Table 2.

Effects of resveratrol on hippocampal plasticity.

Model	Condition studied	RSV treatment	Effects of RSV on behavior	Cellular and molecular effects of RSV in the hippocampus	Conclusion/proposed mechanism	Reference
Male Wistar rats (180–200 g)	Depression (UCMS)	20, 40, and 80 mg/kg (daily i.p. injections, for 5 weeks)	↑ sucrose consumption (all doses); ↓ immobility time in the FST (40 and 80 mg/kg); ↑ locomotor activity and grooming in the OFT (80 mg/kg)	↑ BDNF (80 mg/kg), pERK (80 mg/kg), and pCREB (40 and 80 mg/kg) levels to control levels	Antidepressant effects of RSV likely to be mediated by its ability to regulate HPA axis function and ↑ BDNF, pERK, and pCREB levels in the hippocampus and amygdala	[38]
Male Wistar rats (180–200 g)	Depression (UCMS)	80 mg/kg (daily i.p. injections, for 5 weeks)	RSV prevented stress-induced impairment of spatial working memory in the MWM and recognition memory performance in the NORT	↑ BDNF, pERK, and pCREB levels to control levels	RSV can prevent UCMS-induced cognitive impairment likely via modulating HPA axis function and ↑ BDNF, pERK, and pCREB levels in the hippocampus and PFC	[40]
Male Wistar rats (250–300 g)	Depression (UCMS)	5 mg/kg or 20 mg/kg (daily i.p. injections, for 35 days)	RSV did not prevent the UCMS-induced decrease in locomotor activity; RSV (20 mg/kg) prevented memory impairment in the PAT and MWM	↑ BDNF and c-Fos levels in CA1 and CA3 to nonstressed control levels	RSV can prevent UCMS-induced cognitive impairment likely via ↑ expression of BDNF and c-Fos in the hippocampus and regulating plasma levels of TNF-α and IL-β	[41]
4–6-week-old male Swiss albino mice	Depression (s.c. injection of CORT [40 mg/kg] for 21 days)	80 mg/kg (oral), 30 min prior to CORT injection, for 21 days	↑ sucrose consumption; ↓ immobility time in the FST and TST	↑ BDNF levels	RSV exerts antidepressant effects, likely through restoration of the HPA axis and upregulation of hippocampal BDNF	[47]
Offspring (PND 40) of 3-4-month-old Wistar rats	Prenatal stress (restraint stress during early or late gestational period)	10 mg/kg (oral) throughout pregnancy	N/A	↑ number of DCX+ neurons and ↑ expression of BDNF	Effects of RSV likely to occur via SIRT-1-induced activation of AMPK, which stimulates neuronal differentiation and mitochondrial biogenesis. This, in turn, could lead to ↑ BDNF activation via ↑ production of ATP	[49]
14-15-week-old Wistar-Kyoto rats	Noninduced model of depression	10 or 40 mg/kg (acute or chronic—daily i.p. injections, for 7 days)	↓ immobility time in the FST (acute, 40 mg/kg, and chronic, 10 and 40 mg/kg); no effects in the OFT; ↑ sucrose intake (chronic, 10 and 40 mg/kg)	↑ BDNF expression (chronic, 10 and 40 mg/kg)	Effects of RSV likely to occur via activation of BDNF	[50]
In vivo: PND6-PND14 C57/BL6 mice   In vitro: C17.2 cells	EtOH exposure	In vivo: 20 mg/kg i.p. injection at PND6 (followed by two 2.5 g/kg i.p. injections of 20% EtOH at PND7)  In vitro: 5 µM (for 12 h); EtOH (700 mg/dL) added after 12 h RSV treatment (and kept for 12 h or 36 h)	N/A	In vivo: RSV rescued ↓ in the number of (DG): granule cells; BrdU+, Sox2+, Sox2 & GFAP+, BLBP & nestin+, BrdU & DCX+, BLBP & GFAP+ cells; spine density; mushroom spine proportion; (hippocampus) pERK/ERK ratio; Hes 1 and Sirt1 protein levels  In vitro: ↑ ratio of Ki-67+ cells; reversed cell apoptosis and cell arrest of NPCs	EtOH-mediated ↓ in postnatal hippocampal neurogenesis likely involves expression of pERK and Hes 1 in the neonatal hippocampus; activation of SIRT1 by RSV can protect neonatal neurogenesis from EtOH-induced detrimental effects	[53]
8-week-old female BALB/c mice	CFS	40 mg/kg (oral), daily for 4 weeks	↑ daily activity	RSV rescued ↓ in the number of BrdU+ cells; ↓ apoptosis in the DG; ↑ BDNF mRNA expression; ↓ levels of acetylated p53	RSV can potentially improve fatigue symptoms and enlarge the CFS-related atrophic hippocampus likely through ↓ apoptosis and ↑ cell proliferation in the DG	[60]
Male Wistar rats (325–375 g)	GCI	1 or 10 mg/kg daily i.p. injections for 21 days prior to surgery	Both doses of RSV ↑ swimming time in the target quadrant during the probe trial of the MWM 7-8 weeks following GCI	Both doses of RSV led to ↑ CA1 neuronal density (7 and 85 days after GCI); ↓ DCX/PSA-NCAM colabeled cells in the DG (both doses and at both intervals); ↑ expression of CD31 in CA1 (1 mg/kg at 7 days); ↑ expression of CD31 in CA1 (1 and 10 mg/kg at 85 days); ↑ expression of CD31 in CA3 (1 and 10 mg/kg at 7 days); ↓ expression of CD31 in the GD (1 mg/kg at 7 days); ↑ expression of CD31 in the DG (1 and 10 mg/kg at 85 days)	Chronic RSV administration is associated with neuroprotection against GCI likely through restoration of AHN levels and increased angiogenesis	[65]
Male SD rats (250–280 g)	Poststroke depression	10, 20, or 40 mg/kg (gavage), once daily 7 days prior to MCAO and 1 day or 13 days after insult	RSV (20 and 40 mg/kg) ↑ sucrose preference 13 days after MCAO and ↓ immobility time in the FST	RSV (20 and 40 mg/kg) ↓ CRF protein expression, restored expression of GR, and ↑ BDNF protein expression	RSV exerts neuroprotective effects against stroke and poststroke depression in part mediated by HPA axis regulation	[69]
8–10-week-old male SD rats	Diabetes (streptozotocin-induced)	0.75 mg/kg (oral), 3x/day (8 h interval) for 4 weeks	N/A	↓ number of degenerative neurons in CA3; ↓ astrocytic activation in CA1 and CA3; ↓ hippocampal expression of TNF-α, IL-6, pERK1/2, and phospho-p38; ↓ BBB permeability and VEGF, both in the hippocampus; ↑ mitochondrial genesis in CA3 neurons; ↑ hippocampal pAMPK	RSV could be effective for treating diabetes due to its anti-inflammatory/antineurodegeneration effects in the hippocampus	[75]
7-week-old C57BL/6 mice	Diabetes (streptozotocin-induced)	50 mg/kg mixed with AIN93G diet per day for 6 weeks	N/A	↑ expression of Hdac4 and Jak1 genes; ↓ expression of ApoE and Hat1 genes, in comparison with non-RSV diabetic mice	RSV could be effective for cognitive function in diabetes due to its effects in normalizing the expression of AHN and synaptic plasticity genes in the hippocampus	[76]
Male Wistar rats (250–300 g)	Diabetes (streptozotocin-induced)	20 mg/kg (gavage) for 3 weeks	N/A	RSV could not restore the lower levels of hippocampal cell proliferation (number of BrdU+ cells)	RSV was effective in promoting antioxidant effects in diabetic rats but failed to enhance AHN	[77]
In vitro: (E7) rat hippocampal H19-7 neuronal cell line	AD	75 µM for 2 h before 25 µM of Aβ for 24 h	N/A	RSV ↑ expression of PSD-95, Arc, and synaptophysin	RSV's neuroprotective effects over memory loss in vitro might occur through improvement of expression of memory-associated proteins	[82]
21-month-old male Fischer 344 rats	Aging	40 mg/kg (daily i.p. injections) for 4 weeks (analysis at 25 months of age)	↑ learning and memory in the MWM; ↓ immobility time in the FST	↑ AHN (↑ number of BrdU+ cells; net BrdU+/NeuN+; ↑ number of DCX+ cells); ↑ RECA-1 in CA1 and entire hippocampus; ↓ hypertrophy of astrocytes; ↓ microglia activation	RSV administered in late middle age might ↑ memory and mood likely through modulation of synaptic plasticity and suppression of inflammation	[83]
20–22 g ICR mice	—	1.25, 2.5, 5, 10, and 20 mg/kg + piperine (2.5 mg/kg)	↓ immobility time in the FST and TST (10 and 20 mg/kg RSV + 2.5 mg/kg piperine)	↓ MAO-A activity; ↑ 5-HT and NE	Antidepressant effects of RSV combined with piperine may be due to activation of the 5-HT and NE systems in brain regions including the hippocampus	[92]
4-week-old male C57BL/6 mice	—	1 or 10 mg/kg i.p. injection/day for 14 days	↑ latency to find the hidden platform of the MWM	↓ number of DCX+ cells and of BrdU+/NeuN+ in the DG; ↓ BDNF and pCREB levels	RSV impairs AHN, likely through suppression of CREB and BDNF	[94]
In vitro: 14-day hippocampal neurospheres from adult male C57Bl/6 mice	—	0.1, 1, 3, 5, 10, 20, and 50 µM (assessment of number of neurospheres/hippocampus)  0.5, 1, 2, and 4 µM (assessment of proportion of neurospheres expressing β-III tubulin)	N/A	↓ number of neurospheres/hippocampus (10, 20, and 50 µM RSV); ↓ proportion of neurospheres expressing β-III tubulin (2 and 4 µM)	RSV hinders differentiation of neurons from adult neural precursors, likely through activation of Sirt1 signaling	[95]

AD = Alzheimer's disease; AMPK = 5′ adenosine monophosphate-activated protein kinase; APOE = apolipoprotein E; Arc = activity-regulated cytoskeleton-associated protein; ATP = adenosine triphosphate; BBB = blood-brain barrier; BDNF = brain-derived neurotrophic factor; BLBP = brain lipid-binding protein; BrdU = bromodeoxyuridine; CFS = chronic fatigue syndrome; CORT = corticosterone; CRF = corticotropin-releasing factor; DCX = doublecortin; DG = dentate gyrus; E7 = embryonic day 7; EtOH = ethanol; 5-HT = 5-hydroxytryptamine; FST = forced swimming test; GCI = global cerebral ischemia; GFAP = glial fibrillary acidic protein; GR = glucocorticoid receptor; HAT1 = histone acetyltransferase 1; HDAC4 = histone deacetylase 4; HPA = hypothalamic-pituitary-adrenal; IL-1β = interleukin-1β; IL-6 = interleukin-6; JAK1 = Janus kinase 1; MAO-A = monoamine oxidase A; MCAO = middle cerebral artery occlusion; N/A = not assessed; NE = noradrenaline; NeuN = neuronal nuclei protein; NORT = novel object recognition task; OFT = open field test; PAT = passive-avoidance test; PFC = prefrontal cortex; PND = postnatal day; PSD-95 = postsynaptic density protein 95; RECA-1 = endothelial cell antigen-1; RSV = resveratrol; S.C. = subcutaneous; SD = Sprague-Dawley; SIRT1 = nicotinamide adenine dinucleotide-dependent deacetylase sirtuin-1; TNF-α = tumor necrosis factor-α; TST = tail suspension test; UCMS = unpredictable chronic mild stress; VEGF = vascular endothelial growth factor.