Resveratrol Preconditioning Induces Genomic and Metabolic Adaptations within the Long-Term Window of Cerebral Ischemic Tolerance Leading to Bioenergetic Efficiency

Abstract

Neuroprotective agents administered post cerebral ischemia have failed so far in the clinic to promote significant recovery. Thus, numerous efforts were redirected towards prophylactic approaches such as preconditioning as an alternative therapeutic strategy. Our lab has revealed a novel long-term window of cerebral ischemic tolerance mediated by resveratrol preconditioning (RPC) that lasts for two weeks in mice. To identify its mediators, we conducted an RNA-seq experiment on the cortex of mice two weeks post RPC, which revealed 136 differentially expressed genes. The majority of genes (116/136) were downregulated upon RPC and clustered into biological processes involved in transcription, synaptic signaling, and neurotransmission. The downregulation in these processes was reminiscent of metabolic depression, an adaptation used by hibernating animals to survive severe ischemic states by downregulating energy-consuming pathways. Thus to assess metabolism, we used a neuronal-astrocytic co-culture model and measured the cellular respiration rate at the long-term window post RPC. Remarkably, we observed an increase in glycolysis and mitochondrial respiration efficiency upon RPC. We also observed an increase in the expression of genes involved in pyruvate uptake, TCA cycle, and oxidative phosphorylation, all of which indicated an increased reliance on energy-producing pathways. We then revealed that these nuclear and mitochondrial adaptations, which reduce the reliance on energy-consuming pathways and increase the reliance on energy-producing pathways, are epigenetically coupled through acetyl-CoA metabolism and ultimately increase

Neuroprotective Phytochemicals in Experimental Ischemic Stroke: Mechanisms and Potential Clinical Applications

“…Stilbenoids possess both the cis and trans forms, and the trans form is found to be more bioactive and stable [222]. In total, 7 stilbenoids are reported in the past 10 years for their neuroprotective activity in ischemic stroke, that is, resveratrol [45,[223][224][225][226][227][228][229][230][231][232][233][234][235], polydatin (resveratrol-3-β-D-glucoside) [236,237], malibatol A (a resveratrol oligomer) [88,238], oxyresveratrol [239], mulberroside A (oxyresveratrol-3,4 ′ -diglycopyranoside) [240], pterostilbene [241], and 2,3,5,4 ′ -tetrahydroxystilbene-2-O-β-D-glucoside [242]. Their neuroprotective mechanisms are explained in Table 3, and the chemical structures of the extensively studied stilbenoids are shown in Table 4.…”

Hippocampal Sector–Specific Metabolic Profiles Reflect Endogenous Strategy for Ischemia-Reperfusion Insult Resistance

“…Recently, proteomic and transcriptomic studies paved a new way of looking for a cause of neurons' delayed death or survival after IR episodes and for candidates for ischemic brain treatment [20]. Moreover, metabolomics was applied to investigate cerebral injury and protection in mice and rat models of brain ischemia [21][22][23][24][25]. Research has been carried out using various metabolomic techniques and in various models of global ischemia and stroke.…”

Mitochondrial MPTP: A Novel Target of Ethnomedicine for Stroke Treatment by Apoptosis Inhibition

“…Subsequently, studies confirmed that OGD/R induced bEND3 cerebrovascular endothelial cell edema was associated with monocyte chemoattractant protein and intracellular Ca 2+ overload, while resveratrol could maintain mitochondrial MMP by inhibiting ROS and elevated Ca 2+ ions, thus improving hypoxic brain edema (Panickar et al, 2015). Excitingly, recent study has further demonstrated that the antianoxic brain protection of preadministrated resveratrol may be related to consolidating mitochondrial tolerance to anoxia and increasing VDAC level and energy synthesis (Khoury et al, 2019). However, on the contrary, picroside II could interdict release of pro-apoptotic factor Endo G into the nucleus driven by MPTP opening, ROS production and VDAC1 protein expression (Li S. et al, 2018).…”