# Natural Products for Neurodegeneration: Regulating Neurotrophic Signals

Authors: Md Sahab Uddin; Abdullah Al Mamun; Md Motiar Rahman; Philippe Jeandet; Athanasios Alexiou; Tapan Behl; Md Shahid Sarwar; Eduardo Sobarzo-Sánchez; Ghulam Md Ashraf; Amany A. Sayed; Ghadeer M. Albadrani; Ilaria Peluso; Mohamed M. Abdel-Daim
Journal: Oxidative Medicine and Cellular Longevity
 (2021)

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## Abstract

Neurodegenerative disorders (NDs) are heterogeneous groups of ailments typically characterized by progressive damage of the nervous system. Several drugs are used to treat NDs but they have only symptomatic benefits with various side effects. Numerous researches have been performed to prove the advantages of phytochemicals for the treatment of NDs. Furthermore, phytochemicals such as polyphenols might play a pivotal role in rescue from neurodegeneration due to their various effects as anti-inflammatory, antioxidative, and antiamyloidogenic agents by controlling apoptotic factors, neurotrophic factors (NTFs), free radical scavenging system, and mitochondrial stress. On the other hand, neurotrophins (NTs) including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT4/5, and NT3 might have a crucial neuroprotective role, and their diminution triggers the development of the NDs. Polyphenols can interfere directly with intracellular signaling molecules to alter brain activity. Several natural products also improve the biosynthesis of endogenous genes encoding antiapoptotic Bcl-2 as well as NTFs such as glial cell and brain-derived NTFs. Various epidemiological studies have demonstrated that the initiation of these genes could play an essential role in the neuroprotective function of dietary compounds. Hence, targeting NTs might represent a promising approach for the management of NDs. In this review, we focus on the natural product-mediated neurotrophic signal-modulating cascades, which are involved in the neuroprotective effects.


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## Body

## 1. Introduction

Neurodegenerative disorders (NDs) are global health burdens that result from the progressive defect of neural cells, leading to dysfunction in the nervous system [1, 2]. The World Health Organization (WHO) predicts that, by 2050, people living with dementia are projected to triple from 50 million to 152 million [3]. Various NDs including Alzheimer’s disease (AD), Huntington’s disease, amyotrophic lateral sclerosis, Parkinson’s disease (PD), and frontotemporal dementia exert a deleterious burden not only on the affected persons but also on their family members as well as the society [4, 5]. Every year, USA spends billions of dollars on uninterrupted health care expenses and lost profits, and it is assessed that $100 billion is spent only on AD each year [6]. Apart from these financial matters, there is a huge emotional and pathetic burden on AD individuals and their caretakers [7].Several neurodegenerative diseases share similar pathogenetic mechanisms at various steps of the disease development including mitochondrial dysfunction, increased nitrosative/oxidative stress, protein aggregation/misfolding, loss of synaptic function, and reduced neuronal survival [8–11]. While immune cells and neurons are exposed to lethal proteins, higher energy is required to protect them from the deposited nitrogen and oxygen species responsible for neuronal damage. These latter induce a mitochondrial dysfunction with the release of cytochrome c along with other mitochondrial proteins thus leading to cell death [8, 10]. This protein accumulation disturbs cell signaling as well as neuronal functions which are considered as the main causes of neuronal disorders [12, 13].Neurotrophins (NTs) or neurotrophic factors (NTFs) are a group of essential growth factors, which are required for the regulation, persistence, and renewal of certain neuronal cells in the brain [14, 15]. NTs have been recognized as neuronal survival-promoting proteins in animals and include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3, and NT-4/5 [16, 17]. By modulating synaptic plasticity, BDNF serves as a key molecule in neurodegenerative diseases [18, 19]. Furthermore, BDNF gene delivery is a potential therapy for tau pathology in Alzheimer’s disease [20]. Some phytochemicals stimulate neuronal cell differentiation and upregulate NTs including BDNF and NGF [21–25]. Phytochemicals may thus have the potential to inhibit neurodegeneration by triggering NTs and by upregulating the function of several constituents of the antioxidant system, for example, catalase and superoxide dismutase (SOD) [26, 27]. Also, they may hinder the formation of several inflammatory mediators and reactive oxygen species (ROS) such as nitric oxide (NO), nuclear factor kappa B (NF-κB), intrinsic nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), prostaglandin (PG) E2, and interleukin (IL)-1β. NGF induces the tropomyosin receptor kinase (Trk) A signaling cascade [21–24] by preventing the protein expression pathway [28] and through the breakdown of amyloid β (Aβ) peptides in the brain [29]. Among natural products, polyphenols, in particular, initiate NTs and have antiapoptotic as well as antioxidative actions in neurons. In this review, we present the natural products that can modulate the neurotrophic signals to treat NDs.


## 2. Cellular Interactions between Neurotrophic Factors and Their Receptors for Neuroprotection

NTFs control the development, progression, plasticity, and function of neurons and defend neuronal cells against apoptosis [30]. NTFs are divided into the neurotrophic cytokines (neurokines), the neurotrophin family, the glial cell line-derived neurotrophic factor (GDNF) family of ligands, and new NTF members, such as the mesencephalic astrocyte-derived neurotrophic factor (MANF), the cerebral dopamine neurotrophic factor (CDNF), the basic fibroblast growth factor (bFGF), and the ciliary neurotrophic factor (CNTF) [31]. NTs such as NGF, BDNF, NT-3, and NT-4 bind with two distinct receptors, namely, Trk receptors and p75 neurotrophin receptor (p75NTR). The initiation of Trk receptors stimulates the survival of neurons, while p75NTR induces cell apoptosis. NTs have a selective high affinity to different Trk receptors. For instance, TrkA displays a high affinity toward NGF, whereas TrkB and TrKC show a higher affinity toward BDNF and NT-3 and NT 4/5, respectively [32]. Several NTFs including BDNF, NT-3, NGF, NT 4/5, bFGF-2, and erythropoietin (EPO) prevent neurons from injury. Consequently, they are capable of restoring NDs by interacting with the Trk receptor and enhancing the growth, survival, and regulation of neurons [33]. Among NTs, NGF was the first identified growth factor and has been shown to improve the survival of neurons and outgrowth of neurite ganglia in terrestrial birds by using the tissues of mouse sarcoma [33]. NTs expedite distinct intracellular signaling pathways, such as the Ras/extracellular signal-regulated kinases (ERK), phosphatidylinositol 3-kinase (PI3K)/AKT, and phospholipase Cγ pathways, through their binding to the related receptors [34].Furthermore, NTs activate downstream signaling targets to control cell survival and enhance synaptic as well as neurite outgrowth for maintaining cell volume or to increase rescue from neurodegeneration [35]. NTs accelerate the transcription of the Trk receptor via Brn3a, Kruppel-like factor 7, c-Jun, NeuroD, and cAMP response element-binding (CREB) protein [36]. NTs deficiency that inhibits the expression of the Trk receptor and may result in defects of the cognitive neurons. Interestingly, spicatoside A, a steroidal saponin derived from Liriope platyphylla Wang et Tang, enhances the release of NTFs in primary astrocyte cells and C6 glioma to increase long-term potentiation [23, 37–39]. NTs also exhibit a weak affinity towards p75NTR due to structural resemblances with the receptors of the Trk family [40]. Importantly, p75NTR induces the cell death promoting the TNF receptor superfamily involving several factors, for instance, Fas ligand, TNF receptor-I, TNF receptor-II, OX40, CD40, and TNF [41]. Dimeric NTs interact with p75NTR monomers by the formation of a disulfide bond with a cysteine-rich intracellular repeating domain as well as causing a structural alteration of the receptor [42–44]. This alteration then triggers an enzymatic induction of an adaptor protein by c-Jun N-terminal kinase (JNK) and NF-κB that lead to proliferation as well as survival through B cell lymphoma-2 (Bcl-2), or apoptosis via caspases [42–44].NT binding causes the initiation of the Trk receptor, triggering oligomerization and transautophosphorylation of the tyrosine moiety in the intracellular domain. This event subsequently leads to the initiation of signaling transduction inside the cell through stimulation of the Ras/mitogen-activated protein kinase (MAPK) pathway resulting in CREB-dependent NT secretion and expression of Bcl-2, which finally enhances cell survival, development, and proliferation [45]. Apart from analyses reporting on the functions of NGF itself, analyses of NGF mimetics along with NGF inducers are currently in development. NGF can improve the cellular growth rate and differentiation and the development of neurite, which can positively enhance memory and learning in AD patients [46, 47]. Also, NT insufficiency plays a pivotal role in neuropathy [48]; thus, research on phytochemicals that can potentiate NT is essential to combat NDs [44]. In the brain, neurotrophic factors cannot pass through the blood-brain barrier (BBB), and various approaches have been used to increase their delivery [49, 50]. Furthermore, GDNF had administered into the putamen either directly or indirectly by the transplantation of GDNF-producing cells as well as by using gene therapy employing recombinant lentiviruses or adeno-associated viruses in some clinical studies with PD patients [51, 52]. As a different delivery approach, small molecules that can penetrate through the BBB have been advocated to enhance the endogenous NTF expression for clinical trials. Levodopa and dopamine agonists, glutamate antagonists, antipsychotics, and antidepressants increase the level of GDNF and BDNF in the brain [19, 53–55]. Selegiline and rasagiline elevate the level of BDNF and GDNF in the cerebrospinal fluid in cellular and animal models as well as PD patients [56–59]. Ras-PI3K-Akt survival pathway activation could play a role in rasagiline’s neuroprotective effect in post-1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced parkinsonism [56]. Study also found that selegiline possesses trophic-like properties that are independent of MAO-B inhibition. Selegiline enhances NGF formation and protects neurons from excitotoxicity and ischemia in the central nervous system [57].


## 3. Neurotrophic Activity of Natural Products for Neuroprotection

Epigallocatechin gallate (EGCG), curcumin, epicatechin, quercetin, resveratrol, and citrus flavonoids (i.e., hesperetin and naringenin), all these compounds being polyphenols, can pass through the BBB and possess the function like NTF in the brain [60]. Various phytochemicals display neurotrophic functions by attaching with NTF receptors leading to initiation of the downstream signaling cascades as well as increased production of endogenous NTFs and receptors [9] (Figure 1).Figure 1
Role of phytochemicals involved in neuroprotection against neurodegeneration. Phytochemicals or neurotrophins bind to Trk receptor that subsequently activates PL-Cγ, Ras/MAPK, and PI3K/AKT pathways. Then, these signaling cascades trigger CREB that ultimately plays a pivotal role in protecting neurons to combat neurodegeneration. Furthermore, phytochemicals or neurotrophins also attach with NGF-p75NTR receptor and activate bidirectional cell survival and apoptosis through NF-κB and JNK signaling pathways.Diosmetin (5,7,3′-trihydroxy-4′-methoxy flavone), 7,8,3′-trihydroxyflavone (7,8,3′-THF), 7,8-dihydroxyflavone (7,8-DHF), and deoxygedunin are polyphenols which form complexes by binding to TrkB, initiating PI3K-Akt-ERK cascade, enhancing BDNF, and facilitating survival of spinal ganglion neurons, hippocampal neurons, and cultivated motor neurons [61, 62]. Curcumin triggers TrkB-MAP kinase along with PI3K pathways, elevates the BDNF level, and prevents cerebral cortical neurons from glutamate excitotoxicity in rats [63]. A naturally occurring compound, 6-methylsufinylhexyl isothiocyanate (6-HITC, an analogue of sulforaphane), extracted from Wasabia japonica (Miq.), intensely improved the neurite outgrowth and the expression of light neurofilament-L and TrkA phosphorylation in the presence of NGF because 6-HITC that inhibits the activity of protein tyrosine phosphatase 1B, a specific phosphatase that affects the phosphorylation status of TrkA [64]. Gambogic amide, a natural compound used in Chinese medicine, also triggers the TrkA and neuroprotective signaling pathways [65]. In contrast, epicatechin was proven to prevent the expression of p75NTFR and inhibit retinal neurodegeneration in diabetic rats [66].Furthermore, apigenin inhibits p38 MAPK, ERK1/2, and JNK as well as controls NGF-mediated neurite outgrowth in PC12 cells [67]. Apigenin has also an obvious permeability coefficient in the BBB, and therefore, it considers as a promising phytochemical for treating NDs [68]. Berberine treatment inhibits the generation of Aβ-induced monocyte chemotactic protein-1 and IL-6 and downregulated the expression of iNOS and Cox-2 in primary microglia as well as BV2 cells. This antineuroinflammatory effect was accomplished probably through suppression of the NF-κB activation [69]. Curcumin weakens Aβ mediated apoptosis by suppressing the activation of NF-κB (Figure 1) stimulated by the p75NTR cell death receptor [70]. According to the study by Yang et al. [71], curcumin demonstrated a significant neuroprotective action by upregulating the expressions of BDNF TrkB and PI3K protein level via the activation of the BDNF/TrkB dependent pathway in the 6-hydroxydopamine-mediated PD rat model.Phytochemicals stimulate other receptors for the regulation of brain functions. In animal experiments, flavonoids along with other phytochemicals have shown anxiolytic activities via the binding with receptors calledγ-aminobutyric acid A (GABA-A) at the sites of nonbenzodiazepines and benzodiazepines [72–75]. Furthermore, GABA receptors induce anthocyanin-mediated neuroprotection from ethanol toxicity in prenatal rat hippocampal neurons [76] and by baicalin from global reoxygenation injury in gerbil neurons [77]. The α4 and α7 subunits of nicotinic acetylcholine receptors are linked with the neuroprotection afforded by scutellarin from Aβ1-42-induced cytotoxicity in rats [78] and by EGCG in cultivated cortical neurons [79]. Curcumin prompts serotonin-1A (5-HT1A) receptor and stimulates hippocampal neurogenesis as well as the expression of BDNF in stressed rats [80] and neuroprotection against neural cell death induced by corticosterone [81]. In depressed mouse model analyses, ethanol extracts of Hemerocallis citrina var. vespertina initiate ERK as well as G protein-linked receptors and subsequent cascades and exhibit antidepressant action [82] by binding to 5-HT2, 5-HT1A, and dopaminergic D2 receptors as well as noradrenergic α1-, α2-, and β-adrenoreceptors. The ethanol extract of Scutellaria baicalensis Georgi. protects cell cultures of primary rat cortical neurons against glutamate toxicity by binding with the glycine-binding site of the N-methyl-D-aspartate receptor [83]. Estrogen and insulin-like growth factor-1 (IGF-1) receptors facilitate NTF stimulation and neuronal protection by various flavonoids (i.e., calycosin, luteolin, ginsenoside Rg1, genistein) in the PD rat model [84, 85].


## 4. Signal Regulating Potential of Natural Products Involved in the Neurotrophic Function

Most of the phytochemicals directly trigger enzymes and cellular signal molecules involved in neuroprotection (Figure1) [86, 87]. Genistein, resveratrol, EGCG, and curcumin protect neuronal cell cytotoxicity towards Aβ and 6-hydroxydopamine (6-OHDA) by the initiation of the cytoprotective protein kinase C (PKC) [88–91]. Phytochemicals activate tyrosine kinase, MAPK, PKC, PI3K/Akt, Ras-MEK1/2-ERK1/2 signalling pathway, and phosphorylate CREB, which play essential roles in enhancing the expression of target genes by binding with the CREB-binding protein (CBP) [92]. PKC-ERK1/2 signaling inhibits the decline of Bcl-2, Bcl-xL, and Bcl-w and raises the cytotoxic caspases (caspase-1, -7, -10), Bax, and Bad. Caffeine triggers the PI3K/Akt signaling cascade and inhibits cell death in in vitro cellular PD models through upregulation of the antiapoptotic Bcl-2 function [93]. Besides, ferulic acid deactivates Bad by reducing the downregulation of MEK-ERK-90 kDa ribosomal S6 kinase signaling in ischemia rats [94]. Flavonoids initiate Akt-ERK1/2 signaling and prevent proapoptosis of Bim and Bad and initiation of caspases (i.e., caspase-3, caspase-9) to defend neural cells against death [95].Carotenoids (i.e., lutein, astaxanthin, and lycopene) stimulate nuclear factor erythroid-derived 2-related factor 2 (Nrf2) (Figure2) by binding with the antioxidant response element (ARE) and activate phase II enzymes including glutathione S-transferases (GSTs), glutathione reductase (GR), NAD(P)H quinone oxidoreductase, glutathione peroxidase (GPx), and SOD [96]. Akt induces phosphorylation of forkhead box O3 and activates NF-κB that positively upregulates the expression of the Bcl-2 family and caspase (-3, -6, -9) inhibitors and inhibits the p53 gene [97].Figure 2
Phytochemicals activate the Keap-Nrf2-antioxidant response element cascade to increase the expression of antioxidant enzymes that fight against neurodegeneration.Resveratrol and the citrus flavanones hesperetin and naringenin competitively block adenosine triphosphate (ATP) binding of various protein kinases via linking to the ATP-binding sites of the Ca2+ membrane ATPase, mitochondrial ATPase, PKC, and PKA [98]. Baicalein [99], carnosol, carnosic acid [100], and hydroxytyrosol (i.e., a polyphenol from olive oil) [101] induce upregulation of endogenous antioxidant systems by dissociating the negative regulator, Kelch-like ECH association protein 1(Keap-1), from Nrf2 to stimulate the Nrf2-ARE signaling cascade. Moreover, initiation of polyphenol-mediated Nrf2-ARE signaling exerts neuroprotective effect by inducing heme oxygenase-1 (HO-1) expression in cultured neurons and blocking oxidative stress [102]. HO-1 has been shown to have anti-apoptotic effect. On the other hand phytochemicals can also block the expression of various well-known proapoptotic genes encoding Bax/Bad, cyclin-dependent kinase inhibitor p21, caspase-1, and TNF-linked apoptosis-inducing ligand [103].


## 5. Induction of the Neurotrophic Factor Expression and Their Receptors by Natural Products

In healthy individuals, coffee fruit extracts elevate plasma BDNF concentrations [104]. In females with premenstrual disorder, curcumin triggers the upregulation of serum BDNF concentrations and improves ailment [105]. The elevated expression of various NTFs and BDNF by phytochemicals (Figure 3) in cellular as well as animal experiments are appraised in Table 1. GDNF is induced by smilagenin [106] and catalpol [107] in an animal experiment of PD, in a rat model of EGCG-induced spinal cord damage [108], and a mouse model of hesperidin-induced depression [109].Figure 3
Chemical structures of the several phytochemicals that modulate the neurotrophic signals to attenuate neurodegeneration.Table 1
Promising studies regarding neurotrophic signals modulating potential of phytochemicals against neurodegeneration.
PhytochemicalsSpecies/studied materialExperimental modelDoseTherapeutic usesMechanismsInduced NeurotrophinsReferencesEpigallocatechin-3-gallateC57BL/6 miceSevoflurane-induced neurotoxicity25, 50, or 75 mg/kgNeuroprotectionActivates CREB/BDNF/TrkB and PI3K/Akt/mTOR signalling pathwayBDNF[110]RatsAcrylamide-induced neurotoxicity10 mg/kgNeuroprotectionEnhances acetylcholinesterase activity and reduces the expression of iNOS and COX-2 levelBDNF[111]Sprague–Dawley ratsSpinal cord injury10 and 20 mg/kgNeuroprotectionUpregulation of BDNF and GDNFBDNF, GDNF[112]PC12 cellsOxidative-radical-stress-induced apoptosis0, 50, 100, 150 or, 200μMNeurodegenerative disordersActivates PI3K/Akt and inhibits GSK-3NGF[113]CurcuminRatsStress-induced damage to hippocampal neurons5, 10, and 20 mg/kgEnhances hippocampal neurogenesisUpregulation of 5-HT(1A) receptors and BDNFBDNF[80].Male Sprague–Dawley (SD) rats6-OHDA-induced Parkinson’s disease5, 10, and 20 mg/kgNeural regeneration and neuroprotectionActivates Trk/PI3K signaling pathwaysBDNF[71]C57BL miceMPTP-induced mice0.5% or 2.0% (w/w)Neuroprotective effectIncreases expression of GDNF and TGFβ1GDNF[114]RatsAβ-induced cognitive impairments50 and 2.5 mg/kgImproves cognitive deficit and neuroprotectionActivates PI3K/Akt signaling pathways and inhibits GSK-3BDNF[115]Adult and aged miceD-galactose-induced300 mg/kgImproves cognitive impairmentActivates CREB signaling in the hippocampal dentate gyrusBDNF[116]Rodent cortical neurons5 and 10μMNeuroprotectionMediates through BDNF/TrkB-MAPK/PI-3 K-CREB signaling pathwayBDNF[63]ResveratrolAdult Wistar ratsTwo-vessel occlusion20 mg/kgNeuritogenesis, neuroinflammation, and neuroprotectionActivates ERK-mediated CREB regulation, induces BDNF, NGF, and GDNF secretion, and inhibits IL10, IL-1β, and NF-κB levelsBDNF and NGF[117]Female Wistar ratsDopaminergic neurons25–100μMProduces neurotrophic effectsPromotes the release of neurotrophic factorsBDNF and GDNF[118]Female Wistar ratsAstroglia-enriched cultures25-100μmmol/LNeurological diseasesInduces the phosphorylation of (ERK1/2) andCREB in astrogliaBDNF and GDNF[119].Male Wistar ratsChronic unpredictable mild stress-induced behavioral abnormalities20, 40 and 80 mg/kgAntidepressant-like effectsUpregulates pERK, pCREB, and BDNF levels in the hippocampus and amygdalaBDNF[120]Male Wistar ratsPhenylephrine-induced contraction of vascular smooth muscle cells10 mg/kgNeuroprotectionIncreases BDNF serum concentrations and reduces the contractility of resistance arteries via NOS-3-independent mechanismsBDNF[121]QuercetinMale ChineseKunming miceHigh-fat diet8.5 and 17 mg/kgImproves cognitive impairmentModulates PI3K/AKT/Nrf2 pathway and activates CREB pathwayBDNF[122]Adult male Sprague Dawley ratHypobaric hypoxia-induced memory deficit50, 75 or 100 mg/kgAmeliorates cognitive impairmentRegulates the expression of sirtuin 1, PGC-1α, and the proteins related with mitochondrial biogenesis and dynamicsBDNF[123].Male Wistar albino ratsStreptozotocin-induced diabetes model50 mg/kgNeuroprotectionAkt survival pathway, enhances the level of TrkB and Bcl-2, and reduces the level of both cytochrome c and caspase-3BDNF and NGF[124]Adult male albino ratsPolychlorinated biphenyls-induced neurotoxicity50 mg/kgProtects and prevents neuronal damagePrevents transmembrane tight junctional proteins and cytoplasmic accessory tight junctional proteins in the hippocampus and keeps the level of estradiolBDNF[125]DaidzeinH19-7/IGF-IR neural cell line20 nM -2000 nMNeuroprotectionBlocks a selective Trk receptors inhibitor, K252aBDNF[126]Alpinetin, luteolin, calycosin, isohamnerinPrimary rat astrocytes10μMImproves neurodegenerative diseasesTriggers estrogen signalingBDNF, GDNF and NGF[85]Ginkgolide BCultured hippocampal neuronsAβ25–35-induced apoptosis40μg/mlNeuroprotectionUpregulates BDNFBDNF[127]NaringinSprague-Dawley ratsSpinal cord injury20 and 40 mg/kgNeuroprotectionUpregulates BDNF and VEGF and the inhibits the neural apoptosisBDNF and VEGF[128]GenisteinPrimary rat astrocytes10μMImproves neurodegenerative diseasesTriggers estrogen signalingBDNF, GDNF and NGF[85]H19-7/IGF-IR neural cell line20 nM -2000 nMNeuroprotectionBlocks a selective Trk receptors inhibitor, K252aBDNF[126]Butein, fisetinMiceGlutamate-induced neurotoxicity40 mg/kgEnhances cognitive effectsInhibits iNOS and COX-2 and reactivates CREB-BDNF pathwayBDNF[129]ApigeninMiceMPTP-induced Parkinson’s disease mice5, 10 and 20 mg/kgTreatment of Parkinson’s diseaseReduces oxidative damage, neuroinflammation, and microglial activationBDNF[130]EpicatechinMale C57BL/6 J miceHippocampus of anxiety mice4 mg/dayTreatment of mood disordersModulates monoaminergic and neurotrophic systemsBDNF[131]Rosmarinic acidSprague-Dawley ratsChronic unpredictable stress10 mg/kgImproves depressive-like behaviorsAlters in ERK1/2 signalingBDNF[132]BaicaleinMiceChronic unpredictable mild stress1, 2, and 4 mg/kgTreatment of depressionTriggers ERK-mediated neurotrophic actionBDNF[133].Ferulic acidMiceCorticosterone-induced50, 100, or 250 mg/kgTreatment of mood disordersIncreases CREB phosphorylation and BDNF mRNA level in the hippocampusBDNF[134].Zhang et al. [135] found that chronic curcumin treatments activate ERK or N-methyl-D-aspartate-CREB signaling, accelerate the expression of BDNF, and enhance pathological, biochemical, and behavioral changes in an AD rat model induced by ventricular inoculation of Aβ1-42. An established antidepressant used in China called Xiao Chai Hu Tang (i.e., Minor Bupleurum Decoction) enhances the expression of NGF, BDNF, TrkA, and TrkB in a rat hippocampus of chronic mild stress [136]. In mouse, administration of olive polyphenols accelerates the expression of TrkB and TrkA, GDNF, and NGF in the olfactory bulbs and hippocampus, but not in the frontal cortex and striatum [137]. A Chinese herb, Rehmannia glutinous Libosch. used for the dementia, elevates GDNF mRNA in primary cortical astrocytes and C6 cells [138]. In the hippocampus, the initiation of TrkB, TrkA, and BDNF expressions is related to the antidepressant effects of phytochemicals via the progression of adult neurogenesis [139]. Flavonoids activate BDNF both in vitro and in vivo; however, GDNF is mainly activated by catalpol, resveratrol, curcumin, and various nonflavonoids. Flavonoids might enhance cognition, memory, as well as depression, while curcumin and resveratrol improve neuronal stress and inhibit apoptosis in AD and PD animal models. Besides, in cell line experiments, ginkgolides, EGCG, and curcumin derivatives accelerate the expression of BDNF in U118MG glioma cells more significantly than in SH-SY5Y neuroblastoma cells, advocating that glioblastoma cells may play crucial roles in the initiation of BDNF gene using phytochemicals [140].


## 6. Activation of Other Neurotrophic Pathways by Natural Products

Polyphenols that have numerous valuable functions in the nervous system offer a significant resource for the advancement of novel therapeutics for controlling NDs [141, 142]. Apart from the aforementioned signaling cascades associated with polyphenol-based neurotrophic effects, several other pathways might also be involved. Daidzein activity has resulted in substantial axonal development through the overexpression of the growth-associated protein (GAP)-43 in hippocampal neuronal cell cultures. Remarkably, daidzein-induced phosphorylation of GAP-43 and PKC has been removed by pretreatment with the endoplasmic reticulum (ER) as well as PKC antagonist. These analyses advocate that ER-induced PKC phosphorylation of GAP-43 may perform a pivotal role in daidzein-prompted axonal development [143]. Similarly, hesperetin can show diverse neurotrophic actions through TrkA- and ER-prompted parallel pathways [144].The Na+/K+/2Cl− cotransporter (NKCC) belongs to a member of the cation-chloride cotransporter family, which is involved in the passage of chloride ion(s) together with cation(s) through the plasma membrane [145]. Another experimental analysis has demonstrated that NGF-treated PC12D cells overexpressed the NKCC1 protein [146]. Copious studies revealed that NKCC1 knockdown intensely prevents NGF mediated-neurite development in PC12 cells. Remarkably, quercetin also stimulated NGF-prompted neurite development by rising Cl− ion levels, though NKCC1 knockdown suppressed this stimulation. In PC12 cells, the intracellular chloride ion level influences microtubule polymerization through alteration of the inherent GTPase activity of tubulin [147].A subclass of adenosine receptors A2A was demonstrated to increase the BDNF expression and the synaptic function of BDNF [148, 149]. Adenosine receptors also activate the TrkB receptor as well as the Akt pathway that prompts neuronal cell persistence and controls neurite development in various cell types [150–152]. Recently, Jeon et al. [153] revealed that oroxylin A might trigger BDNF outgrowth in cortical neurons through the stimulation of the A2A receptor that mediates neurite development, synapse formation, and cellular survival. In a subsequent study, the adenosine A2A receptor inhibitor was shown to inhibit methyl 3,4-dihydroxybenzoate-mediated neurite development as well as neuronal survival in primary cultures of cortical neurons [154].


## 7. Inhibition of Neurotoxin-Induced Damage by Natural Products and Associated Neurotrophic Signaling

Experimental analyses have shown that Aβ is an essential factor in AD pathogenesis [155, 156]. Numerous data propose that several polyphenols prevent neuronal cells from Aβ mediated neuronal damage or cell death. For example, icaritin has been revealed to defend primary rat cortical neuronal cells from apoptosis mediated by Aβ25-35 insults [157]. Also, Ushikubo et al. [158] showed that 3,3′,4′,5,5′-pentahydroxyflavone prevents the deposition of Aβ fibrils and that reducing fibril deposition and declines Aβ-mediated cell death in rat hippocampal neuronal cells. In an alternative analysis, p-coumaric acid, gallic acid, and ursolic acid isolated from Japanese Cornus officinalis Sieb. et Zucc. were proven to diminish proapoptotic functions including changes of nuclear morphology, deoxyribonucleic acid division, and Aβ-mediated cell blebbing in PC12 cells [159]. The primary flavonoids of cocoa, catechin, and epicatechin defend PC12 cells against Aβ-mediated neurotoxicity [160].The flavonoid liquiritin and a bioactive phenolic compound (carnosic acid), extracted fromRosemary, display protection against Aβ in primary cultures of hippocampal neurons and SH-SY5Y human neuroblastoma cells, respectively [161, 162]. 6-Hydroxydopamine (6-OHDA) is a neurotoxic synthetic organic compound that triggers pathology-like PD both in cellular and animal models. The trihydroxyflavone baicalein [163], caffeic acid derivatives, and ferulic acid [164] defend SH-SY5Y neuronal cells against 6-OHDA-induced neurotoxicity. Upon experimental analyses, ROS and hydrogen peroxide have been shown to stimulate neuronal cell injury [165]. In this case, numerous polyphenols including 7,8-DHF in RGC-5 and retinal ganglion cells (RGCs) [166], caffeic acid esters in PC12 cells [167], and quercetin in cultivated neuronal ancestor cells [168] are providing protection against ROS. Moreover, other researchers have proposed that the neuroprotective functions of 7,8-DHF are induced by its capacity to enhance the levels of cellular glutathione [169] by scavenging ROS.Additional neurotoxins have also been employed to set up investigational trials to evaluate the neuroprotective capability of polyphenolic compounds. Caffeic acid phenethyl ester (CAPE) prevents PC12 cells from dopaminergic neurotoxin 1-methyl-4-phenylpyridinium [170]. In the mouse brain, administration of 7,8-DHF decreases neuronal cell death stimulated by kainic acid [61]. Icariin, another diglycosylated polyphenolic compound derived from kaempferol, can protect a primary culture of rat hippocampal neuronal cells from corticosterone-mediated death [171]. Similarly, baicalein has been demonstrated to block necrotic cell death injury in nasopharyngeal carcinomas (NPCs) and to reduce the loss of radiation-induced hippocampal neurogenesis [172]. Polyphenols also revealed beneficial effects in animal experiments of NDs triggered by diverse neurotoxins. Oral intake of luteolin alleviates memory and learning dysfunctions, in an Aβ-stimulated mice model of amnesia [173]. Curcumin, derived from Curcuma longa L., has also been demonstrated to be efficient in inhibiting tau hyperphosphorylation, neuroinflammation, and behavioral damages, induced by Aβ in vivo [115].


## 8. Conclusion

The cellular mechanisms underlying the neuroprotective activity of phytochemicals must be elucidated to uncover a novel approach for developing drugs that able to interfere in the deterioration of brain activity in aging and age-related NDs. Mounting evidence recommends that enough attention should be paid towards clinical trials including these compounds. Therefore, it is essential to confirm the neuroprotective effects of these phytochemicals in various preclinical models and humans.



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