Resveratrol preconditioning alters the metabolic phenotype of the brain within the long-term window of ischemic tolerance
Nathalie Khoury1, Kevin Koronowski1, Isabel Saul1, Juan Young1, Miguel Perez-Pinzon1 1Miller School of Medicine University of Miami, Miami, Florida, USA
In the absence of effective neuroprotective agents in the clinic, ischemic and pharmacological preconditioning are gaining increased interest in the field of cerebral ischemia. Our lab recently demonstrated that resveratrol preconditioning (RPC) promotes tolerance for 2 weeks in vivo against a cerebral ischemic insult. We hypothesized that RPC induces epigenetic and transcriptomic changes in the brain within the long-term window (LTW) that create the ischemic tolerant phenotype. Thus, we injected C57Bl6 mice with Vehicle/Resveratrol (10mg/kg); 2 weeks post we performed an RNA-seq experiment on the cortices where we identified 155 differentially expressed genes among which strikingly 126 genes were downregulated. The genes clustered into several biological processes including gene expression, neurotransmitter secretion, and regulation of membrane potential. This was reminiscent of the phenomenon of metabolic depression, an adaptive mechanism used by hibernating animals to resist ischemic states. Using our in vitro model consisting of primary neuronal astrocytic co-cultures, we measured the cells' respiration rates at the LTW post RPC (6 days; 100uM) in order to determine the rate of metabolism. We observed an increase in the rate of glycolysis induced by RPC along with a reduction in oxygen consumption rate. Additionally, we observed an increase in the mitochondrial:nuclear DNA content and mRNA levels of the mitochondrial complexes, along with a reduction in uncoupling proteins. Thus the observed reduction in oxygen consumption reflects more efficient rather than reduced respiration. Since respiration is coupled to gene expression through intermediate metabolites of the mitochondria that act as co-substrates for epigenetic enzymes we evaluated acetyl-coA levels at the LTW where we observed an increase in mRNA levels of enzymes involved in acetyl-coA uptake and metabolism further suggesting maximized energy production. While the enzyme involved in citrate breakdown to acetyl-coA outside the mitochondria was reduced which correlated with reduced abundance of the transcriptional activation marks H3K9ac and H4K16ac. In conclusion, we show that RPC alters brain metabolism by maximizing energy production and reducing energy consumption which allow the cells to endure increased durations of energy deprivation caused by ischemia.
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