Table 2.

Natural compounds that activate Nrf2-ARE and/or neurotrophic PI3K-Akt signaling pathways.

Activator	Target	Outcome	Research Model	Reference
Flavonoids
Pinocembrin	Nrf2-ARE	↑ Nuclear Nrf2, HO-1 and λ-GCS activation ↑ Protection from 6-OHDA-induced oxidative stress	SH-SY5Y cells	[196]
Naringenin	Nrf2-ARE	↑ Nuclear Nrf2 and HO-1, GCLC, GCLM, GSH	SH-SY5Y cells, C57BL/6 mouse	[199]
Genistein	Nrf2-ARE	↑ HO-1, learning and memory, ↓ 8-OHdG, 4HNE ↑ eNOS-mediated S-nitrosylation of Keap1 ↑ Nuclear Nrf2	GCI rat hippocampal CA1 neurons	[202]
Orientin	Nrf2-ARE	↑ HO-1 ↓ ROS, 3-NT, 4HNE, and 8-OHdG, mitochondrial dysfunction, apoptosis, cognitive defects	AD mice	[203]
Eriodictyol	Nrf2-ARE	↑ HO-1, GCLC, GCLM ↓ ROS and apoptosis	Aβ peptide- exposed cortical neurons	[204]
Luteolin *	Nrf2-ARE and neurotrophic	↑ Neurite outgrowth, GAP-43, HO-1, ARE-binding of Nrf2	PC12 cells	[207]
Apigenin *	Antioxidant and PI3K-Akt-ERK/CREB	↓ Excitotoxicity, ROS, ↑GSH ↑ SOD and GPx, learning and memory ↓ Aβ peptide production and deposition	kainic acid-treated neurons and mice APP/PS1 AD mice	[208,209]
7,8-DHF *	Antioxidant and PI3K-Akt-ERK/CREB	↑ TrkB dimerization and phosphorylation, neuron survival	hippocampal, motor, ganglionic neurons	[190,212]
Non-Flavonoid Polyphenols
Curcumin	PI3K-Akt/CREB-ERK/insulin	↑ BDNF, pERK, improved cognitive behavior ↓ Active JNK, inhibitory IRS-1 phosphorylation, memory deficit	Aβ-injected rats (hippocampus) 3xTg-AD mice on HFD	[4,215]
O-Demethylcurcumin	Neurotrophic/ER stress response	↓ Aβ-induced caspase-dependent apoptosis ↓ ER stress protein expression (p-PERK, p-eIF2α, p-IRE1α, XBP-1, ATF6, and CHOP)	SK-N-SH cells	[216]
Topiramate	Neurotrophic	↓ Glutamate-mediated excitotoxicity ↑ BDNF, p-TrkB, p-ERK, p-CREB	hippocampal neurons	[219]
Harpagoside *	Antioxidant and PI3K-Akt-ERK	↑ GR, SOD, GSH ↓ Lipid peroxidation, memory deficit ↑ BDNF, ↓ memory defect ↓ Neurite atrophy and apoptosis	cortex and hippocampus in scopolamine- treated mice Aβ peptide- treated rats, Aβ peptide- treated cortical neurons	[220,221]
Non-Polyphenol Compounds
Taurine *	Akt-CREB-PGC1α	↓ Glutamate cytotoxicity, maintain MMP, ↓ cytosolic ROS ↓ Mitochondrial ROS ↑ MMP, COX, ATP, SOD2 ↑ Hippocampal PGC1α expression, learning and memory	SH-SY5Y cells prenatally-stressed rats that showed defects in learning and memory	[222,223]
R-α-Lipoic acid *	Akt/PI3K and Nrf2-ARE	↑ HO-1 expression, Nrf2 translocation ↓ ROS, 4HNE, cell death	retinal neuronal RGC-5 cells	[228]
Allicin *	Nrf2-ARE and neurotrophic	↓ Aβ-induced memory deficit ↑ Nrf2, antioxidant enzymes, ↓ PERK, p-tau, ROS, lipid peroxidation, protein carbonylation, cognitive defect	AD mouse model rat brains	[229,230]

(↑: increase; ↓: decrease; * Natural compounds that can activate both Nrf2-ARE and neurotrophic signaling pathways.)