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Resveratrol Prevents CA1 Neurons against Ischemic Injury by Parallel Modulation of Both GSK-3β and CREB through PI3-K/Akt Pathways
Abstract
Accumulating evidence indicates that resveratrol potently protects against cerebral ischemia damage due to its oxygen free radicals scavenging and antioxidant properties. However, cellular mechanisms that may underlie the neuroprotective effects of resveratrol in brain ischemia are not fully understood yet. This study aimed to investigate the potential association between the neuroprotective effect of resveratrol and the apoptosis/survival signaling pathways, in particular the glycogen synthase kinase 3 (GSK‐3β) and cAMP response element‐binding protein (CREB) through phosphatidylinositol 3‐kinase (PI3‐K)‐dependent pathway. An experimental model of global cerebral ischemia was induced in rats by the four‐vessel occlusion method for 10 min and followed by different periods of reperfusion. Nissl staining indicated extensive neuronal death at 7 days after ischemia/reperfusion. Administration of resveratrol by i.p. injections (30 mg/kg) for 7 days before ischemia significantly attenuated neuronal death. Both GSK‐3β and CREB appear to play a critical role in resveratrol neuroprotection through the PI3‐K/Akt pathway, as resveratrol pretreatment increased the phosphorylation of Akt, GSK‐3β and CREB in 1 h in the CA1 hippocampus after ischemia/reperfusion. Furthermore, administration of LY294002, an inhibitor of PI3‐K, compromised the neuroprotective effect of resveratrol and decreased the level of p‐Akt, p‐GSK‐3β and p‐CREB after ischemic injury. Taken together, the results suggest that resveratrol protects against delayed neuronal death in the hippocampal CA1 by maintaining the pro‐survival states of Akt, GSK‐3β and CREB pathways. These data suggest that the neuroprotective effect of resveratrol may be mediated through activation of the PI3‐K/Akt signaling pathway, subsequently downregulating expression of GSK‐3β and CREB, thereby leading to prevention of neuronal death after brain ischemia in rats.
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“As an antioxidant agent, RSV can scavenge free radicals and reduce ROS formation, by inhibiting the expression of NADPH and glycogen synthase kinase 3 beta proteins, and upregulating the expression of some antioxidant enzymes, such as SOD2, CAT, GPx, and thioredoxin [320,339,340].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [340]
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“Resveratrol, a polyphenol, provided neuroprotection and prevented neuronal death by activation of the PI3K/Akt pathway, which downregulated GSK-3β and ultimately phosphorylated CREB (Simao et al. 2012; Abdel-Aleem et al. 2016; Park et al. 2019).”
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Research Progress of Mechanism of Action of Resveratrol
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“Correction of these systems with the use of antioxidant agents and support for the expression of proteins Akt, GSK-3β, and CREB prevented hippocampal neuronal loss in acute brain ischemia conditions (Simão et al., 2012).”
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“Interestingly, the flavonoids rosmarinic acid (Paudel et al., 2018) and resveratrol (Simão et al., 2012) reduce the activity of the biomarker glycogen synthase kinase-3 (GSK3B).”
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Review on the Effect of Resveratrol on Central Nervous System Disease
Dong, W., Zhou, Y., & Yang, Z. (2016) · Journal of Behavioral and Brain Science · doi:10.4236/jbbs.2016.63014 · Cited by 1
“In the PD cell model, RV can reduce the expression of α synuclein by partially inhibiting GSK-3β [34].”
InfluentialTreatment of Alzheimer Disease with Phytochemicals Other Than Curcumin
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Metadata
- Authors
- Simão, F., Matté, A., Pagnussat, A. S., Netto, C. A., & Salbego, C. G.
- Affiliations
- Universidade Federal do Rio Grande do Sul (BR)
- Venue
- European Journal of Neuroscience
- Publisher
- Wiley
- Published
- 2012-07-22
- Volume
- 36
- Issue
- 7
- Pages
- 2899-2905
- ISSN
- 0953-816X (ISSN-L)
- 1460-9568
- OpenAlex
- W1939636416
- Cited by
- 111
- References
- 45
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 10 · 2023: 5 · 2022: 7 · 2021: 11 · 2020: 7 · 2019: 3 · 2018: 4 · 2017: 9 · 2016: 10 · 2015: 15 · 2014: 10 · 2013: 7 · 2012: 3
- FWCI
- 5.63
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroprotection in Cerebral Ischemia
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- resveratrol, neuroprotection, cerebral ischemia, ischemia-reperfusion injury, hippocampal CA1, GSK3β, CREB, PI3K/Akt signaling, Akt phosphorylation, neuronal cell death, delayed neuronal death, LY294002, four-vessel occlusion
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Resveratrol, Phosphoinositide-3 Kinase Inhibitors, Animals, Brain Ischemia, Chromones, Male, Morpholines, Neurons, Phosphorylation, Stilbenes, Signal Transduction, Reperfusion Injury, Rats, Wistar, Apoptosis, Cyclic AMP Response Element-Binding Protein, Neuroprotective Agents, Phosphatidylinositol 3-Kinases, Glycogen Synthase Kinase 3, Proto-Oncogene Proteins c-akt, Rats, CA1 Region, Hippocampal
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