Modulation of neurotrophic signaling pathways by polyphenols

Figures & data

Figure 1 Main classes of polyphenols and their chemical structures.

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.

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

Compound	Source	Cell model	Involved signaling pathways			References
			MEK/ERK1/2	PI3K/Akt	PLCγ –PKC
Artepillin C	Chemical	PC12 cells	Y	–a	–	^Citation145
CAPE	Chemical	PC12 cells	–	–	–	^Citation67
Daidzein	Chemical	DRG cultures	Y	–	Y	^Citation69
7,8-DHF	Chemical	Cultured embryonic mouse motoneurons and SGNs	Y^Citation104/N^Citation70	Y	–	^Citation70,Citation104
EGCG	Chemical	PC12 cells	–	–	Y	^Citation66
Fisetin	Chemical	PC12 cells	Y	–	–	^Citation146
Isoquercitrin	Chemical	NG108-15 neuroblastoma/glioma cells	–	–	–	^Citation193
Luteolin	Chemical	PC12 cells	Y	–	Y	^Citation64,Citation144
Methyl 3,4-dihydroxybenzoate	Chemical	Cortical neurons of neonatal rats	–	Y	–	^Citation147
Resveratrol	Chemical	PC12 cells, neuro2a cells, and primary rat midbrain neuron-glia and neuron-astroglia cultures	Y	–	–	^Citation79,Citation194,Citation195
7,8,3′-Trihydroxyflavone	Chemical	SGN	Y	–	–	^Citation104
Auraptene	Citrus plants	PC12 cells	Y	–	–	^Citation151
Baicalein	Scutellaria baicalensis	C17.2 NSCs	Y	–	–	^Citation196
Carnosic acid	Rosmarinus officinalis	PC12 cells	Y	Y	–	^Citation184
Curcuminoids	Curcuma longa	PC12 cells	Y	–	Y	^Citation65
3,7-Dihydroxy-2,4,6-trimethoxy-phenanthrene	Dioscorea nipponica	Mouse neuro2a (N2a) cells	–	–	–	^Citation197
Nobiletin	Citrus depressa	PC12D cells	Y	–	–	^Citation152
Oroxylin	Scutellaria baicalensis	Cultured rat primary neuron	Y	Y	–	^Citation114
Protocatechuic acid	Alpinia oxyphylla	Cultured NSC/NPCs	–	–	–	^Citation198
Quercetin	Caesalpinia mimosoides	P19-derived neurons	–	Y	–	^Citation71,Citation199

Note:

a Not determined.

Abbreviations: N, activation of the pathway is not involved; Y, activation of the pathway is involved; CAPE, caffeic acid phenethyl ester; 7,8-DHF, 7,8-dihydroxyflavone; DRG, dorsal root ganglia; EGCG, epigallocatechin–gallate; ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase kinase; NSC/NPCs, neural stem/progenitor cells; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PLCγ, phospholipase Cγ; SGNs, spiral ganglion neurons.

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

Compound	Cell model	Animal model	Involved signaling pathways	Neurotrophic factors that are modulated	Function	References
Alpinetin	Primary rat astrocytes	–a	Estrogen signaling	BDNF, NGF, GDNF	–	^Citation107
Astilbin	–	Mice	p-ERK/p-Akt	BDNF	Antidepressant-like effects	^Citation128
Baicalein	–	Mouse model of amnesia	p-ERK/p-CREB	BDNF	Antidepressant-like effects	^Citation109,Citation129
Butein	–	Mice	p-ERK/p-CREB	BDNF	Cognition enhancement	^Citation110
CAPE	–	Mice	Nrf2/ARE	BDNF	Protection of nigral dopaminergic neurons	^Citation117
Calycosin	Primary rat astrocytes	–	Estrogen signaling	BDNF, NGF, GDNF	–	^Citation107
Chrysin	–	Mice	–	BDNF	Cognition enhancement	^Citation111
Curcumin	–	Rats	Akt/GSK-3β	BDNF	Suppression of β-amyloid-induced cognitive impairments	^Citation118
Daidzein	H19-7 neural cell line	–	–	BDNF	–	^Citation112
Ferulic acid	NSC/NPCs	Mice	p-CREB	BDNF	Antidepressant-like effects	^Citation72
Fisetin	–	Mouse model of amnesia	p-ERK/p-CREB	BDNF	Cognition enhancement	^Citation110
Genistein	Primary rat astrocytes	–	Estrogen signaling	BDNF, NGF, GDNF	–	^Citation107
Genistein	H19-7 neural cell line	–	–	BDNF	–	^Citation112
HMF	–	Mouse model of ischemia	p-ERK/p-CREB	BDNF	–	^Citation113
Isorhamnetine	Primary rat astrocytes	–	Estrogen signaling	BDNF, NGF, GDNF	–	^Citation107
Luteolin	Primary rat astrocytes	–	Estrogen signaling	BDNF, NGF, GDNF	–	^Citation107
Oroxylin A	Primary cortical neurons	–	PI3K-Akt GSK-3β	BDNF	–	^Citation114
Puerarin	–	Rats	Nrf2/ARE	BDNF	Attenuation of neuronal degeneration	^Citation115
Quercetin	–	Rats	PGC-1α	BDNF	Amelioration of hypobaric hypoxia-induced memory deficit	^Citation116
Resveratrol	Dopaminergic neurons	Rats	p-ERK/p-CREB	BDNF, GDNF	Antidepressant-like effects	^Citation79,Citation130
Rosmarinic acid	–	Rats	p-ERK	BDNF	Antidepressant-like effects	^Citation131
Scutellarin	Primary rat astrocytes	–	p-CREB/p-Akt	BDNF, NGF, GDNF	–	^Citation106
Xiaochaihutang	–	Rats	–	BDNF, NGF	Antidepressant-like effects	^Citation127

Note:

a Not determined in this study.

Abbreviations: CAPE, caffeic acid phenethyl ester; HMF, 3,5,6,7,8,3′,4′-heptamethoxyflavone; BDNF, brain-derived neurotrophic factor; NGF, nerve growth factor; GDNF, glial cell line-derived neurotrophic factor; NSC/NPCs, neural stem/progenitor cells; ERK, extracellular signal-regulated kinase.

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.

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

Compound	Cell model	Activation of pathway			References
		MEK/ERK1/2	PI3K/Akt	PLCγ –PKC
Artepillin C	PC12m3 cells	Y	–a	–	^Citation145
Auraptene	PC12 cells	Y	–	–	^Citation151
Baicalein	C17.2 NSCs	Y	–	–	^Citation196
Caffeic acid phenethyl ester	Rat organotypic midbrain slice cultures	Y	–	–	^Citation117
Carnosic acid	PC12 cells	Y	Y	–	^Citation184
Carnosic acid	PC12 cells	Y	–	–	^Citation200
Curcuminoids	PC12 cells	Y	–	Y	^Citation65
Daidzein	Primary rat DRG neuronal cultures	Y	–	Y	^Citation69
7,8-Dihydroxyflavone	Mouse hippocampal cultures and mouse embryonic motoneuron cultures	N	Y	–	^Citation70
7,8-Dihydroxyflavone	Retinal ganglion cell cultures	Y	Y	–	^Citation103
4′-O-β-D-Glucopyranosyl-3′, 4-dimethoxychalcone	PC12 Cells	Y	N	–	^Citation201
HMF	Mouse neuronal cells	Y	–	–	^Citation113
Hesperetin	PC12 cells	Y	Y	Y	^Citation153
Luteolin	PC12 cells	Y	–	Y	^Citation64
Luteolin	PC12 cells	Y	–	–	^Citation144
Methyl 3,4-dihydroxybenzoate	Rat cortical neuronal cultures	–	Y	–	^Citation147
Nobiletin	PC12D cells	Y	–	–	^Citation152
Oroxylin A	Cortical neuronal cultures	–	Y	–	^Citation114
Puerarin	PC12 cells	Y	Y	–	^Citation82
Resveratrol	Astrocytes cultures	Y	–	–	^Citation119
Rosmarinic acid	PC12 cells	Y	–	–	^Citation200

Note:

a Not determined.

Abbreviations: N, activation of the pathway is not involved; Y, activation of the pathway is involved; DRG, dorsal root ganglion; ERK, extracellular signal-regulated kinase; HMF, 3,5,6,7,8,3′,4′-heptamethoxyflavone; MEK, mitogen-activated protein kinase kinase; NSCs, neural stem cells; PKC, protein kinase C; PLCγ, phospholipase Cγ.

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

Compound	Animal model	Effect on brain function	Involved signaling pathways			References
			MEK/ERK1/2	PI3K/Akt	PLCγ–PKC
Apigenin	Mice	Improvement of learning and memory in APP/PS1 mice	Y	–a	–	^Citation157
Baicalein	Mice	Memory enhancement	Y	–	–	^Citation109
Baicalein	Mice	Prevention of spatial learning and memory deficits following irradiation	Y	–	–	^Citation109,Citation155
Curcumin	Rats	Improvement of amyloid-β-induced cognitive impairment	–	Y	–	^Citation118
Ferulic acid	Mice	Antidepressant-like effect	Y	Y	Y	^Citation202
Fisetin	Mice	Memory enhancement	Y	–	–	^Citation110,Citation203
HMF	Mice	Enhancement of neurogenesis after brain ischemia	Y	–	–	^Citation113
Nobiletin	Mice	Improvement of memory in olfactory-bulbectomized mice	Y	–	–	^Citation152
Pinocembrin	Mice	Improvement of cognitive deficits in APP/PS1 mice	Y	–	–	^Citation158
Resveratrol	Mice	Improvement of hippocampal atrophy in chronic fatigue syndrome mice	Y	–	–	^Citation122
Rutin	Rats	Memory enhancement	Y	–	–	^Citation143

Note:

a Not determined.

Abbreviations: Y, activation of the pathway is involved; ERK, extracellular signal-regulated kinase; HMF, 3,5,6,7,8,3′,4′-heptamethoxyflavone; MEK, mitogen-activated protein kinase kinase; PKC, protein kinase C; PLCγ, phospholipase Cγ.

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

Compound	Animal or cell model	Action of neurotoxin	Involved signaling pathway			References
			MEK/ERK1/2	PI3K/Akt	PLCγ–PKC
Baicalein	C17.2 NSCs^Citation155,Citation196	Irradiation-induced cell death and neurogenesis deficit^Citation155	Y^Citation196	–a	–	^Citation155,Citation196
Baicalein	SH-SY5Y cells^Citation174 C17.2 NSCs^Citation196 Rats^Citation174	6-OHDA-induced damage in SH-SY5Y cells^Citation174	Y^Citation196	–	–	^Citation174,Citation196
Caffeic acid	SH-SY5Y cells^Citation60 Primary rat astrocytes culture^Citation106	6-OHDA-induced damage in SH-SY5Y cells^Citation60	N^Citation106	Y^Citation106	–	^Citation60,Citation106
CAPE	PC12 cells^Citation67 Rat midbrain slice cultures^Citation117	Dopaminergic neurotoxin MPP+ induced injury in PC12 cells^Citation67	Y^Citation117	–	–	^Citation67,Citation117
Carnosic acid	SH-SY5Y cells^Citation173 PC12cells^Citation184,Citation200	Amyloid-β-induced apoptosis in SH-SY5Y cells^Citation173	Y^Citation200	Y^Citation173	–	^Citation173,Citation184,Citation200
Curcumin	PC12 cells^Citation65,Citation204	Cisplatin-induced neurite toxicity^Citation204	Y^Citation65	–	Y^Citation65	^Citation65,Citation204
Curcumin	Rats	Amyloid-β-induced neuronal injury	–	Y	–	^Citation118
7,8-DHF	Mice	Kainic acid-induced neurotoxicity	Y	Y	–	^Citation102
7,8-DHF	HT-22 cells^Citation55 Retinal ganglion cell culture^Citation103	Glutamate-induced toxicity in HT-22 cells^Citation55	Y^Citation55	Y^Citation55	–	^Citation55,Citation103
EGCG	Mice^Citation205	Striatal and substantia nigra dopaminergic neuron loss induced by MPTP^Citation206	–	–	Y^Citation205	^Citation205,Citation206
Icaritin	Cortical neuronal cells	Amyloid-β-induced neurotoxicity	Y	–	–	^Citation142
Icariin	Primary cultured rat hippocampal neurons	Corticosterone-induced apoptosis	Y	–	–	^Citation177
Liquiritin	Primary cultured hippocampal neurons	Amyloid-β-induced neurotoxicity	Y	–	–	^Citation141
Puerarin	PC12 cells Mice	Dopaminergic neuronal damage in PC12 cells and behavioral impairments in MPTP-induced neurotoxicity in mice	Y	Y	–	^Citation82
Resveratrol	Schwann cells^Citation121 Primary astroglia cultures^Citation119	Ethanol-induced injury^Citation121	Y^Citation119	–	–	^Citation119,Citation121
Rutin	Rat	Protective effects against neurotoxicity of Aβ	Y	–	–	^Citation143

Note:

a Not determined.

Abbreviations: N, activation of the pathway is not involved; Y, activation of the pathway is involved; Aβ, Amyloid-β; CAPE, caffeic acid phenethyl ester; 7,8-DHF, 7,8-dihydroxyflavone; EGCG, epigallocatechin–gallate; ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase kinase; MPP+, (1-methyl-4-phenylpyridinium); MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NSC, neural stem cell; 6-OHDA, 6-hydroxydopamine; PI3K, Phosphoinositide 3-kinase; PKC, protein kinase C; PLCγ, phospholipase Cγ.

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.

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