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Review

Modulation of neurotrophic signaling pathways by polyphenols

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Pages 23-42 | Published online: 21 Dec 2015

Abstract

Polyphenols are an important class of phytochemicals, and several lines of evidence have demonstrated their beneficial effects in the context of a number of pathologies including neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. In this report, we review the studies on the effects of polyphenols on neuronal survival, growth, proliferation and differentiation, and the signaling pathways involved in these neurotrophic actions. Several polyphenols including flavonoids such as baicalein, daidzein, luteolin, and nobiletin as well as nonflavonoid polyphenols such as auraptene, carnosic acid, curcuminoids, and hydroxycinnamic acid derivatives including caffeic acid phentyl ester enhance neuronal survival and promote neurite outgrowth in vitro, a hallmark of neuronal differentiation. Assessment of underlying mechanisms, especially in PC12 neuronal-like cells, reveals that direct agonistic effect on tropomyosin receptor kinase (Trk) receptors, the main receptors of neurotrophic factors including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) explains the action of few polyphenols such as 7,8-dihydroxyflavone. However, several other polyphenolic compounds activate extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/Akt pathways. Increased expression of neurotrophic factors in vitro and in vivo is the mechanism of neurotrophic action of flavonoids such as scutellarin, daidzein, genistein, and fisetin, while compounds like apigenin and ferulic acid increase cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation. Finally, the antioxidant activity of polyphenols reflected in the activation of Nrf2 pathway and the consequent upregulation of detoxification enzymes such as heme oxygenase-1 as well as the contribution of these effects to the neurotrophic activity have also been discussed. In conclusion, a better understanding of the neurotrophic effects of polyphenols and the concomitant modulations of signaling pathways is useful for designing more effective agents for management of neurodegenerative diseases.

Introduction

Polyphenolic compounds

Polyphenols are an important group of phytochemicals that are abundantly present in food sources.Citation1 Several lines of evidence have demonstrated beneficial effects of these compounds in the context of several pathologies,Citation2Citation8 and it has been repeatedly shown that consumption of foods rich in phenolic compounds can lower the risk of several diseases.Citation9,Citation10

Polyphenols have been reported to be of therapeutic value in neurodegenerative diseases,Citation11Citation13 hypertensionCitation14 and other cardiovascular diseases,Citation15 cancer,Citation16Citation18 inflammation,Citation19,Citation20 diabetes,Citation21 dyslipidemia,Citation22Citation24 allergy, and immune system diseases.Citation25,Citation26 They have also been reported to have a role in the prevention of different types of cancer ranging from liver,Citation4 prostate,Citation27 and colorectalCitation28 cancer to lymphoblastic leukemia.Citation29

Neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s disease represent rapidly growing causes of disability and death, which have profound economic and social implications; nonetheless, only few effective disease-modifying therapies are available for these diseases.Citation30Citation32 Recent research has shown that certain polyphenols may have considerable neuroprotective effects in different brain pathologies including neurodegenerative diseases.Citation8,Citation11,Citation33,Citation34 Polyphenols from grape juice administered to older adult subjects have been shown to ameliorate the mild cognitive impairment.Citation35 Similarly, Witte et alCitation36 have shown that administration of resveratrol, a polyphenol present in wine, in older adults significantly improves memory performance, indicating potential strategies to maintain brain health during aging. Assessment of cognitive performance in middle-aged individuals has indicated that consumption of different polyphenols such as catechins, flavonols, and hydroxybenzoic acids is strongly associated with language and verbal memory.Citation37 Other studies have also shown similar effects of other polyphenols on cognitive function and memory in older individuals, who are at risk for neurodegenerative diseases.Citation38,Citation39 In another human study, epigallocatechin–gallate (EGCG) significantly improved cognitive deficits in individuals with Down syndrome.Citation40

Several studies have demonstrated that different polyphenolics with neuroprotective activity, such as EGCG,Citation41,Citation42 epicatechin,Citation43 curcumin,Citation44 resveratrol,Citation45 quercetin,Citation46 and citrus flavonoids (naringenin and hesperetin),Citation47 are able to cross the blood–brain barrier and therefore indicate that these compounds localize within the brain tissue and may well exert neuroprotective and neuromodulatory actions in the settings of different brain pathologies.

Polyphenolic compounds can be classified into different groups as described in .Citation1 Among them, flavonoids constitute a major subgroup, which are highly present in fruits and vegetables and possess several biological activities.Citation1

Figure 1 Main classes of polyphenols and their chemical structures.

Figure 1 Main classes of polyphenols and their chemical structures.

Polyphenols have been extensively studied for their antioxidant actionCitation48Citation52 and some of their beneficial effects, including neuroprotective activity, have been attributed to this capacity.Citation53Citation55 The neuroprotective effect of polyphenols against the diseases of nervous system has also been addressed in a number of studies.Citation56Citation59 The aim of this review, however, is to extensively address the alterations of signaling pathways involved in the neurotrophic action of polyphenols that lead to neuronal survival, growth, proliferation, and differentiation. The other aspects of neuroprotective activity of these compounds, which are mainly ascribed to the antioxidant action and mitigation of oxidative stress, have been reviewed elsewhereCitation5,Citation7,Citation8,Citation60Citation62 and are only briefly mentioned here. It should also be mentioned that in in vitro studies, which are the main focus of this report, supraphysiological doses of polyphenols may have been used and, therefore, caution should be exerted in extrapolation of these data to in vivo conditions.Citation56 The structures of some of the most highly studied neurotrophic polyphenols are depicted in and .

Figure 2 Chemical structures of flavonoids with neurotrophic activity.

Figure 2 Chemical structures of flavonoids with neurotrophic activity.

Figure 3 Chemical structures of polyphenols with neurotrophic activity that do not belong to the group of flavonoids.

Figure 3 Chemical structures of polyphenols with neurotrophic activity that do not belong to the group of flavonoids.

Neurotrophic effects of polyphenols: Enhancement of survival in neuronal cells

Survival signaling is important to suppress the cell death machinery and counterbalance apoptotic signaling in the nervous system.Citation63 Several studies have shown that polyphenolic compounds enhance neuronal survival in serum-deprived conditions. Lin et alCitation64 showed that in neuronal-like PC12 cells, luteolin (3′,4′,5,7-tetrahydroxyflavone, ) attenuates serum withdrawal-induced cytotoxicity. Other examples of neuroprotectants that exerted prosurvival action in PC12 cells include curcuminoids, the predominant polyphenolic compounds of Curcuma longa Linn.;Citation65 EGCG (), the major polyphenol of green tea extract;Citation66 caffeic acid phenethyl ester (CAPE, ), an active component of propolis;Citation67 5-hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone (HHMF) from the Citrus genus; and nobiletin (), the most abundant polymethoxyflavone in orange peel extract.Citation68 Furthermore, other investigators have shown that treatment with genistein and daidzein (), isoflavones present in soybeans and soy products, enhances proliferation and survival of the hippocampal neuronal cells.Citation69 In addition, application of 7,8-dihydroxyflavone (7,8-DHF, ), a flavone, promotes survival of cultured motoneurons, spiral ganglion neurons (SGNs), and hippocampal neuronal cells.Citation70 In another study, the protective ability of quercetin (3,3′,4′,5,7-pentahydroxyflavone, ) on P19-derived neurons was determined.Citation71 Ferulic acid (4-hydroxy-3-methoxycinnamic acid, ) was able to significantly increase the survival of neural stem/progenitor cells (NSC/NPCs) cultured from rat embryo, and also increased the number and size of secondary formed neurospheres.Citation72

Promotion of neurite outgrowth in neuronal cells

Neurite outgrowth is a crucial step in the differentiation of neurons, which begins at the cell body and extends outward to form functional synapses. In response to extracellular signals, the growth of neurite processes starts, involving the addition of new plasma membranes, generation of new cytoplasm, and the continued expansion and modification of the cytoskeleton.Citation73 A number of neurotypic proteins have been associated with neurite outgrowth, including growth-associated protein 43 (GAP-43), microtubule-associated protein (MAP) and tau, as well as presynaptic membrane-associated proteins, such as synaptophysin and synapsin.Citation74 Many polyphenolic compounds from natural and synthetic sources have been demonstrated to induce neurite outgrowth in various primary neuronal cultures and neuronal cell lines ().

Table 1 Induction of neurite outgrowth by polyphenols and involvement of neurotrophic signaling pathways

Several studies have shown that different polyphenols including flavonoids such as genistein,Citation75 quercetin, liquiritin from Glycyrrhizae radix plant (),Citation76 isorhamnetin (a flavonolaglycone from Ginkgo biloba plant, ),Citation77 and acetylated flavonoid glycosides from ScopariadulcisCitation78 as well as the stilbenoid compound resveratrol (a polyphenol present in grapes and red wine, )Citation79 cause a significant enhancement of neurotrophin (nerve growth factor [NGF] and brain-derived neurotrophic factor [BDNF])-mediated neurite outgrowth in PC12 cells.

Some of the phenolic compounds are capable of enhancing the expression levels of the differentiation markers (GAP-43, neurofilament light subunit, synaptophysin, synapsin, etc). Flavonoids that are capable of causing such an effect include luteolin,Citation64 daidzein,Citation80 7,8-DHF,Citation81 citrus HHMF,Citation68 puerarin (an isoflavone),Citation82 CAPE,Citation67 curcuminoids,Citation65 tectoridin (an isoflavone from Belamcandachinensis plant), hesperidin (a flavanone glycoside from the genus Citrus of plants), and also flavonols including kaempferol, quercetin, and isorhamnetin.Citation77

The neuropathy induced by chemotherapeutic agents such as cisplatin is an important side effect of these drugs.Citation83,Citation84 Two polyphenolic compounds, in separate studies, have been tested to block or reverse the cisplatin-induced neurite toxicity in PC12 cells. Phenoxodiol (2H-1-benzopyran-7-0,1,3-[4-hydroxyphenyl]), a compound related to genistein, showed significant neurite-protective effects against cisplatin at 1 μM, a concentration that was not toxic to the PC12 cells.Citation85,Citation86 Curcumin () has also shown similar protective effects against cisplatin-induced neurite toxicity in PC12 cells. Moreover, curcumin did not interfere with the cisplatin’s antitumor mode of action as assessed in vitro in HepG2 cells.Citation87

Activation of tropomyosin receptor kinases

Mammalian neurotrophins including NGF, BDNF, neurotrophin 3 (NT3), and neurotrophin 4 (NT4) play major roles in development, maintenance, repair, and survival of specific neuronal populations.Citation88Citation90 Several lines of evidence indicate that decreased functioning of neurotrophins and their receptors can lead to neuronal injury and contribute to the pathogenesis of neurodegenerative diseases.Citation30,Citation91,Citation92 Thus, neurotrophins and bioactive compounds capable of activation of neurotrophin receptors have great potential for management of neurodegenerative diseases and other neurological disorders.Citation93,Citation94

Neurotrophins interact with two principal receptor types: p75NTR and the tropomyosin receptor kinase (Trk) receptors consisting of three receptors of TrkA, TrkB, and TrkC in mammals (also known as Ntrk1, Ntrk2, and Ntrk3).Citation95 Different patterns of Trk receptors’ expression exist throughout the mammalian brain and peripheral nervous system. TrkA is highly expressed in cholinergic neurons in the basal forebrain and also the peripheral nervous system, while TrkB and TrkC are highly expressed in the hippocampus.Citation96 These transmembrane receptors belonging to the group of receptor tyrosine kinases (RTKs) and the larger family of catalytic receptors include an extracellular neurotrophin-binding domain and an intracellular tyrosine kinase domain.Citation92,Citation97 NGF has a higher binding rate with TrkA, while BDNF and NT-4/5 bind with TrkB, and finally, NT-3 is the main ligand for TrkC receptor, with a lower affinity for TrkA and TrkB.Citation98 The neurotrophins-induced dimerization of the Trk receptors leads to activation through transphosphorylation of the cytoplasmic domain kinases and stimulates three major signaling pathways: phoshpatidyloinositol-3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK), and phospholipase C-γ1.Citation92 Downstream signaling principally promotes survival, growth, and neuronal differentiation and mediates neurogenesis and plasticity in many neuronal populations.Citation99Citation101

There are only few polyphenolic compounds that act as direct agonists of Trk receptors and mimic the binding of neurotrophins, while several others stimulate the more downstream pathways leading to the neurotrophic effect (discussed in the following sections). 7,8-DHF provokes TrkB dimerization and tyrosine phosphorylation and activates downstream Akt and extracellular signal-regulated kinase (ERK) as potently as BDNF. 7,8-DHF also inhibits neuronal death in T48, a stably transfected TrkB murine cell line, and hippocampal neurons, and its activity can be inhibited by K252a, a Trk receptor antagonist.Citation102 In another study, 7,8-DHF strongly activated TrkB receptor and its downstream Akt and ERK1/2 pathways, prevented cell death, and promoted neuritogenesis in the retinal ganglion cells.Citation103 It was also shown in a later report that 7,8-DHF as a BDNF agonist causes phosphorylation of TrkB receptors and stimulates survival and neurite growth of cultured motoneurons: PI3K/Akt but not MAPK pathway was responsible for the survival and growth promoting effects of 7,8-DHF,Citation70 which is apparently different from MAPK activation mediated by 7,8-DHF in hippocampal neurons.Citation102

Furthermore, 7,8,3′-trihydroxyflavone, a compound related to 7,8-DHF, has shown similar effects on the survival of SGNs, phosphorylation of TrkB receptor, and ERK.Citation104 Diosmetin, another polyphenol compound belonging to flavonoids class of polyphenols, has also shown antiapoptotic effects, but it induces only weak phosphorylation of TrkB. Diosmetin also increased the phosphorylation of Akt and ERK.Citation102 Another flavonoid, epicatechin, restores TrkA phosphorylation in diabetic animals and reduces diabetes-induced neuronal cell death. It also blocks diabetes-induced p75NTR expression and p75NTR apoptotic pathway in vivo and in Müller cells.Citation105

Modulation of expression of neurotrophic factors and Trk receptors

Several polyphenols increase the expression levels of neurotrophins and Trk receptors (). Scutellarin, isolated from the traditional Chinese herb, Erigeron breviscapus (), alpinetin of the genus Alpinia, and also luteolin, calycosin, genistein, and isorhamnetin effectively upregulate the synthesis and release of NGF, glial cell line-derived neurotrophic factor (GDNF), and BDNF.Citation106,Citation107 The capacity of luteolin, genistein, calycosin, and isorhamnetin in increasing the expression of neurotrophins was mediated through estrogen signaling pathways. In the estrogen receptor (ER)-dependent pathway, the phosphorylated ER dimer was demonstrated to elevate the BDNF messenger RNA levels.Citation108 Scutellarin induced the expression of neurotrophins’ messenger RNAs and proteins through cyclic adenosine monophosphate response element-binding protein (P-CREB) and p-Akt signaling in primary rat astrocytes.Citation106

Table 2 Increased expression of neurotrophic factors by polyphenols in cell and animal models

Several polyphenolic compounds have been reported to increase BDNF levels; different flavonoids such as baicalein (5,6,7-trihydroxyflavone, ),Citation109 butein and fisetin of Rhusverniciflua (),Citation110 chrysin (5,7-dihydroxyflavone, ),Citation111 daidzein and genistein,Citation112 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF),Citation113 oroxylin A (5,7-dihidrixy-6-methoxyflavone, ),Citation114 puerarin,Citation115 and quercetin,Citation116 as well as other polyphenols such as CAPE,Citation117 curcumin,Citation118 and resveratrol,Citation79,Citation119Citation122 have been reported to possess this property.

The aforementioned studies have examined BDNF levels under various experimental conditions. Some of the polyphenolic compounds, including fisetin and baicalin, one of the major flavonoids isolated from the roots of Scutellaria Baicalensis Georgi could activate the ERK-CREB pathway and exhibited memory-enhancing effects through the activation of CREB-BDNF pathway in the hippocampus of a mouse model of amnesia induced by scopolamine.Citation109,Citation110 In another study, chrysin was shown to rescue memory impairment and BDNF reduction caused by aging in mice.Citation111

Other studies have demonstrated the increased BDNF expression and neuroprotective effects of polyphenolic compounds in the settings of in vitro and in vivo models of ischaemia-, 6-hydroxydopamine (6-OHDA)-, or amyloid-β (Aβ)-mediated injury.Citation113,Citation115,Citation118,Citation123,Citation124 For example, HMF enhances BDNF production in astrocytes and induces neurogenesis in the hippocampus after brain ischemia, which is mediated by the activation of ERK1/2 and CREB pathways.Citation113 Puerarin has also a protective effect in 6-OHDA-lesioned rats by modulating BDNF expression and activation of the nuclear factor E2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway.Citation115 Curcumin, on the other hand, was able to block BDNF reduction in the Aβ-infused rats through Akt/GSK-3β signaling pathway.Citation118 Antiamnesic and protective effects of luteolin against Aβ toxicity in mice was associated with the increase of BNDF as well as TrkB expression in the cerebral cortex of mice.Citation123

Many polyphenolic compounds have antidepressant effects that are associated with increased BDNF levels.Citation125,Citation126 Xiaochaihutang, a mixture of seven Chinese herbs that is traditionally used in People’s Republic of China for treatment of depressive-like symptoms, considerably increased BDNF, NGF, TrkB, and TrkA expressions in the hippocampus and also improved depression-like behaviors in chronic unpredictable mild stress (CUMS) model in rats.Citation127 A flavanonol compound, astilbin, reverses depressive-like behaviors in a mouse model of depression and its effect is mediated by the upregulation of BDNF and activation of ERK and Akt pathways.Citation128 Antidepressant effects of baicalein, resveratrol, and rosmarinic acid (a caffeic acid ester) are also mediated by BDNF-ERK-mediated neurotrophic action.Citation129Citation131 Another polyphenol, ferulic acid, not only increases the proliferation of NSC/NPCs in vitro and in vivo but also produces an additive antidepressant-like effect in corticosterone-treated mice, mediated by CREB-BDNF signaling pathway.Citation72 Also, chrysin improves age-related memory decline in mice, an effect that is probably related to the modulation of BDNF production and free radical scavenging action of this compound.Citation111

ERK pathway activation

Modulation of neuronal survival signaling pathways may represent a promising approach to the management of central nervous system diseases. Several pathways including ERK1/2 and PI3K promote cell survival in the nervous system as well as other tissues.Citation132,Citation133 Recently, the ERK pathway, a part of MAPKs, has been implicated in several physiological functions of neurons, including proliferation, differentiation, survival, and regulation of response to various growth factors.Citation134Citation138 The activation of ERK1/2 requires phosphorylation of threonine and tyrosine residues that is carried out by the upstream activator kinase, mitogen-activated protein kinase kinase (MEK). Activated ERK1/2 then changes its localization and phosphorylates different target molecules, including transcription regulators and cytoskeletal proteins ().Citation139,Citation140

Figure 4 Main signaling pathways that mediate the neurotrophic effects of various polyphenols.

Notes: By activation of the Trk receptors, neurotrophic signaling starts mainly through the Ras/MAPK, PI3K/Akt, and PL-Cγ pathways. Trk binding by polyphenols results in the autophosphorylation and activation of these receptors. Receptor phosphorylation forms adaptor-binding sites that couple the receptor to MAPKs, PI3K, and phospholipase Cγ (PLCγ1) pathways, which ultimately result in the phosphorylation of CREB protein. Phosphorylated CREB bound to the CBP leads to the increased transcription of target genes by binding to CRE. These genes are involved in survival, differentiation, growth, synaptic plasticity, and long-term memory. Polyphenols-ER binding also activates neurotrophic effects via PKC pathways. 1: Epicatechin, 2: 7,8,3’-trihydroxyflavone, 3: diosmetin 4: 7, 8-dihydroxyflavone, 5: daidzein, 6: resveratrol, 7: hesperetin, 8: curcuminoids, 9: caffeic acid phenethyl ester, 10: ferulic acid, 11: baicalein, 12: apigenin, 13: honokiol, 14: nobiletin, 15: pinocembrin, 16: astilbin, 17: artepillin C, 18: 3,5,6,7,8,3′,4′-heptamethoxyflavone, 19: 4′-O-β-D-glucopyranosyl-30,4-dimethoxychalcone, 20: fustin, 21: puerarin, 22: scutellarin, 23: oroxylin A, 24: methyl 3,4-dihydroxybenzoate, 25: carnosic acid, 26: rosmarinic acid, 27: luteolin, 28: auraptene, 29: epigallocatechin-3-gallate, 30: icaritin, 31: liquiritin, 32: fisetin, 33: rutin.
Abbreviations: CaMK, Ca2+-calmodulin kinase; CREB, cyclic adenosine monophosphate response element-binding protein; CBP, CREB-binding protein; DAG, diacylglycerol; ER, estrogen receptor; ERK, extracellular signal-regulated kinase; IP3, inositol trisphosphate; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; PI3K, phosphatidylinsoitol-3-kinase; PKC, protein kinase C; PLCγ, phospholipase Cγ; Trk, tropomyosin receptor kinase.
Figure 4 Main signaling pathways that mediate the neurotrophic effects of various polyphenols.

ERK1/2 activation by some of the polyphenolic compounds promotes survival and antiapoptotic signaling in various cell lines (). It has been shown that ERK1/2 activation by luteolin protects PC12 cells against apoptosis. Furthermore, the cell viability of PC12 cells that were pretreated with U0126, a specific inhibitor of ERK1/2 kinase, was significantly reduced.Citation64

Table 3 Neuronal survival and differentiation induced by polyphenols and contribution of different neurotrophic pathways to these effects

Activation of the ERK1/2 pathway has mediated the neuroprotective activity against damaging insults.Citation132 Aβ peptide can cause a significant decrease in cell viability and neurite outgrowth and can induce apoptosis in neuronal cells. Liquiritin’s protection against Aβ-induced neuronal apoptosis and its effect on the differentiation of rats’ primary cultured hippocampal neurons were inhibited with a MAPK inhibitor.Citation141 Similarly, in another study, the decreased cell viability induced by Aβ25–35 was reported to be blocked by icaritin (a prenyl flavonoid derivative from Chinese tonic herb Epimedium). A blocker of ERK/MAPK pathway weakened this protective effect, which implied that ERK1/2 pathway is involved in the neuroprotective action of icaritin.Citation142 Likewise, rutin (3,3′,4,5,7-pentahydroxyflavone-3-rhamnoglucoside) has also shown beneficial effects against Aβ-induced neurotoxicity in rats through the activation of MAPK and BDNF.Citation143

As already mentioned, ERK1/2 signaling is crucial for neuronal differentiation and activation of associated cytoskeletal and synaptic proteins. It has been found that luteolin increases neurite outgrowth and expression of GAP-43 protein, a neuronal differentiation biomarker, and also heme oxygenase-1 (HO-1) expression in PC12 cells. All these effects could be blocked by pharmacological inhibition of ERK1/2.Citation64 In another report, it was established that luteolin induced microRNA-132 expression in PC12 cells and induced neurite outgrowth, while these effects were suppressed by protein kinase A (PKA) and MEK1/2 inhibitors, but not by protein kinase C (PKC) inhibitors.Citation144

Lin et alCitation64 have shown the involvement of both ERK and PKC signaling pathways in PC12 neurite outgrowth. Similarly, the involvement of the ERK and PKC signaling pathways in the process of neuritogenesis in PC12 cells was demonstrated in response to curcuminoids.Citation65 In another study, artepillin C-induced neurite outgrowth of PC12m3 cells has been shown to be inhibited by the ERK and p38 MAPK inhibitors. On the other hand, inhibition of ERK by U0126 entirely blocked artepillin C-mediated p38 MAPK phosphorylation of PC12m3 cells. It was suggested that the activation of p38 MAPK through the ERK signaling pathway is responsible for the artepillin C-induced neurite outgrowth of PC12m3 cells.Citation145 Finally, fisetin has been very effective in induction of PC12 cell differentiation, while MEK inhibitors considerably decreased fisetin-induced ERK activation and neurite outgrowth.Citation146 The different neurotrophic effects of polyphenols involving the ERK pathway are listed in .

Table 4 Improvement of memory and modulation of other brain functions in animal models by polyphenols and involvement of neurotrophic signaling pathways

Table 5 Inhibition of neurotoxin-induced damage by polyphenols and neurotrophic signaling pathways that possibly contribute to this effect

PI3K pathway activation

A number of studies have demonstrated that PI3K and its downstream effector Akt are involved in neuronal survival and increased neurite outgrowth as well as other neurotrophic effects of polyphenolsCitation82,Citation106,Citation118,Citation128,Citation147 (). In this regard, Hoppe et alCitation118 showed that PI3K/Akt pathway is involved in curcumin-mediated neuroprotection in Aβ-induced cognitive impairment in rats. Similarly, scutellarin is reported to protect neurons against hypoxia by increasing neurotrophins through pCREB and pAkt signaling, but not MAPKs.Citation106 In cultured primary cortical neurons, methyl 3,4-dihydroxybenzoate, a phenolic acid derivative, promoted neuronal survival and neurite outgrowth via PI3K/Akt signaling pathway, and these effects could be inhibited by a PI3K-specific inhibitor.Citation147 In another report, evidence was provided that oroxylin A increased BDNF production and neuronal differentiation in primary cortical neurons by activation of the Akt pathway. Puerarin also protected dopaminergic cells and potentiated the effect of NGF on neuritogenesis in PC12 cells via activation of the ERK1/2 and PI3K/Akt pathways.Citation82 Finally, astilbin, a natural flavonoid, has been demonstrated to reduce depressive-like behaviors in mice models of depression by activation of the MAPK/ERK and PI3K/Akt pathways that are the downstream signaling pathways of BDNF.Citation128

Phosphorylation of CREB

Cyclic AMP response element (CRE) sequence is found in the regulatory region of several genes. CREB is a transcription regulator that recognizes CRE sequence and activates gene transcription, a process believed to play an important role in learning and memory in the brain. In neuronal cells, activation of the CREB pathway by neurotrophic factors such as NGF leads to the expression of genes that regulate survival, growth, synaptic plasticity, differentiation, dendritic spine formation, and long-term memory.Citation148,Citation149

Mantamadiotis et alCitation150 provided evidence that mice lacking CREB function in the brain showed neurodegenerative process in the hippocampus and dorsolateral striatum. Considering the importance of this pathway in the nervous system, we hereby summarize the studies on some phenolic compounds that activate CREB pathway and discuss their possible therapeutic effects in neurodegenerative diseases ().

Luteolin,Citation144 auraptene (a coumarin derivative, ),Citation151 curcumin and demethoxycurcumin,Citation65 nobiletin,Citation152 hesperetin (a flavonoid),Citation153 and citrus HHMFCitation68 have all been shown to increase CREB phosphorylation in PC12 cells. Chai et alCitation106 have also suggested that one of the signaling pathways related to neuroprotective effect of scutellarin is pCREB, which stimulates the production and release of neurotrophic factors in primary rat astrocyte cultures.

Resveratrol has shown neurotrophic effect in dopaminergic neuronsCitation79 and antidepressant-like effects in rats via activation of CREB in the hippocampus and amygdala.Citation130 In a study by Li et al,Citation154 green tea catechins-treated mice showed significantly higher CREB phosphorylation than the aged control mice. Ferulic acid has also been reported to increase CREB phosphorylation in the hippocampus of corticosterone-treated mice.Citation72 In an animal model of traumatic brain injury, 7,8-DHF restores the levels of significantly reduced CREB phosphorylation.Citation81 Baicalein increased pCREB in the hippocampus of miceCitation109 and also in NPC.Citation155 Administration of baicalein to rats with cognitive impairment induced by corticosterone significantly improved memory-associated decrease in the expression levels of BDNF and CREB proteins in the hippocampus of these animals.Citation156 Activation of CREB by apigenin (4′,5,7-trihydroxyflavone, )Citation157 and pinocembrin (5,7-dihydroxyflavanone)Citation158 was seen in transgenic Alzheimer’s disease mouse model. Finally, rutin and fustin flavonoids have been demonstrated to increase the expression of CREB in the hippocampi of rats and to attenuate Aβ-induced learning impairment in mice, respectively.Citation143,Citation159

Antioxidant activity

The CNS is unique in its high susceptibility to oxidative stress, which is a result of its high oxygen consumption and also the presence of large amounts of fatty acids and metals.Citation160 Several lines of evidence suggest that oxidative stress is involved in the pathogenesis of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease.Citation61,Citation161 The antioxidant effect of polyphenols has long been studied as a mechanism of their neuroprotection against neurodegenerative disordersCitation61,Citation162 and other neurological diseases.Citation163 Although the direct interaction of polyphenols with reactive oxygen species (ROS) does not seem to be very likely to happen in vivo as a main mechanism of action, their antioxidant effects are most probably exerted through other mechanisms such as activation of Nrf2 pathway, upregulation of antioxidant enzymes, induction of hypoxia signal transduction (HIF-1-α pathway), and interaction with metal ions as sources of ROS.Citation12,Citation161,Citation164

For example, EGCGCitation165 and resveratrolCitation166 have been reported to exert their neuroprotective action through activation of the HIF-1 pathway. Mangiferin and morin (3,5,7,2′,4′-pentahydroxyflavone) revealed considerable antioxidant and antiapoptotic properties through the activation of antioxidant enzymes.Citation167

Protection against damage induced by neurotoxins

Cellular, biochemical, and animal studies have shown that Aβ is a crucial factor in the pathogenesis of Alzheimer’s disease.Citation168,Citation169 There are several reports suggesting that some polyphenols protect neuronal cells against Aβ-induced neuronal cell death or other forms of neuronal injury (). For instance, icaritin was shown to protect primary rat cortical neuronal cells against apoptosis induced by Aβ25–35 insult.Citation142 Similarly, Ushikubo et alCitation170 demonstrated that 3,3′,4′,5,5′-pentahydroxyflavone prevents Aβ fibril formation and that lowering fibril formation decreases Aβ-induced cell death in rat hippocampal neuronal cells. In another study, ursolic acid, p-coumaric acid, and gallic acid extracted from Cornifructus plant were shown to attenuate apoptotic features such as morphological nuclear changes, DNA fragmentation, and cell blebbing induced by Aβ peptide in PC12 cells.Citation171 The major flavonoids of cocoa, epicatechin and catechin, protect PC12 cells from Aβ-induced neurotoxicity.Citation172 Carnosic acid (), a highly bioactive phenolic compound found in rosemary (Rosmarinus officinalis), and liquiritin have shown a protective effect against Aβ in SH-SY5Y human neuroblastoma cells and primary cultured hippocampal neurons, respectively.Citation141,Citation173

6-OHDA is a compound used to induce a Parkinson-like pathology in vitro and in vivo. It has been reported that baicaleinCitation174 and also ferulic acid and caffeic acid derivatives, both belonging to hydroxycinnamic acid family (),Citation60 protect neuronal SH-SY5Y cells against 6-OHDA.

Hydrogen peroxide is an ROS that has been shown to induce neuronal cell damage in experimental models.Citation175 It has been shown that several polyphenols such as quercetin in cultured neuronal precursor cells,Citation176 7,8-DHF in retinal ganglion and RGC-5 cells,Citation103 and caffeic acid esters in PC12 cellsCitation53 are able to exert protective effects against ROS. In addition, other authors suggest that the neuroprotective effects of 7,8-DHF are mediated by its ability to scavenge ROS and increase cellular glutathione levels.Citation55

Other neurotoxins have also been applied to produce experimental models to assess the neuroprotective capacity of polyphenolic compounds. CAPE protects PC12 cells against dopaminergic neurotoxin MPP+ (1-methyl-4-phenylpyridinium).Citation67 Administration of 7,8-DHF prevented neuronal death in mouse brain induced by kainic acid.Citation102Icariin is another polyphenol compound that protects primary cultured rat hippocampal neuronal cells against corticosterone-induced apoptosis.Citation177 In addition, baicalein was also shown to inhibit necrotic cell death damage in NPCs and to attenuate impairment of hippocampal neurogenesis caused by irradiation.Citation155

Polyphenols have also shown therapeutic potential in animal models of neurodegenerative diseases induced by various neurotoxins. In an Aβ-induced amnesia model in mice, oral administration of luteolin mitigated learning and memory impairment.Citation123 Curcumin has also been shown to be effective in preventing neuroinflammation, tau hyper-phosphorylation, and behavioral impairments, triggered by Aβ in vivo.Citation118

Activation of the Nrf2 signaling pathway

One of the elegant mechanisms that neuronal cells have adapted to protect themselves against oxidative stress and other insults is Nrf2 pathway and the binding of this master transcriptional regulator with ARE in the regulatory region of many genes, which leads to the expression of several enzymes with antioxidant and detoxification capacities ().Citation178 The main enzymes that are transcribed under the control of ARE include γ-glutamylcysteine synthetase, glutathione peroxidase, glutathione S-transferase, HO-1, NADPH quinine oxidoreductase 1, peroxiredoxin, sulfiredoxin, thioredoxin, and thioredoxin reductase all of which have important roles in the protection of cells.Citation179Citation181 The pivotal finding that Nrf2-knockout mice exhibit a severe deficiency in the coordinated regulation of gene expression and their susceptibility to oxidative damage indicate the crucial role of Nrf2 in maintaining intracellular redox homeostasis and antioxidant defense mechanism.Citation182 The role of this pathway and the detoxification enzymes that it regulates has been especially emphasized in CNS diseases.Citation181

Figure 5 Polyphenols activate Keap1/Nrf2/ARE pathway and increase the expression of detoxification/antioxidant enzymes.

Notes: In the cytoplasm, Keap1 protein is always bound to Nrf2 transcription regulator and prevents its signaling. Polyphenols directly or indirectly cause dissociation of Nrf2–Keap1 complex and subsequent nuclear translocation of Nrf2. In the nucleus, Nrf2 binds to the ARE in the regulatory region of the target genes and stimulates transcription of detoxification/antioxidant enzymes HO-1, GCL, GPx, GST, SOD, CAT, PRX, and Trx.
Abbreviations: ARE, antioxidant response element; CAT, catalase; EGCG, epigallocatechin–gallate; ERK, extracellular signal-regulated kinase; GCL, γ-glutamylcysteine synthetase; GPx, glutathione peroxidase; GST, glutathione S-transferase; HO-1, heme oxygenase-1; Nrf2, Nuclear factor E2-related factor 2; PKC, protein kinase C; PRX, peroxiredoxin; SOD, superoxide dismutase; Trx, thioredoxin.
Figure 5 Polyphenols activate Keap1/Nrf2/ARE pathway and increase the expression of detoxification/antioxidant enzymes.

Some phenolic compounds such as luteolinCitation64 and puerarinCitation82 in PC12 cells and also CAPE in dopaminergic neuronsCitation117 enhance the binding of Nrf2 to ARE and increase the expression of HO-1. In cultured neurons, EGCG was able to protect cells against oxidative stress by increasing HO-1 expression via activation of the transcription factor Nrf2.Citation183 Li et alCitation184 evaluated the neuroprotective effect of puerarin on lesioned substantia nigra induced by 6-OHDA. Their findings showed that puerarin effectively protects neurons in substantia nigra by modulating brain-derived neurotrophic factor (BDNF) expression and also by activating the Nrf2/ARE pathway.Citation115 Carnosic acid and common sage (Salvia officinalis) plants also showed neuroprotective effects by activating Nrf2 in PC12h cells.Citation184

Polyphenols and activation of other neurotrophic pathways

Polyphenols having multiple beneficial effects on the nervous system could provide an important resource for the development of new drugs for management of neurodegenerative diseases. In addition to the aforementioned signaling pathways involved in the neurotrophic action of polyphenols, other mechanisms may also be involved. Daidzein has caused significant axonal outgrowth via upregulation of GAP-43 expression in hippocampal neurons in culture. Interestingly, daidzein-promoted phosphorylation of PKC, and GAP-43 was abolished by pretreatment with ER and PKC antagonist. These results suggest that ER-mediated PKC phosphorylation of GAP-43 may play a role in daidzein-mediated axonal outgrowth.Citation80 Hesperetin can also exhibit multiple neurotrophic effects via ER- and TrkA-mediated parallel pathways.Citation153

The Na+/K+/2Cl cotransporter (NKCC) is a member of the cation–chloride cotransporter family and is involved in the transport of chloride ion(s) coupled with cation(s) across the plasma membrane.Citation185 A previous study has shown that NGF treatment of PC12D cells increased the expression of NKCC1 protein.Citation186 In another report, it has been demonstrated that knockdown of NKCC1 strongly inhibits NGF induced-neurite outgrowth in PC12 cells. Interestingly, quercetin also promoted NGF-induced neurite outgrowth by increasing Cl, and knockdown of NKCC1 inhibited this stimulatory effect. In these cells, intracellular Cl affects microtubule polymerization via modulation of intrinsic GTPase activity of tubulin.Citation187

A2A subtype of adenosine receptors has been reported to elevate the expression of BDNF as well as synaptic actions of BDNF.Citation188,Citation189 This receptor also activates TrkB receptor and Akt signaling pathway, which induces neuronal survival and modulates neurite outgrowth in several different cell types.Citation190Citation192 Jeon et alCitation114 have recently shown that oroxylin A could induce BDNF production in cortical neurons via activation of A2A receptor, which induced cellular survival, synapse formation, and neurite outgrowth. In another report, the adenosine A2A receptor inhibitor could block methyl 3,4-dihydroxybenzoate-induced neuronal survival and neurite outgrowth in cultured primary cortical neurons.Citation147

Conclusion

Polyphenols with multiple beneficial effects in the nervous system could provide an important resource for the discovery of new neurotrophic agents. Agonistic action on Trk receptors, activation of the ERK, PI3Kinase/Akt and CREB pathways, activation of the Nrf2 pathway and upregulation of antioxidant and detoxification enzymes, as well as several other mechanisms underlie the neurotrophic action of different polyphenols. A better understanding of the neurotrophic effects and the molecular mechanisms of action of these compounds could help design better agents for management of neurodegenerative diseases and other disorders of the nervous system.

Acknowledgments

The authors thank the support provided by the vice chancellor for research, Shiraz University of Medical Sciences.

Disclosure

The authors report no conflict of interest in this work.

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