by the activation of numerous immune cascades, which play a key role in neuroinfammation and infammatory cytokines. Te activated immune cascade disrupts the bloodbrain barrier (BBB) and blood-nerve barrier (BNB), allowing infammatory cells to infltrate the nervous system further and the development of neuroimmune disorders. Te activation of the various immune cascades stimulates T and B lymphocytes and infammatory cells in the nervous system, such as microglia, oligodendrocytes, and astrocytes, and plays a pivotal role in neuroinfammation and infammatory cytokines. Te activated immune cascade causes disruption of the BBB and BNB, which allows additional infltration of infammatory cells into the nervous system and the development of neuroimmune diseases [3][4][5].
ALS is a known neurodegenerative disease with a poor prognosis, with few United States Food and Drug Administration (FDA) approved disease-modifying drugs that produce only minimal survival benefts [6]. Studies have estimated that approximately 35 million people worldwide are sufering from the debilitating efects of AD, yet only one recently FDA-approved drug is available to mitigate disease progression [7]. Although approved immunomodulatory therapeutic modalities for MS are available, these drugs have limited efcacy in preventing the transition to the progressive phase of MS, and severe adverse efects have become a major issue with these disease-modifying drugs [8]. Te scenario for PD is no exception, as there are limited available therapeutic options to treat PD, and these therapies do not alter the nondopamine-dependent features of PD, especially cognitive impairment [9]. Patients sufering from the aforementioned incurable and debilitating neuroimmune diseases have devastating lifelong functional, physical, and mental disabilities. Additionally, they may have to undergo very expensive, therapeutic interventions that are unafordable for many, thus creating a great economic burden on their families, especially in developing countries [1]. Several preclinical investigations have found that natural products and their bioactive components can protect against neuroimmune disorders. Terefore, alternative drug discovery based on authentic natural products has the potential to improve the quality of life of patients with neuroimmune diseases by ameliorating disease progression and reducing comorbidities [1,10,11].
Te authors aim to provide a review of the existing clinical studies that utilised natural products in South Asia targeted at neuroimmune diseases. Moreover, this review suggests some solutions for enhancing the bioavailability of natural products by optimizing the appropriate dosage, synergetic efects of phytochemicals, chemical modifcations, and encapsulation with nanoparticles.

Review Methodology
Te review process was divided into three major steps: title, abstract, and content screening. Te previous South Asian natural products studies on neuroimmune disease are reviewed in this article. Articles were searched in databases including PubMed, Medline, Scopus, Embase, and Springer. Te search was based on the key words: neuroimmune diseases, neuroimmune crosstalk, and South Asian natural products where a total of 3024 publications were identifed.
All the titles were screened, and 1578 documents were downloaded for abstract screening. Te inclusion criteria were having the key words "South Asian natural products" and "neuroimmune diseases." After the abstract screening, a total of 333 articles out of 1578 that met the inclusion criteriawere retained. Finally, full texts of all 333 retained documents were critically assessed using the same inclusion/ exclusion criteria as the abstract screening, leaving 105 papers to be included in this review. Te review methodology has been summarised in Figure 1.

Neuroimmune Crosstalk in Neuroimmune Diseases.
According to Deczkowska and Shwartz, "Immune cells patrol the immune-privileged CNS and support its function"; thus, the modulation of bidirectional neuroimmune crosstalk will open up possibilities to fght against neurological diseases [12,13]. Although the CNS is comparatively isolated from the peripheral immune system, glial cells play a major anti-infammatory and neuroprotective role by upregulating anti-infammatory processes to protect the CNS from stress and noxious pathogens, hence regulating homeostasis [14]. On the other hand, exorbitant or tedious glial activation leads to neuroinfammation and subsequently neurodegeneration [15,16]. Intriguingly, infammatory mediators, such as cytokines, chemokines, and cytotoxic molecules, trigger astrocytes to induce secondary infammatory factors to stimulate a neuroinfammatory cascade [17,18] (Figure 2).
Even though the adaptive response from the acute infammatory response is benefcial to defending against pathogens, chronic neuroinfammation causes tissue destruction and neuronal dysfunction [19]. Te underlying molecular mechanisms have been demonstrated by in vitro studies, including the upregulation of peroxisome proliferator-activated receptor gamma (PPARc) and the downregulation of the nuclear factor kappa B (NF-κB) pathway [20,21]. Tis leads to inhibition of the activation of microglia, thus diminishing the generation of proinfammatory cytokines and reducing reactive oxygen species (ROS) production via suppression of the Janus kinase 2/ signal transducer and activator of transcription 3 (JAK2/ STAT3) pathway [22,23]. Due to the ability of microglia to regulate neuroinfammation, the homeostatic proteins of the microglia have been considered drug targets by modulating signaling pathways such as JAK/STAT and NF-κB [24]. Te metabolite of cinnamon and sodium benzoate (NaB) has been shown to reduce glial infammation, upregulate Tregs via reduction of nitric oxide (NO) inhibition, suppress T helper 17 (T17) cells and Type 1 T helper (T1) cells, inhibit infammatory infltration, restore the integrity of the BBB, and protect myelin in mouse models of MS [25,26]. Te immunomodulatory properties of NaB may be used against a variety of neuroinfammatory disorders, including MS, as a primary or adjunct therapy [27]. Tis reduces redox imbalance, oxidative stress, and neuroinfammation, hence combating neuronal damage in neurodegenerative diseases.
Prior studies have suggested that the activated, polarized M1 (proinfammatory macrophage) phenotype can be used as a therapeutic target of natural products to treat neurodegenerative diseases [24,28].
Tere is a clinical necessity to identify novel compounds to mitigate or treat the diseases associated with neuroimmune communication to reduce the negative efects of microglia and infammatory cytokines. As summarized in Table 1, natural products may potentially be used as immune modulators to treat neuroimmunological disorders due to their ability to participate in numerous functions of adaptive/innate immunity. In this scenario, natural products and their bioactive compounds, such as curcumin, epigallocatechin-3-gallate (EGCG), ginkgo special extract, ashwagandha, Centella asiatica, Bacopa monnieri, ginseng, and cannabis can be used as protective agents against neuronal damage caused by infammation and oxidative stress [24,28].

Curcumin.
Curcumin is a yellow-coloured spice that comes from the Curcuma longa plant and is widely used in India and Sri Lanka [45]. Curcumin is a lipophilic phenolic diferuloylmethane that has been shown to inhibit a variety of transcription factors, cytokines, protein kinases, interleukins, and enzymes linked to infammation, making it a potential therapeutic option for neuroimmune diseases such as MS, PD, AD, and ALS [46][47][48]. Despite multiple encouraging outcomes from in vivo and in vitro investigations, similar progress in human trials against AD with a 24-week study of a daily dosage of 2 grams or 4 grams of oral Curcumin C3 Complex [32] has not been made. Curcumin's limited bioavailability and solubility likely limit its capacity to reach signifcant concentrations in the CNS to provide beneft [32]. Curcumin is also poorly absorbed when taken orally, and it undergoes hepatic conjugation, resulting in the generation of biologically inactive metabolites [31], Future research should be designed to optimize curcumin's therapeutic efectiveness. Clinical research comparing the bioavailability of curcumin and piperine, an inhibitor of hepatic and intestinal glucuronidation, revealed that the bioavailability of curcumin rose when piperine was consumed simultaneously, which could explain the reported increase in curcumin activity [45]. Dolati et al. [44] found that supplementing with nanocurcumin for six months can drastically reduce the mRNA expression and secretion levels of proinfammatory cytokines and transcription factors in MS patients. As a result, nanocurcumin could be administered to alleviate MS symptoms.
Polyherbal extracts will be a superior choice for increasing curcumin bioavailability and thus improving its therapeutic efcacy by altering hepatic and intestinal metabolic enzymes and transporters. Chico et al. [31] investigated the efcacy of oral supplementation of Brainoil, a nutraceutical curcumin-based compound, consisting of curcumin (600 mg), 100 mg of Coenzyme Q10, 300 mg of Bacopa monnieri, and 250 mg of Withania somnifera and Centella asiatica. Moreover, Coenzyme Q10 is a potent antioxidant that acts to enhance mitochondrial activity and addition of piperine (1 mg of Piper nigrum) to enhance bioavailability. Following 6 months on clinical parameters (Table 1) and biochemical markers in ALS patients found that treatment with curcumin modifes lactate production profle during muscular exercise suggesting improvement in mitochondrial function aerobic metabolism and oxidative damage thus slowing down the disease progression [31].
Te exploitation of the synergistic mechanisms of herbal compounds will lead to the discovery of more accomplishable phytomedicines that can avert the probable negative efects of single compounds. It is necessary to conduct human studies to identify possible compounds that could act synergistically with curcumin to enhance its bioavailability and activity [49].  Evidence-Based Complementary and Alternative Medicine

Epicatechin Gallate (EG) and Epigallocatechin-3-Gallate (EGCG).
Catechins are antioxidants that can be found in fruits such as apples, cherries, apricots, strawberries, and blackberries, as well as in beverages such as black tea and green tea. Its anti-infammatory and neuroprotective properties could open up new avenues for treating neuroimmune diseases [50]. In a phase 1 clinical trial to investigate the efcacy of EGCG in individuals with MS, 800 mg of polyphenon E failed to restore N-acetyl aspartate (NAA) levels and resulted in increased liver enzyme levels in the participants (Table 1) [39]. To estimate the toxic dosage and bioavailability of EGCG, more clinical investigations are needed. Factors that reduce catechin concentration and inactivation, such as hard water with high Ca2+ and Mg2+ concentrations or even drinking milk with EGCG, should be considered [51]. Te intake of EGCG in combination with other dietary components, which modify the context of EGCG before absorption and alter its biological response, has a direct impact on its absorption and stability.
According to Naumovski et al. [52], systemic absorption of EGCG given in capsules without food following an overnight fast was substantially higher than when it was given in capsules with a light breakfast. As a result of these fndings, the most appropriate technique for the oral delivery of EGCG in future clinical studies where EGCG is to be investigated as a potential bioactive nutraceutical in humans is to take it with water on an empty stomach [52]. Concomitant administration of bioenhancers such as ascorbic acid, fsh oil, and piperine may act synergistically to improve EGCG bioavailability by inhibiting oxidation and suppressing glucuronidation, resulting in increased EGCG absorption [53,54].

Ginkgo Special
Extract. Ginkgo biloba is the sole surviving plant in the Ginkgo family, and it has been used to prevent neurological illnesses since antiquity [55,56]. Active components in the standardized EGb 761 ginkgo extract include 24 percent ginkgo-favone glycosides, 6 percent   Figure 2: Bidirectional communication between the nervous system and the immune system. Activated neurons release neuropeptides that activate infammatory cells, and then various cytokines, chemokines, growth factors, leukotrienes, and prostaglandins are released from these infammatory cells to act on nerve terminals. Substance P release from nerve terminals causes vasodilatation. IL-4 and IL-13 play a role to induce macrophages. Once induced, the macrophages produce various anti-infammatory cytokines including IL-10, IL-13, and TGF-β, neurotrophic factors (insulin-like growth factor-1 (IGF-1)), brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor, epidermal growth factor, and IL-1 receptor antagonist. Furthermore, macrophages play a role to block iNOS to reduce infammation, protect cells, and maintain the stability of the environment in the body. Evidence-Based Complementary and Alternative Medicine 5   [37] Evidence-Based Complementary and Alternative Medicine 7   [42] Evidence-Based Complementary and Alternative Medicine 9 10 Evidence-Based Complementary and Alternative Medicine  [44] Evidence-Based Complementary and Alternative Medicine terpenoids, and 5-10 percent organic acids. Ginkgo's antioxidant qualities, vascular remodelling properties, and neurotransmitter-potentiating activities can be utilized to treat a variety of neurological diseases, including AD and depression [57]. Clinical trials in Germany by Kanowski and Hoerr [58] and the United States by Le Bars et al. [35] to test the efcacy of Ginkgo biloba on dementia has yielded positive fndings (Table 1) in both 240 mg daily doses for 24 weeks and 120 mg daily dose for 26 weeks investigations. Te research was extended for another 26 weeks; however, only 50 percent of EGb-treated patients and 38 percent of placebo-treated participants made it to the 52-week visit [36]. Te active treatment outperformed the placebo in terms of improving patients' cognitive function and neuropsychiatric symptoms. Te clinical signifcance of the pharmacological efects was demonstrated by the consistency of both primary and secondary outcomes, such as functional status, global evaluation, quality of life, and response rates. Ginkgo biloba extract appears to be well tolerated in the studies reviewed, without any signifcant diferences between treatment and placebo, considering adverse efects and study withdrawals [58]. Johnson et al. conducted a clinical trial to investigate if the consumption of 240 mg of a ginkgo extract (EGb 761) per day for four weeks enhanced functional performance in MS patients. On measures of fatigue, symptom severity, and functionality, the ginkgo group had considerably more participants exhibiting improvement on four or more measures and less fatigues [33]. Despite the fact that ginkgo appeared to have therapeutic efects in some of the subjects, it is conceivable that the treatment duration was short. Furthermore, the individual therapeutic responses might vary. Tus, the result is that combining positive and negative responses in analyses may disguise or obfuscate some of the ginkgo's benefcial benefts [33,34].

Ashwagandha (Withania somnifera).
From ancient times, Withania somnifera (WS), also known as ashwagandha, has been a signifcant plant in Ayurvedic and traditional medical systems [59]. Te two main active components in ashwagandha are withaferin A and withanolide D, which have antioxidant, anti-infammatory, immunomodulatory, anxiolytic, antidepressive, and neuroprotective properties [60,61]. Because of these alleged healing efects, WS is widely used in Ayurvedic medicine, and it has been explored as a treatment for a variety of disease conditions including anxiety, infammation, PD, and cognitive impairment [62]. Withania somnifera is also used as an immunological stimulant in individuals with low white blood cell counts and as an adaptogen for patients with fatigue, sleeplessness, and stress disorders [62,63]. A study that looked at the efects of a Withania extract on calcium antagonism in the central nervous system shed some information on a possible anxiolytic mode of action. In this investigation by Grunze et al. [64], treatment with Withania extract caused extracellular calcium antagonism in neurons, counteracting excitement. Calcium excitation has been found to play a role in a variety of psychiatric diseases, including anxiety, so inhibiting calcium excitation should have an anxiolytic efect.
According to a clinical trial conducted by Langade et al. [29], Ashwagandha root extract (KSM 66 pill) of 300 mg twice daily dosage for a period of 10 weeks improved sleep parameters in individuals with insomnia and anxiety (Table 1). When compared to the placebo group, signifcant improvements in sleep quality and sleep metrics such as sleep onset latency (SOL), sleep efciency (SE), Pittsburgh Sleep Quality Index (PSQI), and anxiety parameters such as the Hamilton Anxiety Rating Scale (HAM-A) were seen. In this context, oral administration of capsules containing Ashwagandha can be used as a potential anxiolytic agent (Table 1) [29].
2.6. Centella asiatica (L). Centella asiatica is a herbaceous plant that can be found all throughout India, the Middle East, and Asia including Sri Lanka. Te main bioactive compound of this plant is triterpene saponosides [65]. Furthermore, pharmacological studies have demonstrated that C. asiatica and its constituents, primarily asiaticoside and ursolic acid, exhibit a wide range of pharmacological actions, including memory boosting, sleep-inducing, anxiolytic, and antioxidant characteristics [66][67][68]. C. asiatica has also been shown to mitigate neurodegeneration and protect against oxidative stress-induced brain aging [66]. By these mechanisms, C. asiatica can exert neuroprotective efects against neuroimmune diseases such as AD, PD, depression, and anxiety [69][70][71].
A clinical study conducted by Jana et al. [30] to investigate the therapeutic efcacy of C. asiatica to treat psychiatric conditions such as generalized anxiety disorder found that oral administration of encapsulated 500 mg of C. asiatica plant extract twice daily after a meal for two months has been shown to efectively decrease stress anxiety-depression disorders (Table 1). No other anxiolytic drugs were given to the study subjects during the study period. Te study found that after 60 days of treatment, the anxiety index, depression index, adjustment score, and attention level were signifcantly reduced, with no negative side efects. As a result, C. asiatica could be an alternative treatment agent for stress-related clinical illnesses [30].

Bacopa monnieri.
Bacopa monnieri, often known as "Brahmi," is a native plant that can be found in the Indian subcontinent, East Asia, and some parts of the United States. Its antianxiety, anti-infammatory, memory boosting, and immunomodulatory properties are thought to be due to its antioxidant properties. Bacosides, one of its bioactive ingredients, have been proven to help with anxiety, depression, and cognitive impairment [72][73][74]. A clinical study of newly diagnosed AD patients found that taking a standardized extract of Bacopa monnieri (Bacognize ® ) 300 mg twice daily for six months improved their quality of life, enhanced their memory power, and reduced their irritability and insomnia, and some even reported positive changes in their family behavior (Table 1) [74].
It has been demonstrated that the natural product formula containing B. monnieri efectively increased minimental state examination (MMSE) scores in AD patients. A polyherbal compound's synergistic properties may aid in achieving benefcial results [42]. Sadhu et al. [43] reported that providing a polyherbal formula comprising B. monnieri at a dose of 500 mg over a 12-month period was efective in improving cognitive skills in individuals with senile dementia of Alzheimer's type (SDAT) when compared to the donepezil-treated group. Diminished infammation and oxidative stress were indicated by reducing levels of homocysteine, C-reactive protein, superoxide dismutase, tumor necrosis factor-alpha (TNF-α), and glutathione peroxidase, in the SDAT patients treated with the test formulation when compared to the donepezil-treated group ( Table 1). Tese results showed a protective efect of the test formulation in managing cognitive decline associated with the aging process [43]. A prior in vivo study showed that bacoside A encapsulation with nanoparticles might be a potential strategy to facilitate BBB penetration, thus enhancing therapeutic efcacy while treating neurodegenerative diseases. Terefore, B. monnieri may be a plausible therapeutic agent to enhance cognitive function in AD patients via a nanotechnological approach [42,75].

Ginseng.
Ginseng is a well-known herbal remedy that is widely used in traditional Chinese medicine as a tonic, restorative, and antiaging agent [76]. Ginsenosides are the main bioactive compounds in the plant, although there are also polysaccharides, triterpenoids, and favonoids [77,78]. Free radicals and oxidative stress may have a role in the development of fatigue in people with MS [79,80]. Ginseng's antifatigue properties could be attributed to its antioxidant properties and ability to control GABAergic neurotransmissions [81].
Etemadifar et al. [37] conducted a pilot study to assess the efcacy and safety of ginseng in the treatment of fatigue in MS patients and found that the ginseng supplement was well tolerated with no signifcant adverse events after three months of daily administration of 500 mg of ginseng. Te results showed that when ginseng was used instead of a placebo, the mean scores for the fatigue impact scale (MFIS) "physical" subscale improved signifcantly (p � 0.046) [37]. Furthermore, as compared to the placebo group, most of the scores for the individual domains of the Multiple Sclerosis Quality of Life Questionnaire (MSQOL-54), including physical health, emotional well-being, energy, cognitive function, health distress, and quality of life, were signifcantly higher in the ginseng-treated group [37]. However, a human trial conducted by Kim et al. on the treatment of fatigue in 47 MS patients with progressively increasing doses of ginseng over a 6-week period found it to be safe but inefective. Tis could be related to the study's short duration and the severity and stages of the disease [82]. Terefore, future clinical trials should be conducted over a considerable period of time to determine the efcacy of ginseng at various stages of the disease.

2.9.
Cannabis. Cannabis plants are native to Central Asia that are grown all over the world [83]. D9tetrahydrocannabinol (THC) is the main psychoactive component of cannabis, but other derivatives may have medicinal or synergistic properties. Te most promising of these is cannabidiol (CBD), which is nonpsychoactive and may regulate THC's intoxication and/or memory efects. For its intoxicating qualities, high quantities of THC are preferred in the illegal market [83]. Terefore, standardized whole plant cannabis medical extracts (CBMEs) have recently been developed [84]. Inhalation and vaping are the most common ways to consume cannabis. Cannabinoids are rapidly absorbed into the bloodstream in this manner, with peak plasma THC concentrations reaching within minutes. Oral cannabis absorption and metabolism are unpredictable, and plasma concentrations are often sustained for longer periods of time (8-20 hours), resulting in inconsistent psychotropic efects [83].
With low degrees of intoxication, single case-crossover studies have shown that these CBMEs have the ability to diminish symptoms such as spasticity, pain, and spasms, in patients with MS [85]. Wade et al. conducted a trial using a whole plant extract including equal quantities (120 mg) of THC and CBD gave in a pump-action spray for the relief of MS symptoms. To mask the taste and appearance of CBME, all preparations included peppermint favouring and colouring. Patients on an active treatment whose primary complaint was spasticity exhibited a substantial reduction (p � 0.001) in contrast to placebo at the end of the study duration of six weeks. Patients with stable MS were given a two-week dose titration phase from 5 mg to a maximum of 25 mg of tetrahydrocannabinol daily, followed by a ten-week maintenance phase, according to Zajicek et al. [38]. After 12 weeks, the rate of relief from muscle stifness was nearly twice as high with cannabis extract (CE) compared with place (Table 1). Even if the medical use of cannabis is clearly benefcial, it is important to be attentive in order to discover the potential for harm, particularly in relation to inhaled tobacco [83].

Future Prospects for Natural Product Clinical Research against Neuroimmune Diseases.
Many factors should be considered in order to attain expected results from a natural product clinical trial. Te fndings of natural product clinical trials will be infuenced by factors such as dose range, study period, number of patients enrolled, patient compliance, and clinical and biochemical response evaluations [86]. Adequate dose selection for confrmatory trials is still one of the most difcult problems to solve. Te goal is to fnd the ideal target concentration that provides the most beneft with the least amount of side efects [87]. Acceptability of favour, texture, and/or ease of swallowing capsules or tablets is critical for the participant's adherence to the study [88]. Future research should look into the mechanisms that explain why some people beneft from natural products while others do not so that treatment can be more useful and costefectively targeted to specifc patients [33].
Novel drug-delivery systems, including liposomes, marinosomes, niosomes, and lipid-based systems, can improve bioavailability by increasing the rate of delivery and the ability to traverse lipid-rich biomembranes [89]. Phospholipid-based drug-delivery systems have been demonstrated to be efective and efcient in the delivery of herbal drugs [90]. Bioenhancers such as Piper longum, black pepper (Piper nigrum), long pepper (P. longum), and ginger (Zingiber ofcinale) are drug facilitators that enhance the activity of drug molecules which can be used in clinical studies to increase drug bioavailability across the membrane [91,92]. Nanocarriers are being developed to overcome unmet drug-delivery hurdles and enable cross BBB. Extracellular vesicles have recently emerged as a natural carrier mechanism for therapeutic administration [93,94]. Furthermore, gold nanoparticle-based drug-delivery systems are also capable of reaching the central nervous system [87]. It is worth noting that drug-delivery nanoparticles can either stimulate or inhibit the immune response, and they can reside in the body, so researchers must design appropriate nanodrugs, modify them according to disease characteristics, and conduct extensive immunotoxicology research before moving forward with clinical trials [95]. Natural product extracts may have a high concentration of constituents, and the combination of various active ingredients in extracts can provide synergistic efects, resulting in improved antioxidant and disease-modifying action [96,97]. Identifying the compounds responsible for a particular biological action is challenging. For fnding constituents that engage in synergistic efects, metabolomics and biochemometric methods are potential tools [98,99]. Untargeted approaches to discovering synergistic molecular targets and unravelling synergistic mechanisms of action should be investigated [99]. Strategies to improve the outcome of natural product clinical studies are summarised in Figure 3. However, this review only focused on South Asian natural products, and due the discrepancies in clinical evaluation batteries/criteria in reviewed articles, we could not conduct a meta-analysis. We acknowledge this as a limitation in our study.

Conclusions
Positive results of clinical studies of natural products and their phytochemicals, such as curcumin, epigallocatechin-3gallate (EGCG), ginkgo special extract, ashwagandha, Centella asiatica, Bacopa monnieri, ginseng, and cannabis against neuroimmune diseases, amply prove that they have therapeutic potential. One of the challenges that remain with their use is to maintain the stability of the unstable active ingredients of these natural products until they reach the target site. Inadequate dosages, poor aqueous solubility, and inadequate oral absorption via the oral route due to metabolism in the gastrointestinal tract and the inability to cross the BBB are the main considerations for natural products in clinical studies. Terefore, it is very important to evaluate the kinetic and physicochemical properties to develop such drugs and their delivery systems. Te importance of multitarget combination therapies and the concept of synergy in the polyherbal formulation have risen to the fore. Future research should focus on identifying the combination of efects within complex mixtures, assuring a favourable outcome in natural product clinical studies. Chemical modifcation and encapsulation into nanoparticles may boost their efcacy and curtail systemic toxicity. Future studies are required to determine the correct techniques for natural products and their nanoformulations to convert them into probable drug candidates to treat neuroimmune diseases. Te development of such nutraceuticals may pave the way toward novel therapeutic strategies to mitigate chronic neuroinfammation and overcome neuroimmune disorders.  14 Evidence-Based Complementary and Alternative Medicine Abbreviations CNS: Central nervous system AD: Alzheimer's disease PD: Parkinson's disease ALS: Amyotrophic lateral sclerosis HD: Huntington's disease MS: Multiple sclerosis BBB: Blood-brain barrier BNB: Blood-nerve barrier FDA: United States Food and Drug Administration NaB: Sodium benzoate EG: Epicatechin gallate EGCG: Epigallocatechin-3-gallate MMSE: Minimental state examination SDAT: Senile dementia of Alzheimer's type THC: D9-tetrahydrocannabinol CBME: Cannabis medical extracts.

Data Availability
Te data used to support the fndings of this study are available from the corresponding author on request.

Conflicts of Interest
Te authors declare that they have no conficts of interest.