Table 2.
Flavonoid phytochemicals exerting neuroprotective activities in Alzheimer’s disease models.
| Phytochemical tested | Plant | Concentration/Dose tested | Disease model | NRF2-related mechanism | Other observed AD-related effects | Reference |
|---|---|---|---|---|---|---|
| Quercetin | Fruits, vegetables, grains | • 50 mg/kg (i.p.) | • STZ-induced AD rats | • Upregulation of a7 nAChR/NRF2/HO-1 pathway | • Attenuation of STZ-induced cholinergic dysfunction in hippocampus, prefrontal cortex and amygdala of rats | (100) |
| Quercetin | Fruits, vegetables, grains | • 0, 10, 20, 40 and 80 μmol/L | • Aβ25-35-induced PC12 cells | • Increase of NRF2 | • Increase of HO-1, SOD, GPx, CAT, T-AOC and sirtuin1 | (101) |
| Quercetin + sitagliptin | Fruits, vegetables, grains | • 100 mg/kg p.o. dissolved in olive oil | • Aβ-induced Male Sprague–Dawley rats | • Upregulation of NRF2/HO-1 pathway | • Upregulation of SOD, CAT, GSH • Decrease of MDA and Aβ aggregation |
(102) |
| Cyanidin-3-glucoside | Dark-colored fruits, plants and vegetables | • 0-100 μM | • Glutamate-induced HT22 mouse hippocampal neuronal cells | • Upregulation of NRF2 and ERK | • Suppression of calpain, caspase-12 and CHOP • Upregulation of SOD, CAT, GPx and phase II enzymes |
(103) |
| Anthocyanin supplement | Korean black beans | • 25, 50, 100 μg/ml • 12 mg/kg/day i.p. for 30 days |
• HT22 cells • APP/PS1 AD mouse model |
• Activation of NRF2/HO-1 pathway | • Activation of PI3K/Akt/GSK-3β pathway • Reduced AβO-induced oxidative stress and neurotoxicity • Improvement of memory • Increased pre- and postsynaptic protein markers and decreased apoptotic markers; activated caspase-3 and PARP-1 |
(18) |
| Folecitin | Hypericum oblongifolium | • 30 mg/kg/day | • BALB/c mouse model induced by LPS | • NRF2 and HO-1 activation by stimulating Akt phosphorylation | • Decrease of LPS-induced apoptotic proteins BAX, PARP-1 and caspase-3 • Inhibition of BACE1 |
(104) |
| Isoliquiritigenin | Licorice | • 10 and 20 μM | • BV-2 cells stimulated with AβO | • NRF2 activation | • NF-kB suppression | (105) |
| Nobiletin | Citrus peels | • 10 mg/kg/day (p.o) | • AB-induced Wistar rats | • Upregulation of NRF2 | • Decrease of MDA and ROS levels • Partial reversal of SOD activity • Downregulation of TLR4, NF-kB and TNF-a |
(106) |
| Hawthorn Leaf flavonoids | Crataegus pinnatifida | • 50, 100 and 200 mg/kg p.o. | • Aβ25-35-induced AD mouse model | • Upregulation of NRF2/ARE | • Upregulation of HO-1, NQO1, SOD and CAT • Decrease of ROS and MDA |
(107) |
| Farrerol | Rhododendron dauricum L. | • 1, 5, and 10 μM | • BV-2 microglial cells | • Enhancement of NRF2/Keap1 activation | • Decrease of ROS, MDA, IL-6, IL-1β and TNF-a • Attenuation of SOD inhibition |
(108) |
| Genistein | Genista tinctoria | • 10, 30 or 50 μM | • Aβ25-35- induced SH-SY5Y cells | • Upregulation of NRF2/HO-1/PI3K pathway | (109) | |
| Umuhengerin | Lantana trifolia | • 30 mg/kg p.o. | • STZ-induced AD mouse model | • Increase of NRF2 expression • Downregulation of Keap1 |
• Upregulation of HO-1 and GSH • Downregulation of NF-kB, p65, MDA, H2O2, AChE, TNF-a and BACE1 |
(110) |
| Hesperetin | Citrus fruits | • 50 mg/kg • 10, 20 or 50 μM |
• Aβ mouse model • BV-2 cells • HT22 cells |
• Upregulation of NRF2 both in vivo and in vitro | • Decrease of ROS and LPO • Regulation of TLR4 and p-NF-kB |
(111) |
| Isoastilbin | Hypericum perforatum | • 10 or 30 μM • 40 mg/kg/day |
• L-Glu-induced PC12 cells • AlCl3/D-galactose AD mouse model |
• Upregulation of NRF2 nuclear levels | • Upregulation of SOD-1, CAT and HO-1 • Decrease of AChE levels, Aβ and tau expression and ROS levels |
(112) |
| Complanatoside A | Semen Astragalus Complanatus | • 50 μM | • C. elegans | • SKN-1/NRF2 activation | • DAF-16/FOXO activation • Decrease of Aβ accumulation |
(113) |
i.p., intraperitoneally; STZ, streptozotocin; AD, Alzheimer’s disease; a7 nAChR, a7 nicotinic acetylcholine receptor; NRF2, nuclear factor erythroid 2-related factor 2; HO-1, heme oxygenase-1; Aβ, β-amyloid; SOD, superoxide dismutase; GPx, glutathione peroxidase; CAT, catalase; T-AOC, total antioxidant capacity; p.o., per os; GSH, glutathione; MDA, malondialdehyde; ERK, extracellular signal-regulated kinase; CHOP, C/EBP homologous proteins; APP/PS1, amyloid precursor protein/presenilin 1; PI3K, phosphoinositide-3 kinase; Akt, protein kinase B; GSK-3β, glycogen synthase kinase 3 beta; PARP-1, poly (ADP-ribose) polymerase 1; LPS, lipopolysaccharide; BAX, bcl-2 associated X protein; BACE1, beta-secretase 1; NF-kB, nuclear factor kappa B; ROS, reactive oxygen species; TLR4, toll-like receptor 4; TNF-a, tumor necrosis factor a; ARE, antioxidant response element; NQO1, NAD(P)H quinone oxidoreductase 1; Keap1, Kelch like ECH associated protein 1; IL-6, interleukin 6; IL-1β, interleukin 1β; H2O2, hydrogen peroxide; AChE, acetylcholinesterase; LPO, lipid peroxidation; L-Glu, L-glutamate; AlCl3, aluminum chloride; C. elegans, Caenorhabditis elegans; SKN-1, protein skinhead-1; FOXO, forkhead box protein O.