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| Model | Condition studied | RSV treatment | Effects of RSV on behavior | Cellular and molecular effects of RSV in the hippocampus | Conclusion/proposed mechanism | Reference |
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| 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] |
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| 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] |
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| 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] |
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| 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] |
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| 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] |
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| 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] |
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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] |
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| 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] |
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| 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] |
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| 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] |
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| 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] |
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| 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] |
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| 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] |
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| 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] |
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| 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] |
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| 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] |
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| 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] |
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| 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] |
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