Table 1.
Evidence on neuroprotective and cognitive role of resveratrol and hydroxytyrosol. AMPK, AMP-activated protein kinase; βA, beta amyloid, COX, cyclooxygenase; CSF, cerebrospinal fluid; ERβ, estrogen receptor β; ERK, extracellular signal-regulated kinase; LPS, lipopolysaccharide; MMP9, matrix metalloproteinase 9; NF-κB, nuclear factor κB; NO, nitric oxide, PGES-1, prostaglandin E synthase-1; TNF, tumor necrosis factor.
| Study Type | Subject | Component | Dose | Main Findings | Ref. |
|---|---|---|---|---|---|
| Neuroinflammation | |||||
| Retrospective study | 38 patients with Alzheimer disease and CSF Aβ42 < 600 ng/mL | Resveratrol | 500 mg | Reduction of CSF MMP9, modulation of neuroinflammation, and induction of adaptive immunity. | [109] |
| Animal study | Rat model of Alzheimer’s disease | Resveratrol-Selenium nanoparticles | Not clear | Reduced neuroinflammation and neurotoxicity by regulating Sirt1/miRNA-134/GSK3β expression | [110] |
| Animal study | Adult Sprague-Dawley rats: 6-OHDA-induced Parkinson’s disease rat model. | Resveratrol | 10–40 mg/kg per day for 10 weeks | Alleviation of 6-OHDA-induced chromatin condensation, mitochondrial tumefaction, and vacuolization of dopaminergic neurons in rat substantia nigra. Reduction of the reduced inflammatory reaction by lowering levels of COX-2 and TNF-α mRNA in the substantia nigra. | [111] |
| In vitro animal study | Primary microglial cell cultures prepared from cerebral cortices of neonatal rats | Resveratrol | 1–50 μM | Reduction of microglial activation.Resveratrol is the first known inhibitor, which specifically prevents PGES-1 expression without affecting cyclooxygenase-2 (COX-2) levels. | [112] |
| In vitro animal study | Rat astroglioma C6 cells | Resveratrol | up to 50 μM | Reduction of microglial pro-inflammatory responses by modulation of PG, NO, and NF-κB activity | [113] |
| In vitro animal study | Rat astroglioma C6 cells | Resveratrol | 200 μM | Modulation of NF-κB | [114] |
| In vitro animal study | Rat astroglioma C6 cells | 21 resveratrol derivatives | Variable | 3 derivatives demonstrated to be able to reduce of microglial pro-inflammatory activity by modulating TNF-α and NO synthase expression | [115] |
| In vitro animal study | Primary cortical neuron-glia cultures of female Wistar rats | Resveratrol | 15–60 μM | Inhibition of LPS-induced microglial activation and subsequent production of multiple pro-inflammatory and cytotoxic factors (TNF-α, NO, and interleukin-1β) | [116] |
| In vitro | BV-2 cells | Resveratrol | 0–1000 nM | Neuroprotection against hypoxia-induced neurotoxicity through inhibiting microglial activation by suppressing the activation of NF-ĸB, ERK, and JNK-MAPK signaling pathways | [117] |
| In vitro | Vascular adventitial fibroblasts isolated from rats | Hydroxytyrosol | 12.5, 25, 50, 100, 200, 400 μM | Regulation of the autophagy of vascular adventitial fibroblasts through SIRT1-mediated Akt/mTOR suppression.Inhibition of the inflammatory response of vascular adventitial fibroblasts | [118] |
| In vitro and ex vivo | Hypoxia-reoxygenation in rat brain slices | Hydroxytyrosol | 1, 5 and 10 mg/kg per day | Neuroprotective effect due to antioxidant and anti-inflammatory activity | [119] |
| In vitro and ex vivo | Hypoxia-reoxygenation model in rat brain slices | Hydroxytyrosol derivatives | Variable | Neuroprotective effect due to reduction in oxidative and nitrosative stress and anti-inflammatory activity.Reduction in brain cell death. | [120] |
| Experimental animal study | APP/PS1 transgenic mice | Hydroxytyrosol | 5 mg/kg/day | Ameliorated mitochondrial dysfunction, reduced mitochondrial carbonyl protein, and enhanced superoxide dismutase 2 expression, reversed the phase 2 enzyme system and reduced the levels of the brain inflammatory markers | [121] |
| Oxidative stress | |||||
| In vitro | HepG2 cells | Resveratrol | 10–60 μM | Protection of mitochondria against oxidative stress through AMPK-mediated glycogen synthase kinase-3β inhibition | [122] |
| In vitro | Rat hippocampal cells | Resveratrol | 5–25 μM | Protection of hippocampal neuronal cells against toxicity induced by NO | [123] |
| Experimental animal study | Caenorhabditis elegans | Hydroxytyrosol | 100 μg/mL | Prevention of oxidative stress and β-amyloid aggregation | [124] |
| In vitro and ex vivo | Type-1-like diabetic hypoxia-reoxygenation model in brain slices | 3’,4’-dihydroxyphenylglycol and hydroxytyrosol | 5 mg/kg/day (hydroxytyrosol) and 0.5 or 1 mg/kg/day (3′,4′-dihydroxyphenylglycol) | A 1:1 ratio of hydroxytyrosol/3’,4’-dihydroxyphenylglycol results in reduced brain cell death, neuroprotective, and antioxidant effects | [125] |
| Animal study | Wistar rats | Hydroxytyrosol | 2.5 mg/kg per day | Brain protection against the oxidative stress caused by 3-nitropropionic acid | [126] |
| Cerebrovascular function | |||||
| Randomized, double-blinded clinical trial | 22 healthy adults | Resveratrol | 250 and 500 mg | Increases cerebral blood flow during cognitive task performance in health adults but lacking interpretable cognitive effects | [127] |
| Randomized, double-blinded clinical trial | 60 adults | Resveratrol | 500 mg | Increases cerebral blood flow but lacking interpretable cognitive effects | [128] |
| Randomized clinical trial | 80 post-menopausal women | Resveratrol | 75 mg twice daily | Enhance both cerebrovascular function and cognition in post-menopausal women | [129] |
| Randomized, double-blinded clinical trial | 125 postmenopausal women | Resveratrol | 75 mg twice daily | Enhance cognition, cerebrovascular function, and insulin sensitivity | [130] |
| Randomized, double-blinded clinical trial | 129 postmenopausal women | Resveratrol | 75 mg twice daily | Enhance cognition and cerebrovascular function | [131] |
| Randomized, double-blinded clinical trial | 36 dementia-free, non-insulin dependent type 2 diabetes mellitus adults | Resveratrol | 0, 75, 150, and 300 mg at weekly intervals | Acute enhancement of vasodilator responsiveness in cerebral vessels.The maximum improvement was observed with the lowest dose used. | [132] |
| Autophagy | |||||
| Animal study | Rats with chronic cerebral hypoperfusion | Resveratrol | 50 mg/kg per day | Autophagy activation via the AKT/mTOR signaling pathway to improve cognitive dysfunction. | [133] |
| Animal study | 120 Sprague-Dawley rats | Resveratrol | 60 mg/kg | Neuroprotective effects due to regulating autophagy and apoptosis mediated by the Akt/mTOR pathway | [134] |
| Animal study | Rats | Resveratrol | 1.8 mg/Kg | Neuroprotective effects due to regulating autophagy through AMPK | [135] |
| Neuroprotective effect enhancement | |||||
| Randomized, double-blinded clinical trial | 23 adults | Resveratrol andpiperine | 250 mg (resveratrol), 20 mg (piperine) | Co-supplementation of piperine with resveratrol enhances the effects of resveratrol on cerebral blood flow effects without altering bioavailability. | [136] |
| In vitro animal study | Murine HT22 hippocampal cells | Resveratrol and melatonin | Resveratrol: 0.1, 1, 5, 10, and 20 µM.Melatonin: 1, 10, 50, 100, and 500 µM. | Melatonin potentiates the neuroprotective properties of resveratrol against Aβ-induced toxicity by modulating GSK3β and AMPK activity | [137] |
| Detoxification | |||||
| In vitro/in vivo animal study | Primary hippocampal cell cultures from pregnant Sprague–Dawley rats | Resveratrol | 15–40 µM | Neuroprotection against βA-induced neurotoxicity by inducing the phosphorylation of protein kinase Cδ isoform | [138] |
| In vitro | C12 cells | Hydroxytyrosol | Hydroxytyrosol -rich extract based with 45.5% of hydroxytyrosol | Brain cell cryoprotection | [139] |
| Animal study | Piglets | Hydroxytyrosol | 1.5 mg/kg per day | Upregulation of proteins related to brain cell detoxification. | [140] |
| Cognitive impairment | |||||
| Randomized double-blinded controlled trial | 119 patients with mild to moderate Alzheimer disease | Resveratrol | 500 mg | Resveratrol is well tolerated and seems to be able to penetrate the blood–brain barrier to produce its neuroprotective effects | [141] |
| Animal study | Mice | Resveratrol | 5 and 10 mg/kg | Protection from 3-nitropropionic acid-induced motor and cognitive impairment | [142] |
| In vitro/in vivo animal study | Hippocampal slice cultures from Sprague–Dawley rats exposed to ischemia | Resveratrol | 75 and 100 μM | Reduction of neuronal death in CA1 region of the hippocampus by activation of SIRT1 pathway | [143] |
| Experimental animal study | APP/PS1 transgenic mice | Hydroxytyrosol | 5 mg/kg/day | Improves the cognitive function in ERβ-dependent manner | [144] |
| Animal study | C57BL/6 mice | Hydroxytyrosol | 10 mg/kg per day | Attenuation of the spatial-cognitive deficits induced by oligomeric Aβ1–42 plus ibotenic acid | [145] |
| Animal study | Sprague–Dawley rats | Hydroxytyrosol | 10 and 50 mg/kg per day | Restoration of learning capacity and memory performance, promoting cognitive function | [146] |
| Animal study | wild-type and B-cell translocation 1 gene knockout mice | Hydroxytyrosol | 100 mg/kg/day | Stimulates neurogenesis in aged dentate gyrus by enhancing stem and progenitor cell proliferation and neuron survival | [147] |
| In vitro and ex vivo | Hypoxia-reoxygenation in rat brain slices | Hydroxytyrosol | 5 or 10 mg/kg per day | Reduction in brain cell death | [148] |
| Animal study | Piglets | Hydroxytyrosol | 1.5 mg/kg per day | Maternal supplementation with hydroxytyrosol during pregnancy affects the neurotransmitters profile in a brain-area-dependent mode and accelerates cell differentiation in the hippocampal CA1 and GD areas. | [149] |