Neuroprotective Effect of Resveratrol on Ischemia/Reperfusion Injury in Rats Through TRPC6/CREB Pathways

Abstract

Previous studies have provided evidences that resveratrol can protect the brain from ischemia/reperfusion injury; the mechanisms of its neuroprotective effects remain unknown. To investigate whether resveratrol has neuroprotective effects on ischemia and reperfusion injury and whether resveratrol exerts its neuroprotective effects through inhibition of calpain proteolysis of TRPC6, a transient middle cerebral artery occlusion (MCAO) model was employed in rats. Western blot analysis was performed to detect the protein levels of aII-spectrin, transient receptor potential canonical (subtype) 6 (TRPC6) and phosphorylated cAMP/Ca(2+) response element-binding protein (p-CREB). The immunoreactivity of p-CREB and TRPC6 were measured by quantum dot-based immunofluorescence analysis. Our results showed that MCAO rats showed large cortical infarct volumes and neurological scores. By contrast, resveratrol, when applied for 7 days before MCAO onset, significantly reduced infarct volumes and enhanced neurological scores at 24 h after reperfusion, and these results were accompanied by elevated TRPC6 and p-CREB activity and decreased calpain activity. When MEK or CaMKIV activity was inhibited by the addition of PD98059 or KN62, the neuroprotective effects of resveratrol were attenuated, and we observed a correlated decrease in CREB activity. Our results demonstrated that resveratrol prevented the brain from ischemia/reperfusion injury through the TRPC6-MEK-CREB and TRPC6-CaMKIV-CREB pathways.

Deletion of TRPC6 Attenuates NMDA Receptor-Mediated Ca2+ Entry and Ca2+-Induced Neurotoxicity Following Cerebral Ischemia and Oxygen-Glucose Deprivation

“…In contrast, TRPC6 expression levels were decreased in the brain after I/R and activation of TRPC6 had protective effects on ischemic brain damage in rats (Du et al, 2010). Furthermore, TRPC6 activator Hyperforin and Resveratrol has been shown to suppress MCAO-induced brain damage via inhibition of TRPC6 degradation in rats (Lin et al, 2013a,b). Thus far, the exact reasons for these discrepancies among these studies are not known.…”

Revealing the Underlying Mechanism of Ischemia Reperfusion Injury Using Bioinformatics Approach

“…The protein domains in Module 4 significantly enriched in Transient receptor potential channel, and canonicaltransient receptor potential channel 6 (TRPC6) was among the genes in this module. TRPC6 have been reported to be associated with I/R in the lung [34], brain I/R injury is reported to be prevented through TRPC6-MEK-CREB and TRPC6-CaMKIV-CREB pathways [35], and activating TRPC channels before ischemia is believed to have early neuroprotective effects on retinal ganglion cells in vitro [36]. In this study, log FC for TRPC6 between normal and I/R injury rats samples was 1.53, indicating that TRPC6 was an up-regulated DEG.…”

Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases

“…Resveratrol also prevents diabetes-induced impairment of eNOS-dependent vasorelaxation in cerebral arterioles, suggesting an important therapeutic potential of resveratrol in treating cerebrovascular dysfunction in diabetic patients [145]. Several other studies have attributed the protective effects of resveratrol from stroke to its neuroprotective effects [145][146][147][148][149][150], which have been reviewed previously [151]. Although there is no human clinical trial that investigated the protective effects of resveratrol in stroke patients, a single dose of resveratrol has been shown to increase the cerebral blood flow during a performance task in healthy adult subjects [152,153].…”