Table 2.

Details of preclinical and clinical studies reporting the effects of various flavonoids on adult neurogenesis.

Model	Flavonoid	Outcome Measurement (Technique)	Pathway	Outcome	References
Mouse C17.2 cells Male C57BL/6 mice (6 weeks old)	Baicalein In vitro (1 or 10 mM) In vivo (10 mg/kg/day)	ROS measurements, cell counting, immunohistochemistry, immunostaining, and BDNF assay	Decreased oxidative stress and increased BDNF-pCREB signaling	Attenuate impaired hippocampal neurogenesis Protected neural progenitor cells against irradiation-induced necrotic cell death	[151]
Male Sprague-Dawley rats (5 weeks old)	Hesperidin (100 mg/kg)	Immunofluorescence, cell counting, Western blot, and biochemical analysis	Increased levels of BDNF, Nrf2, and antioxidant enzymes	Alleviated methotrexate-induced neurogenesis decline	[162, 163]
Male Fischer 344 rats (20 months old)	Flavonoid-rich extract from blueberry and green tea (135 mg/kg/day)	Immunohistochemistry, stereology, real time PCR, and ELISA	Anti-inflammatory effects, increased Nrf2, and activated Wnt/ β-catenin pathway	Increased neurogenesis and the number of proliferating cells in SVZ Activated pro-neurogenic gene expression in the hippocampal SGZ and SVZ	[168-169]
Male Fischer 344 rats (19 months old)	Flavonoid-rich blueberry extract (20 g/kg)	Immunohistochemistry and cell quantification	Activated IGF-1, IGF-1R, and ERK1/2	Increased hippocampal neurogenesis and hippocampal plasticity	[171]
C. elegans nematodes	Multiple flavonoids including isoquercitrin	Drug screening and network-based analysis, genetic tests, drug assays, real time PCR, and Western blot	Increased daf-16/FoxO sir2-1/SIRT1 and ucp-4/UCP	Promoted neuronal function in C. elegans nematodes with neuronal stable expression of human polyglutamine-expanded (128Q) exon-1 huntingtin	[172]
Male Wistar rats	Naringin (40 and 80 mg/kg)	Biochemical analyses	Attenuated mitochondrial oxidative damage and acetyl cholinesterase activity	Neuroprotective effects against aluminium chloride-induced cognitive dysfunction	[175]
Male ICR mice (6 weeks old)	Spinosyn (5 mg/kg)	Immunohistochemistry, immunofluorescence, Western blot, and cell counting	Increased pERK, pCREB and mature BDNF	Increased proliferation and survival of neuronal cells, and the number of immature neurons	[177]
Male ICR mice (6 weeks old)	Oroxylin A (1.25, 2.5, 5, or 10 mg/kg)	Immunohistochemistry and immunofluorescence	-	Increased progenitor cell proliferation and new-born cell survival	[178]
Ts65Dn mice (12 weeks old)	Luteolin (10 mg/kg)	Immunohistochemistry, Nissl staining, and Western blot	Activated ERK1/2 and increased BDNF levels	Enhanced neuron proliferation in the hippocampal DG	[179]
Rat PC12 cells	Luteolin (5, 10, and 20 μM)	Cell culture, neurite outgrowth analysis, real time PCR, Western blot, and analysis of Nrf2	ERK-dependent induction of Nrf2-driven HO-1 expression	Induced neurite outgrowth and neuronal differentiation	[180]
Rat PC12 cells	Luteolin (20 mM)	Quantification of neurite outgrowth, real time PCR, Western blot, and enzyme immunoassay	Activated cAMP/PKA and ERK-dependent CREB signaling pathways	Enhanced neurite outgrowth	[182]
Male C57BL/6 mice (9 weeks old)	Heptamethoxyflavone (25 or 50 mg/kg/day)	Western blot and immunofluorescence microscopy	Activated ERK1/2 and increased pCREB and BDNF	Enhanced neurogenesis after brain ischemia	[183]
Male C57BL/6J mice (6-7 weeks old)	Baicalin (40, 80 or 160 mg/kg)	Immunohistochemistry and Western blot	Normalized GR function through SGK1- and FKBP5-mediated GR phosphorylation	Restored corticosterone; induced suppression of hippocampal neurogenesis	[184]
Male ICR mice (7-8 weeks old)	Baicalin (50 and 100 mg/kg)	Nissl staining, immunofluorescence, Western blot, and real time PCR	Activated Wnt/β-catenin pathway	Restored stress-induced suppression of hippocampal neurogenesis and improved nerve cells’ survival	[185]
Male ICR mice (6 weeks old)	Quercetin (50 mg/kg/day)	Immunohistochemistry and Western blot	Increased Akt phosphorylation	Enhanced NSC neurogenesis in the hippocampal DG	[186]
Female Sprague-Dawley rats and C57B6/BL mice Hippocampal NPC from day 18 rat fetuses	Ginkgo biloba extract containing quercetin (3-15 μM)	Cell proliferation assay, immunostaining, and immunoblotting	Increased pCREB and BDNF	Enhanced hippocampal cell proliferation Restored amyloid-β oligomer-induced synaptic loss	[187]
Male ICR mice NPCs from brain of embryonic day 12-14 and SH-SY5Y cells	Quercetin In vivo (15 or 30 mg/kg) In vitro (0-90 μM, NPCs; 0-480 μM, SH-SY5Y)	Immunofluorescence and immunohistochemistry	Activated FoxG1/ CREB/BDNF pathway	Increased neurogenesis markers in the hippocampal DG	[188]
Pathogen-free female mice (4 weeks old)	Purple cauliflower (174.32 mg/g anthocyanin)	Western blot, immunohistochemistry, and Golgi staining	Activated ERK/CREB/ BDNF pathway	Enhanced hippocampal neurogenesis and dendrite development	[189]
NSCs from SVZs of 3-week-old and 23-month-old C57BL/6 mice C57BL/6 mice (12 months old)	Ribes meyeri anthocyanins (100 mg/kg) Naringenin (20 mg/kg)	Cell counting, cell cycle analyses, real time PCR, telomere length measurement, ROS assay, neurosphere and differentiation assays, immunofluorescence, RNA-sequencing, and ELISA	Decreased NSC senescence markers, and downregulated TNF-α	Accelerated NSC proliferation, and reversed age-dependent neuronal loss	[190]
Male ICR mice	Cyanidin (25 or 50 mg/kg)	Immunofluorescence and Western blot	Activated PI3K/AKT/ FoxG1/FGF-2 pathway	Enhanced neurogenesis	[191]
Male C57BL/6J mice (3 months old)	(-)-Epicatechin (1 mg/kg) (+)-Epicatechin (0.1 mg/kg)	Immunohistochemistry, immunofluorescence, nitrate/nitrite measurements, and Western blot	Enhanced capillary formation and nitric oxide triggering	Increased neuronal proliferation and neurofilament	[194]
Healthy subjects (50-69 years old)	High-flavanol cocoa (900 mg/day flavanols, 138 mg/day (-)-epicatechin)	fMRI and cognitive testing	-	Enhanced DG function	[195]
Male C57BL/6J mice (10 weeks old)	Cinnamtannin A2 (100 mg/kg)	Immunohistochemistry	-	Enhanced neurogenesis in the hippocampal DG	[196]
Female Balb/c mice (6 weeks old)	Puerarin (80 mg/kg/day)	Histology analysis, immunostaining, and real time PCR	Increased GR, DCX, and BDNF expression	Ameliorated d-galactose-induced loss of neurogenesis	[197]
Female C57BL/6J mice (12 months old)	Daidzein (25 mg/kg)	Tissue sectioning, molecular marker analyses, immunohistochemistry, optical dissector analysis, morphometric analysis, fluorescence intensity analysis	-	Increased markers of hippocampal neurogenesis, such as: increased numerical densities of late transient amplifying progenitors, neural progenitors, immature granule cells, and arborization of dendrites	[198]

Abbreviations: ROS, reactive oxygen species; BDNF, brain-derived neurotrophic factor; CREB, cAMP-response element binding; pCREB, phosphorylated CREB; Nrf2, nuclear factor erythroid 2-related factor 2; PCR, polymerase chain reaction; ELISA, enzyme-linked immunosorbent assay; SVZ, subventricular zone; SGZ, subgranular zone; IGF-1, insulin-like growth factor 1; IGF-1R, IGF-1 receptor; ERK, extracellular signal-regulated kinase; pERK, phosphorylated ERK; FoxO, forkhead box transcription factor O; sir2-1/SIRT1, sirtuin 1; DG, dentate gyrus; HO-1, heme oxygenase-1; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; GR, glucocorticoid receptor; FKBP5, FK506 binding protein 5; SGK1, serum- and glucocorticoid-inducible kinase 1; NSC, neural stem cell; NPC, neuronal precursor cell; FoxG1, forkhead box G1; TNF-α, tumor necrosis factor alpha; PI3K, phosphoinositide 3-kinases; FGF-2, fibroblast growth factor 2; fMRI, functional magnetic resonance imaging; DCX, doublecortin.