Lukasz Ciesla, University of Alabama, United States

REVIEWED BY

Marcella Reale, University of Studies G. d’Annunzio Chieti and Pescara, Italy Amala Soumyanath, Oregon Health and Science University, United States

*CORRESPONDENCE

Rania M. Salama,

[email protected]

RECEIVED 30 May 2023 ACCEPTED 23 August 2023 PUBLISHED 06 September 2023

CITATION

Darwish SF, Elbadry AMM, Elbokhomy AS, Salama GA and Salama RM (2023), The dual face of microglia (M1/M2) as a potential target in the protective effect of nutraceuticals against neurodegenerative diseases. Front. Aging 4:1231706. doi: 10.3389/fragi.2023.1231706

COPYRIGHT

© 2023 Darwish, Elbadry, Elbokhomy, Salama and Salama. This is an openaccess article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Samar F. Darwish1, Abdullah M. M. Elbadry2,3, Amir S. Elbokhomy2, Ghidaa A. Salama2 and Rania M. Salama4*

1Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo, Egypt, 2Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo, Egypt, 3Nanotechnology Research Center (NTRC), The British University in Egypt (BUE), El-Sherouk City, Egypt, 4Pharmacology and Toxicology Department, Faculty of Pharmacy, Misr International University, Cairo, Egypt

The pathophysiology of different neurodegenerative illnesses is significantly influenced by the polarization regulation of microglia and macrophages. Traditional classifications of macrophage phenotypes include the proinflammatory M1 and the anti-inflammatory M2 phenotypes. Numerous studies demonstrated dynamic non-coding RNA modifications, which are catalyzed by microglia-induced neuroinflammation. Different nutraceuticals focus on the polarization of M1/M2 phenotypes of microglia and macrophages, offering a potent defense against neurodegeneration. Caeminaxin A, curcumin, aromaticturmerone, myricetin, aurantiamide, 3,6′-disinapoylsucrose, and resveratrol reduced M1 microglial inflammatory markers while increased M2 indicators in Alzheimer’s disease. Amyloid beta-induced microglial M1 activation was suppressed by andrographolide, sulforaphane, triptolide, xanthoceraside, piperlongumine, and novel plant extracts which also prevented microgliamediated necroptosis and apoptosis. Asarone, galangin, baicalein, and a-mangostin reduced oxidative stress and pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha in M1-activated microglia in Parkinson’s disease. Additionally, myrcene, icariin, and tenuigenin prevented the nod-like receptor family pyrin domain-containing 3 inflammasome and microglial neurotoxicity, while a-cyperone, citronellol, nobiletin, and taurine prevented NADPH oxidase 2 and nuclear factor kappa B activation. Furthermore, other nutraceuticals like plantamajoside, swertiamarin, urolithin A, kurarinone, Daphne genkwa flower, and Boswellia serrata extracts showed promising neuroprotection in treating Parkinson’s disease. In Huntington’s disease, elderberry, curcumin, iresine celosia, Schisandra chinensis, gintonin, and pomiferin showed promising results against microglial activation and improved patient symptoms. Meanwhile, linolenic acid, resveratrol, Huperzia serrata, icariin, and baicalein protected against activated macrophages and microglia in experimental autoimmune encephalomyelitis and multiple sclerosis. Additionally, emodin, esters of gallic and rosmarinic acids, Agathisflavone, and sinomenine offered promising multiple sclerosis treatments. This review highlights the therapeutic potential of using nutraceuticals to treat neurodegenerative diseases involving microglial-related pathways.

KEYWORDS

microglia, M1/M2 pathway, neurodegeneration, nutraceuticals, aging diseases

1. 1.1 Microglia pathway

Microglia are specialized macrophages, that constitute the primary central nervous system (CNS) innate immune cells. They are the first glial cells that enter the CNS during prenatal development. They represent approximately 10%–15% of all CNS cells. Microglia control CNS homeostasis at rest by eliminating pathogens and cell residue through phagocytic activity. Resting microglia become activated and generate inflammatory mediators, thus providing neurons protection and defense against infections. In addition to supporting the CNS, they are linked to the development of many inflammatory and neurodegenerative disorders (Colonna and Butovsky, 2017; Saitgareeva et al.,

1. 2020). Depending on the activation, microglia are separated into two categories: M1 microglia, which stimulates inflammation and neurotoxicity, and M2 microglia, which stimulates anti-inflammatory and neuroprotective effects (Qin et al., 2023).

M1 cells act as the innate immune system’s first line of defense, frequently within the first few hours or days. They use a wide range of immunological receptors to detect harmful stimuli; for example, nucleotide-binding oligomerization domains (NODs), NOD-like receptors, toll-like receptors (TLRs), and multiple scavenger receptors. They are activated by interferon-gamma (IFN-γ) and lipopolysaccharide (LPS). After activation, microglial cells are motivated to release pro-inflammatory factors with neurotoxic effects. Furthermore, IFN-γ stimulates the transcription factor signal transducer and activator of transcription 1 (STAT1) via Janus kinase (JAK)1/JAK2 signaling and stimulates the production of reactive oxygen species (ROS) and nitric oxide (NO) in addition to pro-inflammatory chemotactic factors and cytokines, like tumor necrosis factor-alpha (TNF-α), interleukin-23 (IL-23), IL-2, IL-1β, C-X-C motif chemokine ligand-9 (CXCL9), and CXCL10 (Orihuela et al., 2016). Activation of M1 can also be induced by another pathway through the activation of TLR4 by LPS or damage-associated molecular pattern (DAMP). After that, an “activation complex” is formed, comprising P65, P38, myeloid differentiation factor 88 (Myd88), interferon regulatory factor 3 (IRF3), and nuclear factor kappa B (NFκB), which is a highly conserved transcription factor that controls a variety of crucial physiological processes, including inflammatory reactions, cellular proliferation, and apoptosis. In turn, the complex formed controls the expression of inflammatory mediators from the polarized cell, such as inducible nitric oxide synthase (iNOS), CD16, and CD32, and the major histocompatibility complex-II, CD86, and other cell surface markers (Zhao et al., 2017). On the other hand, M2 microglia are activated by IL-4, IL-10, or IL-13, which motivate microglial cells to release abrineurin, found in inflammatory zone 1, Ym1, and anti-inflammatory cytokines, such as transforming growth factor ß (TGF-β), IL-1, and IL-4, which suppress inflammatory responses, encourage repair and regeneration and have neuroprotective effects (Yao and Zu, 2020; Li et al., 2021; Guo et al., 2022). The impact of microglia

polarization to M1 or M2 on neurodegeneration and the involved mediators is illustrated in Figure 1.

Non-coding RNAs (ncRNAs) are a diverse class of ncRNA transcripts that do not play any role in protein coding. Nevertheless, it has been proven that they are key factors in many biological processes, including disease progression (Sun and Chen, 2020). Regulatory ncRNAs can be further divided into small non-coding RNAs (sncRNAs), which contain transcripts with fewer than 200 nucleotides (nt), and long non-coding RNAs (lncRNAs), which contain transcripts with more than 200 nt. The three primary types of small ncRNAs are PIWI-interacting RNAs (piRNAs), small-interfering RNA (siRNA), and microRNAs (miRNAs). Certain ncRNAs have different lengths, such as circular RNAs (circRNAs), enhancer RNAs (eRNAs), and promoter-associated transcripts (PATs) may belong to two classes at the same time (Zhang et al., 2019).

ncRNAs play key roles at the post-transcriptional level in different pathways and diseases, including neurodegenerative disorders (Nhung Nguyen et al., 2022; Salama et al., 2022; Elazazy et al., 2023) Table 1. Numerous studies have been conducted on the dynamic ncRNA alterations caused by microglia-induced neuroinflammation (J. Huang et al., 2023; Li et al., 2020; 2022). In the context of Alzheimer’s disease (AD), miRNA-155 regulates synaptic homeostasis of microglia Aβ internalization and synaptic pruning. Deletion of the microgliaspecific miRNA-155 resulted in early onset hyper-excitability, frequent spontaneous seizures, seizure-related mortality, and decreased amyloid-beta (Aβ) pathology. As miRNA-155 deletion changed how the microglia internalized synaptic material, this impacted how the microglia mediated the synaptic pruning (Aloi et al., 2023).

Metastatic-associated lung adenocarcinoma transcript 1 (MALAT1), also known as the nuclear-enriched abundant transcript 2, is a lncRNA that is a crucial factor in the pathogenesis of Parkinson’s disease (PD) (Abrishamdar et al., 2022). PD onset and prognosis were correlated with MALAT1relevant single nucleotide polymorphisms (SNPs), and MALAT1 contributed to increasing the neuronal inflammation of the pathogenesis of PD (Yang, 2021). MALAT1 is overexpressed due to participation in activating inflammatory vesicles in microglia (Geng et al., 2023). In PD models, MALAT1 induces apoptosis of dopamine neurons via sponging miRNA-124 (Liu et al., 2017) and acts as a miR-23b-3p sponge that inhibits microglial autophagy and inflammatory responses to promote dopaminergic neuronal apoptosis. The potential mechanism is that the miR-23b-3p/αsynuclein molecular axis is regulated to promote dopaminergic neuronal cell apoptosis by affecting the endocytosis and intercellular communication of the a-synuclein (α-syn) nucleoprotein. As a result, microglia may exhibit impaired autophagy and inflammatory reactions. Consequently, this

1. TABLE 1 The role of different ncRNAs in neurodegenerative diseases.

provides a new treatment target for PD (Geng et al., 2023). Due to its effects on dopaminergic neuron apoptosis, lncRNA MALAT1 may be a new treatment target in PD.

In the CNS, miRNA-124 is highly expressed and perfectly conserved (Wohl and Reh, 2016; Chen et al., 2023). It plays an important role in a variety of neurodegenerative diseases, as well as memory development. Huang et al. found that miRNA-124 polarization of microglia from M1 to M2 significantly reduced the neuroinflammation generated by d-galactose. This was also shown by the presence of iNOS, arginase-1 (Arg-1), and ionized calcium-binding adapter molecule 1 (Iba-1), which also upregulated the antiinflammatory mediators IL-4 and IL-10 and downregulated the inflammatory mediators TNF-α and IL-1β (J. Huang et al., 2023). Another study focused on miRNA-124 discovered that human serum

and cerebrospinal fluid (CSF) both showed significantly higher levels of circHIPK3 expression in PD compared to controls, but miRNA-124 expression was markedly decreased. In BV2 cells (a type of microglial cells), the overexpression of circHIPK3 enhanced the release of IL-6, IL1β, and TNF-α. Following the expression of circHIPK3, the microglia markers CD11b and Iba-1 protein expressions and pyroptosis-related factors, nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3), caspase-1, and apoptosisassociated speck-like protein containing a caspase recruitment domain (ASC) were elevated. When miRNA-124 was added, all these effects were reversed. This is due to circHIPK3 increasing neuroinflammation via sponging miRNA-124 and controlling the miRNA-124-mediated STAT3/NACHT, LRR, and PYD domainscontaining protein 3 pathway (Zhang et al., 2022). Nutraceuticals

may play an important role in the treatment of different diseases by targeting ncRNAs (El-Shehawy et al., 2023; Jiang et al., 2023; Zhang et al., 2023). However, no studies were found that demonstrate an effect of nutraceuticals on the microglia pathway acting via the ncRNAs pathways.

Neurodegenerative disorders such as AD, PD, Huntington’s disease (HD), amyotrophic lateral sclerosis, and multiple sclerosis (MS) are distinguished by neurodegeneration in particular parts of the CNS and share very similar pathophysiological processes (Song and Suk, 2017). Microgliainduced neuroinflammation has become widely recognized as a dualistic phenomenon in the field of neurodegenerative disorders, comprising both negative and positive effects on neuronal functioning and the surrounding environment (Tang and Le, 2016).

In various neurodegenerative disorders, neuroinflammation caused by microglia, macrophages that are found in the brain, is a prevalent hallmark, and various inflammatory mediators generated by M1 microglia have a role in the development of neurodegeneration and myelin damage in these diseases. Nevertheless, M2 microglia activation is required for tissue maintenance and repair (Jha et al., 2016; Song and Suk, 2017). Multiple studies have confirmed that natural products can both prevent and treat neurodegenerative diseases by influencing the polarization of microglia towards M1/M2 phenotypes. These natural compounds can potentially inhibit or reduce the inflammatory toxicity of M1 microglia. Furthermore, they can help repair and regenerate damaged neurons, axons, or myelin by improving the release of neurotrophic factors or cytokines from M2 microglia (Jin et al., 2019).

1. 3.1 Alzheimer’s disease

1. 3.1.1 Role of microglia in Alzheimer’s disease Alzheimer’s disease is the prevailing type of dementia, associated

with damaged locomotor ability, thinking, judgment ability, increasing memory loss, and cognitive decline (Fu et al., 2016). It is distinguished by the abnormal presence of Aβ-containing plaques extracellularly and the creation of neurofibrillary tangles inside the cell composed of hyperphosphorylated tau protein (Prince et al., 2016; Baufeld et al., 2017).

Postmortem analysis revealed an overwhelming number of “plaques” and “tangles” as distinguishing signs of AD. These senile plaques are accumulations of fibrils and aggregations of Aβ located outside of cells caused by abnormal proteolytic degradation of the amyloid precursor protein (APP), which is enhanced by presenilin-1 (PS1) (Citron et al., 1992; Mattson, 2004). In vivo, amyloid plaques can attract and stimulate microglia cells (MeyerLuehmann et al., 2008), while in vitro studies have demonstrated that Aβ peptides can stimulate primary microglia activation and promote NO generation. However, this microglia activation can result in the adoption of many phenotypes, which is further

increased by the presence of amyloid fibrils and extracellular Aβ peptides (Walker et al., 2006; Maezawa et al., 2011).

Furthermore, neuroinflammation has an important role in the etiology of AD (Baufeld et al., 2017). In the CSF of mild memory impairment patients who developed AD, researchers discovered higher TNF-α (a pro-inflammatory cytokine) and lower TNF-β (antiinflammatory cytokine) levels compared to controls who had not experienced AD (Tarkowski et al., 2003). The neuroinflammatory response is demonstrated by modifications to the structure of microglia and astrocytes in proximity to senile plaques (Glass et al., 2010).BothastrocytesandmicrogliainteractwithAβ,andinterruptions in their metabolism and functioning can result in Aβ depositions (Yan et al., 2013; Hickman et al., 2018). As a result, Aβ uses TLRs to stimulate astrocytes and microglia, promoting neurodegeneration by causing the production of neuroinflammatory mediators (Glass et al., 2010).

Microglia also can respond to potentially damaging stimuli such as misfolded Aβ proteins (Sarlus and Heneka, 2017). M2 microglia, which are mainly accountable for up-taking and eliminating insoluble fibrillar Aβ deposits, perform a protective function in the brain. Microglia can break down Aβ by producing enzymes such as insulin-degrading enzymes (Heneka, 2017), hence minimizing AD incidence (Hansen et al., 2018).

At the outset of Aβ pathology, the microglia that encircle the Aβ plaques are typical of the neuroprotective phenotype, identified as Ym1. Thus, Microglia perform an important role in reducing the accumulation of potentially neurotoxic Aβ aggregates while also protecting neurons from localized toxicity (Condello et al., 2015). However, an age-dependent rise of both the size and amount of Aβ plaques in AD may represent a reduction in microglial phagocytic abilities (Mawuenyega et al., 2010), and this neuroprotective phenotype eventually changes to the neurologically harmful proinflammatory one at the final stages of the disease (Tang and Le, 2016).

Pro-inflammatory cytokines reduce microglia phagocytic activity and additionally are likely to shift microglia into proinflammatory phenotypes. Consequently, pro-inflammatory microglia promote tau phosphorylation (Lee et al., 2010). Furthermore, Microglia release neurotoxic cytokines that directly harm neurons or activate neurotoxic astrocytes (Hansen et al., 2018). It was also revealed that synaptic loss and aberrant tau phosphorylation in AD are caused by the dysregulation of Wnt pathways and that Wnt signaling regulates microglial inflammation (Yang and Zhang, 2020).

The dynamic nature of microglial activation involves constant transitions between different phenotypes. In a study conducted by Fan et al., it was suggested that microglial activation in AD may exhibit two distinct peaks (Fan et al., 2017). The first peak, occurring in the preclinical stage, is characterized by an anti-inflammatory response. The second peak, observed in the clinical stage as the disease advances and Aβ clearance mechanisms fail, demonstrates a pro-inflammatory reaction. These findings align with microglia’s dual role in AD pathogenesis.

3.1.2 Nutraceuticals that influence microglial activation in Alzheimer’s disease

The impact of different natural products and nutraceuticals on AD through regulation of M1/M2 microglia polarization is presented in Table 2 and Figures 2, 3.

1. 3.1.2.1 Origanum majorana L. Origanum majorana L. is an aromatic plant used to treat

various diseases in folk medicine, including intestinal antispasmodic, intestinal hypertension, allergies, respiratory infections, diabetes, and stomach pain (Bouyahya et al., 2021). Origanum majorana is a plant rich in phenolic compounds like rosmarinic acid and its derivatives. Origanum majorana extract and rosmarinic acid strongly protected microglial cells from oxidative stress-induced cell death by the antioxidant activity of rosmarinic acid. Origanum majorana additionally protected mice from the alterations in recognition and spatial memory induced by LPS and reduced expression of glial fibrillary acidic protein and cyclooxygenase-2 (COX-2) in mouse brain tissue (Wagdy et al., 2023).

3.1.2.2 Caesalpinia dinax

Caesalpinia minax Hance is a species of plant that belongs to the Fabaceae family and spreads throughout Southeast Asia’s tropical and subtropical regions. This plant’s seeds, known in China as “Kushi-lian,” have long been used in traditional medicine to treat fever, diarrhea, and the common cold (Jing et al., 2019; Ruan et al., 2019). Twenty cassane diterpenoids were identified in the leaves of Caesalpinia minax, including two unique ones (caeminaxins A and B). To evaluate the anti-neuritis activity of these 20 compounds, Lu et al. measured the amount of NO production of mouse microglia BV-2 cells stimulated by LPS as neuroinflammatory diseases are characterized by an increase in NO production. The most potent inhibitory effect was produced by caeminaxin A. Different concentrations of this compound (3, 10,

and 30 μM) were used to treat BV-2 cells stimulated by LPS. Caeminaxin A at 30 μM significantly inhibited iNOS and COX-2 protein expression. Additionally, Caeminaxin A reduced the production of p-ERK, p-JNK, and p-p38 in the mitogen-activated protein kinase (MAPK) signal pathway, which suppressed neuroinflammation (Lu et al., 2023).

1. 3.1.2.3 Dracaena cochinchinensis Dracaena cochinchinensis is a tropical forest plant belonging to
2. 3.1.2.4 Polygonum multiflorum Polygonum multiflorum is traditional Chinese herbal medicine

used for centuries as a treatment for a wide range of conditions, including dizziness, liver disease, graying of the hair, and constipation (Xue etal., 2020; Guoet al., 2023). Chinese knotweed, Fo-Ti, Shou Wu Pian, and He Shou Pian are other names for P. multiflorum (Gumber and Barmota, 2023). The main active compound from Polygonum multiflorum is tetrahydroxystilbene-2-O-D-glucoside (TSG, C20H22O9) (Wang et al., 2022). TSG caused a decrease in cyclic GMP-AMP synthase (cGAS), a decrease in the immune response that was induced by the stimulator of interferon genes (STING), and

decreased the expression of NLRP3 inflammasome by inhibition of the activation of the cGAS-STING pathway in APP/PS1 mice. Additionally, cell culture using LPS and IFN-γ to activate microglia indicated that TSG reversed the polarization status of M1-type microglia to restore quiescence and inhibit cGAS-STING pathway as active microglia showed higher cGAS-STING levels. TSG also reduced the inflammatory response induced by LPS/IFN-γ in BV2 cells by inhibiting the synthesis of pro-inflammatory cytokines such as IL-1β, IL-6, TNF- α, IFN- α, and IFN- β, as well as the expression of IFN regulatory proteins like IFIT1 and IRF7 (Gao et al., 2023a).

3.1.2.5 Myricetin

Myricetin is a flavonoid compound in various natural plants (Song et al., 2021). It can be found in foods, including fruits, vegetables, tea, and wine. The richest sources of myricetin are the families Myricaceae, Polygonaceae, Primulaceae, Pinaceae, and Anacardiaceae. Previous studies have demonstrated that myricetin has various pharmacological effects, including its anticancer, anti-diabetic, anti-obesity, cardiovascular, antiosteoporosis, anti-inflammatory, and hepatoprotective (Imran et al., 2021). Myricetin has neuroprotective action, which has been demonstrated in preclinical studies on amyotrophic lateral sclerosis, PD, AD, and HD (Taheri et al., 2020). According to the findings of in vitro AD model (BV-2 microglia cells stimulated with Aβ25–35), myricetin prevented the hyperactivation of microglia and the conversion from the M2 to the M1 type and inhibited NLRP3 activation by inhibiting the activation of the P38 MAPK signaling pathway. In 3 × Tg-AD mice, myricetin reduced microglia hyperactivation, encouraged microglia conversion from M1 type to M2 type, and effectively reduced neuroinflammation through reduced IL-1β, TNF-α, and IL-6 expression, whereas increased IL-4 and IL-10. In addition, it could significantly enhance memory loss, spatial learning

capacity, Aβ plaque formation, and neuronal and synaptic damage (Liu et al., 2023).

1. 3.1.2.6 Aurantiamide Aurantiamide is a natural product found in various plants,
2. 3.1.2.7 3,6′-Disinapoylsucrose 3,6′-Disinapoylsucrose is an oligosaccharide ester bioactive
3. 3.1.2.8 Curcumin Curcumin is an important polyphenolic component found in
4. 3.1.2.9 Aromatic-turmerone Aromatic-turmerone, a prominent phytoconstituent found in

Curcuma longa essential oil, has a comparable chemical structure and potential bioactivities to curcumin and 6-shogaol derived from ginger. In an in vitro study, the aromatic-turmerone was shown to decrease the synthesis of pro-inflammatory chemicals in BV-2 cells,

derived from C57/BL6 murine, which is a well-characterized and extensively employed model system for microglia, triggered by LPS via inhibiting the STATs and mitogen-activated protein kinase pathways (Park et al., 2012b). Another in vitro study found that administrating aromatic-turmerone reduced neuronal damage and lowered microglia activation towards the M1 phenotype. These data support the anti-inflammatory and neuroprotective properties of aromatic-turmerone. These positive benefits were connected to avoiding neuronal injury by limiting microglial M1 activation and decreasing inflammatory cytokine production (Park et al., 2012a).

1. 3.1.2.10 Resveratrol Many different plants produce resveratrol, a natural phenol, and
2. 3.1.2.11 Andrographolide Andrographolide is a labdane diterpenoid present throughout
3. 3.1.2.12 Sulforaphane Sulforaphane, an organosulfur isothiocyanate substance, is

mainly found in cruciferous vegetables such as broccoli, mustard radish, and cabbage. It is a powerful activator of the nuclear factor erythroid 2 related factor 2/heme oxygenase 1 (Nrf2/HO1) pathway with a wide range of biological and pharmacological actions, including anti-inflammatory and antioxidant properties (Zhang et al., 2017). An in vitro study found that sulforaphane at a dose of 5 μM decreased IL-1 release in a cellular model employing Aβinduced human microglia-like THP-1 cells. This was accomplished via inhibiting STAT1 phosphorylation and activation of the NLRP3 inflammasome. The activation of the Nrf2/HO-1 pathway relates to sulforaphane’s latent mechanism (An et al., 2016). Furthermore, previous in vitro research found that sulforaphane at doses ranging from 5 to 15 μM inhibited the phosphorylation of

JNK, p38 MAPK, and NFκB p65 in mentioned BV-2 cells, derived from C57/BL6 murine, triggered by LPS. Microglia-mediated necroptosis and apoptosis were reduced due to this indirect suppression of pro-inflammatory responses (Qin et al., 2018).

1. 3.1.2.13 Triptolide Triptolide, a diterpenoid molecule produced from the plant
2. 3.1.2.14 Xanthoceraside Xanthoceraside is a novel triterpenoid saponin isolated from the
3. 3.1.2.15 Piperlongumine Piperlongumine, an amide alkaloid produced from the fruit of

the long pepper plant (Piper longum), which is native to southern India and Southeast Asia, has piqued the interest of pharmacologists due to its possible medicinal qualities (Kumar et al., 2011). Numerous studies have been undertaken employing various animal models to evaluate the effects of piperlongumine on ADlike pathology. Piperlongumine (50 mg/kg/day, i. g, for 2.5 months) was given to APP/PS1 mice in an in vivo study, resulting in significant restoration of cognitive function (Go et al., 2018b). This improvement was attributable to a decrease in Aβ deposition and inhibition of microglia M1 activation in the cerebral cortex (Go et al., 2018a). Furthermore, previous studies have proven that piperlongumine has neuroprotective benefits in AD rat models via blocking the NFκB pathway predominantly in M1 microglia (Gu et al., 2018).

1. 3.2 Parkinson’s disease

1. 3.2.1 Role of M1/M2 in Parkinson’s disease Just behind AD, PD ranks as the second most prevalent

neurodegenerative disorder. It is distinguished by the slow

degeneration of dopamine neurons in the midbrain’s substantia nigra pars compacta (SNpc) and A1 neurotoxic astrocyte activation. Lewy bodies (LBs), which are primarily composed of filamentous a-syn, are a distinguishing hallmark of PD. These protein aggregates are a fundamental illness feature and are important in its pathogenesis. Additionally, there is an excessive proliferation of reactive microglia, a type of immune cell in the brain (Eriksen et al., 2005; Tang et al., 2013; Song and Suk, 2017). Through functional alterations, astrocytes play key roles in PD pathogenesis (González-Reyes et al., 2017). Dopamine regulates Ca2+ signals in astrocytes (Vaarmann et al., 2010). Dopamine neuron loss may alter astrocyte Ca2+ homeostasis, and Ca2+ imbalance may result in the generation of toxic compounds and cell death in PD (Zaichick et al., 2017). Furthermore, emerging data from multiple studies suggest that glia maturation factor (GMF) produced from astrocytes stimulates the NFκB signaling pathway and consequent granulocyte macrophage-colony stimulating factor (GM-CSF) release. Increased levels of GM-CSF have been implicated in microglia activation and subsequent generation of inflammatory molecules such as IL-1β, TNF-α, and macrophage inflammatory proteins-1 beta (MIP-1β) (Zaheer et al., 2007; Fan et al., 2018).

The presence of a-syn in dopaminergic cells has been associated with increased amounts of ROS. This implies that a-syn may contribute to oxidative damage by influencing mitochondrial activity. Overexpression of mutant a-syn has been demonstrated to make dopaminergic neurons more susceptible to mitochondrial toxins such as 6-hydroxydopamine (6-OHDA) and mitochondrial processing peptidases 1-methyl-4-phenylpyridinium ion (MPP+), leading to elevated protein carbonylation and lipid peroxidation. These results demonstrate that a-syn may regulate oxidative stress and mitochondrial dysfunction in dopaminergic cells (Chinta and Andersen, 2008).

Microglia-mediated neuroinflammation has a complicated function in PD since it can have both neuroprotective and neurotoxic effects. Microglia are triggered in the early stages of PD by factors such as a-syn, infections, or environmental pollutants. At this stage, microglia are generally static and have little relationship with the severity of clinical symptoms (Tang and Le, 2016). During this initial stage, microglia secrete anti-inflammatory cytokines to decrease the inflammatory response and promote tissue healing and repair (Du et al., 2018). This activation is critical for immunological defense and survival of neurons (Tang et al., 2013). However, when PD advances, persistent microglial activation becomes harmful. Prolonged stimulation can exacerbate motor impairments and cause extensive neuronal damage in neighboring areas (Song and Suk, 2017). Moreover, aggregated a-syn can directly motivate microglia to adopt a proinflammatory M1 phenotype. This aggravates motor impairments and severely damages adjacent neurons. Understanding the dynamic nature of microglial activation and its role in the etiology of PD is critical for developing treatment techniques to control neuroinflammation and offer neuroprotection (Tang and Le, 2016; Song and Suk, 2017; Du et al., 2018).

3.2.2 Nutraceuticals that influence microglial activation in Parkinson’s disease

The impact of different natural products and nutraceuticals on PD through regulation of M1/M2 microglia polarization is presented in Table 3 and Figure 4.

1. TABLE 3 The effects of different nutraceuticals on microglia in Parkinson’s disease related models.

1. TABLE 3 (Continued) The effects of different nutraceuticals on microglia in Parkinson’s disease related models.

1. 3.2.2.1 a-Cyperone α-Cyperone, a major active compound of Cyperus rotundus L.,

which is often known as purple nutsedge or nut grass, is a common and widespread weed in tropical, subtropical, and temperate climates (Azimi et al., 2016). This plant has received a lot of attention for its medicinal potential, thanks to centuries of traditional medicine (Seo et al., 2001). It has been praised for its anti-arthritic, antidiarrheal, and antiplatelet characteristics, as well as its potential to treat numerous CNS illnesses such as epilepsy, depression, and inflammatory conditions (Jebasingh et al., 2012; Azimi et al., 2016). In a conducted investigation, researchers discovered that a-Cyperone at a dose of 10 mg/kg per day significantly improved motor function impairment, protected dopaminergic neurons, and counteracted the decrease of dopamine and its metabolites in a rat model of PD caused by lipopolysaccharide (LPS). Furthermore, a-Cyperone substantially reduced microglia activation and the production of many neuroinflammatory factors, including IL-6, IL-1β, TNF-α, iNOS, ROS, and COX-2 (B. Huang et al., 2023). The protective effects

of a-Cyperone on microglia were explained by its ability to suppress neuroinflammation and oxidative stress, which was accomplished by activating the Nrf2/HO-1 pathway while simultaneously blocking the NFκB signaling pathway, according to meticulous molecular mechanism studies (B. Huang et al., 2023; Li et al., 2021). Furthermore, a-Cyperone aided in the overexpression of antioxidant enzymes such as glutamatecysteine ligase catalysis, glutamate-cysteine ligase modifier, and nicotinamide quinone oxidoreductase 1 in microglia, adding to its neuroprotective characteristics (B. Huang et al., 2023; Jayaram and Krishnamurthy, 2021).

3.2.2.2 Myrcene

Myrcene, sometimes known as ß-myrcene, is an abundant monoterpene found in a variety of plant species, including hops and cannabis (Surendran et al., 2021). Notably, myrcene is widely used in the food and beverage industries as a flavor and aroma enhancer, and it is also used as a food additive throughout the

production process (Tyler, 1996; Surendran et al., 2021). Myrcene at a dose of 50 mg/kg, provided 30 min before rotenone (ROT) injections, demonstrated neuroprotective benefits in a mouse model of Parkinson’s disease (PD). ROT exposure resulted in the death of dopaminergic neurons, a decrease in antioxidant defenses, a rise in lipid peroxidation, and the activation of microglia and astrocytes. Pro-inflammatory cytokine levels were also raised, and the autophagy lysosomal pathway was disrupted, both of which contributed to dopaminergic neurodegeneration. Myrcene therapy, on the other hand, significantly restored antioxidant defenses, reduced lipid peroxidation, and pro-inflammatory cytokines, and reduced microglial and astrocyte activation. It also increased mTOR phosphorylation, which helped to restore neuronal homeostasis and autophagy-lysosomal activity. Surprisingly, myrcene treatment reduced a-synuclein expression, resulting in dopaminergic neuron preservation and rescue (Azimullah et al., 2023).

1. 3.2.2.3 Daphne genkwa flower In East Asia, the flower buds of Daphne genkwa have been used
2. 3.2.2.4 Citronellol Citronellol (CT) is a monoterpene alcohol found in the essential
3. 3.2.2.5 Methanolic extract of Boswellia serrata gum For centuries, the resin of Boswellia species, namely, Boswellia

serrata (Salai/Salai guggul), has been employed in religious, cultural,

and medical traditions (Salama et al., 2023). The oleo gum resin is extracted from the tree’s trunk and comprises resin, essential oils, and polysaccharides. It is derived from many states in India and has historically been used in folk medicine to treat chronic inflammatory illnesses (Siddiqui, 2011). The researchers examined the neuroprotective properties of Boswellia serrata gum extract in PD in previous research. The extract activated AMPK and downstream neuroprotection pathways. In vivo, it protected nigrostriatal dopaminergic neurons while decreasing a-synuclein accumulation (Ameen et al., 2017).

During Phase I, to investigate whether Boswellia extract increases neuroprotective molecules, oral Boswellia extract (500 mg/kg/day) was given for 2 weeks, and Western blotting was used to identify neuroprotective compounds. In Phase II, to explore the neuroprotective effects of Boswellia extract on ROT neurotoxicity, four groups were studied: one as a control, one receiving oral Boswellia extract group, one receiving ROT (4 mg/kg/day, i. p.), and one receiving both Boswellia extract and ROT. Boswellia enhanced AMPK phosphorylation, decreased p-mTOR and p-α-synuclein in the striatum, and raised the expression of Beclin1 and brain-derived neurotrophic factor. Boswellia reduced dopaminergic neuron loss, microglial activation, and a-synuclein accumulation in ROT-injected rats, increasing striatal dopamine levels and motor performance (Shadfar et al., 2022).

1. 3.2.2.6 Kurarinone Kurarinone is a naturally occurring prenylated flavanone
2. 3.2.2.7 Urolithin A Urolithin A is synthesized by gut bacteria from ellagitannin-rich

food (Singh et al., 2021). Urolithin A therapy showed neuroprotective effects in a mouse model of PD. In mice, Urolithin A effectively reduced dopaminergic neuron loss, corrected behavioral impairments, and reduced neuroinflammation caused by MPTP (Ren et al., 2018). Further research indicated that Urolithin A induced mitophagy in BV2 cells (a type of microglial cell derived from C57/BL6 murine) that were exposed to LPS, restored mitochondrial function, and decreased the pro-inflammatory response. Furthermore, urolithin A significantly reduced NLRP3 inflammasome activation. To create the MPTP mouse model, mice were given 15 mg/kg MPTP intraperitoneally four times a day within a 2-h interval. Mice were given 20 mg/kg urolithin A intraperitoneally for 7 days before MPTP injection for urolithin A therapy. The rotarod, pole, and suspension tests all revealed significant impairment in motor activity after MPTP treatment. However, Urolithin A treatment dramatically corrected these motor abnormalities, suggesting the potential

therapeutic advantages of Urolithin A in reducing motor impairments associated with PD (Qiu et al., 2022).

1. 3.2.2.8 Asarone Asarone represents a phenylpropanoid found in plants such as
2. 3.2.2.9 Galangin Galangin, a natural flavonol, predominantly exists in the

rhizome of the therapeutic plant Alpinia officinarum (Zingiberaceae). This molecule was widely investigated and has been shown to stimulate PPAR-γ, a receptor involved in cellular process regulation. Galangin suppressed inflammatory responses of M1 microglia in tests employing BV-2 cells treated with LPS.

This was accomplished by activating the Nrf2/cAMP response element-binding protein (CREB) signaling pathway at doses ranging from 10 to 50 μM (Choi et al., 2017). Furthermore, galangin showed encouraging results in an in vivo experimental rat model mimicking PD by inhibiting excessive inflammatory activation of microglia. Galangin also dramatically suppressed microglial M1 activation produced by LPS, lowering proinflammatory chemical expression. These effects were linked to changes in the JNK, Akt, and NFκB communication pathways. These findings emphasize galangin’s possible therapeutic role in modulating microglial inflammation, implying its potential as a therapy method for neurodegenerative disorders such as PD (Chen et al., 2017).

3.2.2.10 Baicalein

Baicalein, which is derived from the root of Scutellaria baicalensis (Labiatae), has the potential to be used as a treatment for inflammatory conditions. Baicalein significantly suppressed the expression of iNOS in experiments involving BV-2 cells and primary microglia activated with LPS and IFNγ. The effect mentioned was obtained by blocking the MAPKs and NFκB signaling pathways (Chen et al., 2004). Furthermore, baicalein displayed neuroprotective properties in a PD in vivo experimental model using MPP + neurotoxin. Baicalein protected injured DA neurons by reducing the activation of microgliainduced inflammation by reducing inflammasome activity. These findings emphasize baicalein’s medicinal potential in reducing inflammatory responses and protecting against neurotoxicity (Hung et al., 2016).

1. 3.2.2.11 a-Mangostin α-Mangostin is a plant polyphenol produced from various parts
2. 3.2.2.12 Icariin Icariin is a flavanol glycoside that has been prenylated and
3. 3.2.2.13 Tenuigenin Tenuigenin is a bioactive terpenoid found naturally in the roots of
4. 3.2.2.14 Nobiletin Nobiletin is a flavonoid compound in Tangerine peel (Citri

reticulatae pericarpium). Numerous studies have demonstrated its antioxidant, anti-atherogenic, and anti-inflammatory qualities. Nobiletin administration at various doses (range from 1 to

50 μM) significantly suppressed the generation of proinflammatory cytokines, including IL-1β and TNF-α in a dosedependent manner in a previous in vitro study using LPS-stimulated BV-2 microglia. According to detailed analysis, the underlying mechanism includes suppressing of phosphorylation of MAPKs and the translocation of NFκB into the nucleus (Cui et al., 2010). One notable feature of nobiletin is that it can penetrate the BBB and concentrate more in the brain than in peripheral organs. This distinct characteristic enables nobiletin to alleviate neuroinflammation and mitigate neuronal damage caused by M1activated microglia (Singh et al., 2011). Furthermore, in a PD in vivo animal model, in which rats were injected with MPP+ in the middle forebrain bundle, using nobiletin (20 mg/kg, i. p., for 7 days) gave significant protection to DA neurons located in the SNpc. Nobiletin has also been shown to decrease M1 microglia activation, lowering inflammatory cytokines release (Jeong et al., 2015).

1. 3.2.2.15 Taurine Taurine, a non-protein amino acid containing sulfur, is found in
2. 3.2.2.16 Plantamajoside Plantamajoside, a natural product that comes from plantain seeds,

has a wide range of biological activities, including anticancer, antiinflammatory, and antioxidative features (Ravn et al., 2015). In an earlier in vivo research study, researchers used male C57BL/6 mice to induce a PD animal model by injecting LPS into the substantia nigra (SN) located in the midbrain region on the right side. The researchers discovered that Plantamajoside substantially alleviated the behavioral impairment caused by LPS in Parkinson’s disease rats. In addition, Plantamajoside has been shown to reduce SN damage produced by LPS and to decrease microglial cell over-activation in PD rats. Further investigation revealed that Plantamajoside exerted its effects in both PD mice and BV-2 cells by suppressing the activation of the histone deacetylase-2 (HDAC2)/MAPK pathway. Notably, Plantamajoside

demonstrated its ability to reduce microglia polarization by inhibiting HDAC2 (Guo et al., 2023).

1. 3.2.2.17 Swertiamarin Swertiamarin, a widely researched natural compound, has anti-
2. 3.3.1 Role of microglia M1/M2 in Huntington’s disease

Huntington’s disease is a neurodegenerative condition with hereditary autosomal dominant traits. The main cause is a gene identified as huntingtin, which is found on the short arm p) of chromosome 4 and mutated to cause the disease (Gómez-Jaramillo et al., 2022). The CAG trinucleotide repeat expansion on chromosome

1. 4 is the root cause of HD. Atypical involuntary motions, cognitive deterioration, and behavioral alterations are features of HD, in which the most apparent symptom is chorea (Gibson and Claassen, 2021). In contrast to normal control brains, considerable astrogliosis and microgliosis were found in the post-mortem brains of HD patients. According to a previous study, the density of microglia in the brains of HD patients fluctuated relative to the severity of neuronal loss (H. M. Yang et al., 2017). Furthermore, the extensive detection of M1 microglia significant biomarkers in HD brain suggests that M1 microglia may be important in the pathophysiology of HD. An alternatively activated M2 phenotype, however, has the potential to be neuroprotective, which contributes to HD recovery (Ji et al., 2018). Consequently, Pena-Altamira et al. concentrated on nutritional methods through the consumption of food-bioactive substances like carotenoids, phytosterols, and other substances that may affect microglial polarization, aid in neuron survival, and consequently lessen cognitive impairment associated with aging (Tang, 2018).

1. 3.3.2 Nutraceuticals that influence microglial activation in Huntington’s disease

The impact of different natural products and nutraceuticals on HD through regulation of M1/M2 microglia polarization is presented in Table 4 and Figure 5.

1. 3.3.2.1 Pomiferin The main components of Maclura pomifera fruits are prenylated
2. 3.3.2.2 Gintonin Gintonin is a glycolipid protein conjugated with
3. 3.3.2.3 Schisandra chinensis A versatile traditional Chinese medicine; schisandra (Schisandra
4. 3.3.2.4 Iresine celosia Iresine celosia is a cytochrome-flavoprotein with potent

antioxidant properties (Porru et al., 2017). Neurological

1. TABLE 4 The effects of different nutraceuticals on microglia in Huntington’s disease and Multiple sclerosis related models.

1. TABLE 4 (Continued) The effects of different nutraceuticals on microglia in Huntington’s disease and Multiple sclerosis related models.

diseases, such as HD, are influenced by aberrant inflammatory responses in the central nervous system (Nayak et al., 2011). A recent research investigated managing neuroinflammation using natural therapies like Iresine celosia to address this. The researchers looked at the effects of Iresine celosia extract on LPS-stimulated BV2 cells in mouse models. NO and proinflammatory cytokines in microglia cells were considerably reduced by Iresine celosia extract at various doses (1–100 μg/ mL) without causing any harm. In mice with neuroinflammation, it also prevented NFκB translocation and improved behavioral impairments (Kim et al., 2019).

1. 3.3.2.5 Elderberry Sambucus spp. elderberries are cultivated in Europe, Asia, North

Africa, and North America. Recent research indicates that elderberry assists in reducing some viral infections’ symptoms (Zakay-Rones et al., 2007). It has been established that anthocyanins, such as cyanidin-3-O-sambubioside and cyanidin3-O-glucoside, and flavonoids, such as quercetin and rutin, are the antioxidative and anti-inflammatory substances present in the highest concentration in berries and flowers (Mikulic-Petkovsek et al., 2012). According to several additional studies, elderberry possesses various neuroprotective qualities (by reducing microglial activation), which can lower the loss of neuronal cells (Jiang et al., 2015; Zielińska-Wasielica et al., 2019).

To demonstrate the extreme nature of neuro-inflammatory processes, immunohistochemistry staining for the microglia marker (Iba-1) was performed in recent investigations. The results showed that rats given elderberry had significantly decreased microgliosis. The study concluded that elderberry’s antioxidant action increased GSH concentration and reduced ROS production in the tissue that had been damaged. Additionally, by reducing microglia’s production of TNF-α, this study sheds new illumination on using elderberry as neuroprotective medicine to treat HD by improving neuron survival due to microglial inactivation (Moghaddam et al., 2021).

1. 3.3.2.6 Curcumin According to a previous in vivo study in YAC128 HD mice,

solid lipid nanoparticles of curcumin reduced HD-like neurodegeneration. By boosting glutathione levels and reducing superoxide dismutase activity, solid lipid nanoparticles of curcumin greatly reduced protein carbonyl formation, lipid peroxidation, ROS levels, and mitochondrial swelling (Gharaibeh et al., 2020). Additionally, in a 3-NPA-induced HD model in rats, curcumin therapy is believed to improve cognitive and motor abilities, regain succinate dehydrogenase activity, and lessen oxidative stress (Sandhir et al., 2014). Curcumin can cross across the BBB because it is lipid soluble. It then blocks the activation of microglia by decreasing the expression of iNOS. Curcumin suppresses cytokines release and oxidative stress and lowers NO generation, and the related signaling pathways, which has an anti-inflammatory effect on microglia. In addition, curcumin inhibits apoptosis, PI3k/Akt and iNOS, lipoxygenase, and COX-2, and induces activation of HO-1, Nrf-2, and the antioxidant response element mechanism in neuronal cells as well as microglia (Ghasemi et al., 2019). Furthermore, curcumin also rescues downregulated molecular chaperones in HD,

including Hsp40 and Hsp70, which have superior roles in the disease progression (Suzuki et al., 2023).

3.4 Multiple sclerosis

1. 3.4.1 Role of M1/M2 in multiple sclerosis The most prevalent autoimmune disease that results in non-
2. 3.4.2 Nutraceuticals that influence microglial activation in multiple sclerosis

The impact of different natural products and nutraceuticals on MS through regulation of M1/M2 microglia polarization is presented in Table 4 and Figure 6.

3.4.2.1 Emodin

Emodin (1, 3, 8-trihydroxy-6-methylanthraquinone), a chemical derived from herbs such as rhubarb, has a neuroprotective effect (Zhu et al., 2019). Emodin has been shown in studies to have a variety of pharmacological actions, including antioxidant, immunomodulatory, and anticancer activities involving autophagy and apoptosis (Mitra et al., 2022). Emodin suppresses the action of the casein kinase 2 protein kinase. In EAE, which is an inflammatory, autoimmune demyelinating condition that affects rodents’ CNS and is clinically and

pathologically similar to MS in humans, systemic casein kinase

1. 2 inhibition or its reduction in CD4+ T cells has neuroprotective effects (Gibson and Benveniste, 2018). In vitro investigations with female Sprague-Dawley rats and guinea pigs indicated that emodin reduced the severity of EAE; also, the expression levels of NLRP3 signaling pathway components, COX-2, TNF-α, and IL-

1. 6 were lowered in the EAE group treated with emodin (Cui et al.,

1. 2023). COX-2 is secreted by immune cells, and its greater expression could indicate immune cell activity and increased inflammation (Nitric et al., 2005). Treatment with emodin restored iNOS and NO production in the research, which is consistent with the benefits of Emodin treatment found in other animal models of disease, suggesting the therapeutic effects of emodin in EAE rats and the probable involvement of the

NLRP3 signaling system (Hu et al., 2021). Furthermore, produced inflammatory cytokines can encourage the aggregation and activation of resting microglia, which in response produce inflammatory cytokines, creating a vicious cycle (Wu et al., 2021). However, they discovered that emodin therapy decreased microglial aggregation and activation in EAE mice and lowered inflammatory levels in BV2 cells, resulting in neuroprotective advantages. Nonetheless, they discovered that EAE rats had lower levels of sirtuin 1 and Peroxisome proliferator-activated receptor-gamma coactivator expression and higher levels of NLRP3 inflammasome component expression than EAE + emodin rats. In EAE rats, emodin therapy resulted in elevated sirtuin 1 and Peroxisome proliferator-activated receptor-gamma coactivator levels as well as symptom relief (Cui et al., 2023).

1. 3.4.2.2 Gallic acid Gallic acid (GA), a secondary metabolite abundant in many

plants, nuts, and fruits, has been associated with anti-inflammatory activities. GA’s anti-inflammatory activities have been attributed to its capacity to interfere with MAPK and NFκB signaling, restricting immune cell activation and effector qualities (Bai et al., 2021). The phenethyl ester of gallic acid (PEGA) was developed to enhance gallic acid bioavailability and consequently its therapeutic potential. PEGA has been demonstrated to affect the inflammatory activities of T-cells and macrophages/microglia in an in vivo study of its effects on encephalitogenic cells (Stegnjai et al., 2022b) PEGA lowered the inflammatory potency of T-cells and microglia by inhibiting their ability to produce or release IL-17 and IFN-γ, as well as IL-6 and NO. Additionally, it significantly limits ongoing inflammatory responses against the CNS while also alleviating EAE. The reported effect of PEGA on T cells in the lymph nodes and the spinal cord’s ability to produce IFN-γ and IL-17 is particularly relevant for its advantageous effect on EAE.

Furthermore, limiting NO production by immune cells in the CNS is critical for PEGA’s beneficial impact on EAE. Much of the CNS tissue death during neuroinflammation is caused by the harmful effects of NO and its metabolite peroxy-nitrite (Spasojevic and Miljkovic, 2013). Furthermore, macrophage/ microglia production of inflammatory cytokines TNF-α and IL-6 have been related to the etiology of CNS autoimmunity (Shemer and Jung, 2015; O’Loughlin et al., 2018). As a result, the suppressive impact of PEGA on the release of IL-6 in macrophages/microglia and TNF-α in microglia may contribute to the agent’s amelioration of EAE. PEGA’s inhibitory effects on NO, TNF-α, and IL-6 are consistent with the previously reported effects of GA and GA-like substances on immune cells in both in vivo and in vitro studies (Stegnjai et al., 2022b).

1. 3.4.2.3 Flavonoids Flavonoids are plant-derived natural chemicals that have

powerful anti-oxidant, anti-inflammation, and antineurodegeneration properties (Lima et al., 2016). Agathisflavone (FAB) is a bioflavonoid isolated from Poincianella pyramidalis that has minimal toxicity and a variety of biological activities, including anti-inflammatory, neuroprotective, and neurogenic properties, as well as the ability to reduce astrogliosis and microgliosis after lysolecithin-induced demyelination (Almeida et al., 2020; dos Santos Souza et al., 2018). Proteolipid protein, a cholesterolassociated protein with important roles in myelin membrane intracellular trafficking; myelin basic protein, is a key protein involved in myelin compaction. Meanwhile, cyclic nucleotide phosphodiesterase is an important protein involved in the maintenance of a normal inner tongue during the myelination of small-diameter axons. The absence of any of these proteins results in significant myelin sheath alterations and/or demyelination (Snaidero et al., 2017). In the previous investigations at doses above 5 μg, FAB enhances the amount of myelin basic protein immunolabelling of NF+ axons in postnatal cerebellar slice cultures. At these doses, however, the numbers of oligodendrocyte progenitor cells and oligodendrocytes were unaltered, showing that FAB enhanced the degree of myelination per oligodendrocyte rather than increasing their overall number (Almeida et al., 2022). Although, they

demonstrate how FAB affected microglial morphology, reducing soma size and ramification while enhancing the expression of the calcium-binding protein Iba1. On the other hand, FAB did not influence microglial connections with oligodendrocytes, which may be essential to the release of trophic substances onto oligodendrocytes (Ioannidou et al., 2014; Domingues et al., 2016). FAB modulates microglia, which is consistent with in vitro data that FAB is anti-inflammatory and may shift microglia to a less active state (Almeida et al., 2022).

1. 3.4.2.4 Sinomenine An alkaloid called Sinomenine exists in the roots of Sinomenium
2. 3.4.2.5 Rosmarinic acid Rosmarinic acid is a polyphenolic chemical found in abundance

in Lamiaceae herbs. It has been shown to have powerful antiinflammatory effects both in vitro and in vivo studies (Luo et al., 2020). Rosmarinic acid has been demonstrated to block the T helper-17 axis in psoriasis-like illness in mice, as well as dendritic cell antigen-presenting potency in vitro (Zhang et al., 2021). These rosmarinic acid actions are crucial for MS therapy because T-helper17 cells are among the most significant pathogenic cells in this disease (Murúa et al., 2022). Rosmarinic acid’s in vivo effects are limited because its polar carboxylic acid group inhibits the compound’s ability to permeate cellular membranes. To increase its bioavailability, lipophilic ester- and amide-derivatives of rosmarinic acid (Gerogianni et al., 2018), such as phenethyl ester of rosmarinic acid (PERA), were synthesized (Stegnjai et al., 2022a). A recent study showed that PERA significantly lowers the clinical course of EAE. This effect corresponds to a decrease in NO in both the CNS and the peripheral immune compartment. In addition, PERA inhibits IFN-γ and IL-17 production by popliteal lymph node cells and spinal cord immune cells in an in vitro study (Stegnjai et al.,

2022a). NO, and its product peroxynitrite is a significant participant in the destruction of CNS tissue during neuroinflammation (Cross et al., 1997). Indeed, significant amounts of NO released locally within the CNS were found to be harmful in DA rats with EAE (Miljković et al., 2011; Petković et al., 2013). Thus, the reported NOinhibiting actions of PERA on macrophages and microglia are extremely relevant to the PERA model’s positive benefits. Furthermore, PERA’s inhibitory effect on microglia release of the inflammatory cytokines; TNF-α and IL-6, is likely to contribute to the compound’s demonstrated positive effects in EAE, as microglia production of these cytokines has been linked to the etiology of CNS autoimmunity (Shemer and Jung, 2015; O’Loughlin et al., 2018). These PERA effects are consistent with the previously documented effects of rosmarinic acid and its related compounds on NO, TNF-α, and IL-6 in vivo and in vitro (Stegnjai et al., 2022a).

1. 3.4.2.6 a-Linolenic acid–valproic acid conjugate Rossi et al. developed medications that incorporated valproic

acid and a-linolenic acid, either linked or conjugated. By using N9 microglial cells that have been treated with 100 ng/mL LPS, they found that diamide conjugate and ethanolamide conjugate significantly reduced microglia production of the M1 proinflammatory marker iNOS at low concentrations (0.5 μM) (Rossi et al., 2020).

1. 3.4.2.7 Resveratrol Resveratrol regulates TLR4 signaling, and immunological

activators such as LPS, along with additional immune stimulants (Malaguarnera, 2019). The NF-kB pathway, COX-2 pathway, TLR expression, and activation of the NLRP3-inflammasome are all inhibited by resveratrol, which mediates these effects and promotes the production of anti-inflammatory M2 macrophages (Moudgil and Venkatesha, 2023). As a result, an approach being developed to treat MS involves intranasal delivery of RAW-Exo formulation with added resveratrol had led to improving the clinical progression of MS in an in vivo study, and greatly reduced inflammatory responses in the CNS and peripheral system, by affecting microglia (Zheng et al., 2023).

3.4.2.8 Huperzia serrata

Huperzia serrata has been demonstrated to play a role in several animal models of neurological illnesses, as well as to alleviate cognitive impairment, diminish neuroinflammation, improve neuroprotection by boosting cortical inhibition, and enhance neuroprotection at low dosages. Multiple in vivo and in vitro research investigations have demonstrated that H. serrata may directly influence microglia to decrease CNS inflammation. It was discovered that the hippocampus and corpus callosum both had considerably fewer microglia following H. serrata therapy. In the H. serrata-treated mice, there were significantly fewer microglia branch endings and shorter overall branch lengths, indicating that H. serrata could effectively control microglia activation (H. Zhang et al., 2022). It has been proven that the pathophysiology of MS corresponds to the microglia-associated mRNA of proinflammatory and anti-inflammatory genes. Quantitative RT-PCR was applied to assess the mRNA expression of several proinflammatory and anti-inflammatory genes in the microglia to examine the potential role of H. serrata in cuprizone-induced

inflammation. According to the study’s results, H. serrata significantly upregulated the mRNA expression of antiinflammatory microglia-associated genes (iNOS and CD16) while significantly downregulating the mRNA expression of genes related to pro-inflammatory microglia (Zhang et al., 2022).

1. 3.4.2.9 Icariin Icariin is a naturally present flavonoid glucoside that has been
2. 3.4.2.10 Baicalein The primary flavonoid found in S. baicalensis Georgi, a

traditional Chinese medicine, is called baicalein. It exhibits antioxidant, anti-inflammatory, anticancer, antiviral, and neuroprotective pharmacological activities. (Ma et al., 2022). Iba1 is an indication of activated macrophages and microglia. Arg1 is a polarized marker for M2 microglia/macrophages, while iNOS is a marker for M1 microglia/macrophages. In recent in vivo and in vitro studies, the number of microglia and macrophages that were both iNOS- and Iba-1-positive decreased considerably after baicalein therapy. In addition, resulting from baicalein treatment, Iba-1, and iNOS expression significantly lowered in comparison to the EAE model group. Nonetheless, qRT-PCR was applied to identify the expression of M1 inflammatory markers in each group’s mouse spinal cord. The outcomes demonstrated that animals receiving baicalein or dexamethasone had significantly lower mRNA levels of iNOS, CD86, IL-12p35, IL-12p40, and IL-18 in their spinal cords than the EAE model group (Ma et al., 2022).

Concerning human data, a few randomized clinical trials have been conducted for neurodegenerative disorders after natural product administration. Only a small number of clinical research has looked at the impact of curcumin on human cognitive performance in AD, compared with animal studies. The findings of these investigations are contradictory. Some studies show no cognitive enhancing benefits of curcumin (Baum et al., 2008; Ringman et al., 2012), whilst other studies suggested a positive effect of curcumin on cognition (Cox et al., 2015; Rainey-Smith et al., 2016; Small et al., 2018). Several investigations reveal protective

mechanisms of curcumin against cognitive impairment, similar to animal research (Baum et al., 2008; Small et al., 2018). However, neuroimaging suggests that curcumin reduces Aβ deposits in the brain (Small et al., 2018). Results regarding Aβ reduction are ambiguous because most peripheral measurements, such as plasma, serum, and CSF levels, have not detected significant changes in Aβ or tau levels between curcumin and placebo (Baum et al., 2008; Ringman et al., 2012). Unfortunately, only one study by Baum et al. published measures of oxidative stress biomarkers, while no other study reported measurements of inflammatory biomarkers, even though these are the principal targets of curcumin and have demonstrated significant improvement in animal research (Baum et al., 2008). Meanwhile, data from human studies of curcumin in Huntington’s disease is lacking, and clinical trials should be strongly promoted in this area.

Regarding resveratrol, a phase II clinical trial evidenced the safety and well-tolerated effects of 500 mg orally once daily resveratrol on mild to moderate AD patients for 52 weeks, with no observed effects on AD biomarkers (Turner et al., 2015). However, decreased MMP 9 in CSF, controlled neuroinflammation, adaptive immunity generation, and attenuated cognitive decline were confirmed in further investigation (Moussa

1. et al., 2017). Meanwhile, another randomized placebo-controlled study on a small number of AD patients that received resveratrol (5 mg/day), showed less cognitive deterioration. In contrast, a dose of 200 mg/day of RV for 26 weeks did not experience any appreciable improvements in verbal memory function in 60 elderly individuals (Huhn et al., 2018).

Furtherly, in patients with AD, H. serrata appears to positively impact the restoration of cognitive function, performing everyday tasks, and overall clinical assessment (Yang et al., 2013). In addition, according to a clinical investigation, taurine has a positive effect on PD patients’ motor symptoms, and its levels in their plasma were decreased (Zhang et al., 2016). A prospective cohort study showed that a-Linolenic acid is associated with improved magnetic resonance imaging lesions activity in 87 multiple sclerosis patients (Bjornevik et al., 2019).

In our review, we emphasized the role and polarization control of microglia in the pathophysiology of neurodegenerative disorders and briefly introduced the function and phenotype of microglia to explore prospective therapeutic approaches. Transcription factors, receptors, and cytokines are merely a few examples of the numerous categories that modulate microglia polarization from M1 to M2. TNF-α, ILs, CXCLs, ROS, and NO, which have pro-inflammatory and neurotoxic effects, are released when the M1 phenotype is activated by IFN- γ, LPS, and TLR pathways. Meanwhile, M2 microglia are activated by different types of ILs to release abrineurin and anti-inflammatory cytokines, such as TGF-β, which suppress inflammatory responses and have neuroprotective effects. NcRNAs, such as miRNA-155, miR-23b-3p, and circHIPK3, seem to represent key factors in shifting microglia from M1 to M2. Consequently, inhibiting M1 microglia and promoting M2 microglial activation is required for neurodegenerative cure.

In AD, curcumin, aromatic-turmerone, caeminaxin A, myricetin, aurantiamide, 3,6′-disinapoylsucrose, and resveratrol restored the normal balance of M1/M2 markers in microglia, which was also achieved by plant extracts of D. cochinchinensis stemwood and O. majorana L. Microglia-mediated apoptosis was prohibited because of andrographolide, sulforaphane, triptolide, xanthoceraside, and piperlongumine inhibition of Aβ-induced microglial M1 activation. In PD, urolithin A, kurarinone, asarone, galangin, baicalein, and mangostin hindered ROS and pro-inflammatory cytokines in M1activated microglia. Further, icariin and tenuigenin suppressed microglial neurotoxicity via inhibiting NLRP3 inflammasome. Likewise, citronellol, myrcene, a-cyperone, nobiletin, taurine, plantamajoside, and swertiamarin showed neuroprotective effects in Parkinson’s. Similarly, elderberry, curcumin, iresine celosia, Schisandra chinensis, gintonin, and pomiferin showed promising results in improved symptoms in HD patients. In MS, linolenic acid, resveratrol, H. serrata, icariin, and baicalein are potent inhibitors of microglial activation, in addition to emodin, PEGA, FAB, sinomenine, and PERA, which all showed improved disease outcomes. Therefore, additional studies are required to resolve the significant enigma surrounding microglia polarization. It is important to note that these studies in the particular context of neurodegenerative illnesses clearly demand additional research. Moreover, several regulators of the microglia phenotype, which connects cytokine and signal pathways, may be linked to one another. It is still unknown how other risk genes affect microglia polarization in neurodegenerative disorders. Finally, the available findings encourage incorporating the natural product in treatment guidelines for neurodegenerative diseases, but more proof from randomized controlled studies on their effectiveness is highly warranted.