Abstract 48: Dysregulated Glucose Metabolism Pathway Specific Genes in Aged and Post-stroke Rat Brains Implicating Hexokinase 3 in Glucose Regulation

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Background: Metabolic dysregulation associated with aging impacts stroke incidence and outcome. Hyperglycemia occurs in 30% of patients with ischemic stroke, and is associated with poor stroke recovery. On the other hand, depletion of glucose within the brain prevents production of ATP, leading to energy reduction and neuronal death. Thus, balanced glucose metabolism is critical for normal brain function. However, our understanding of the regulation of genes involved in glucose metabolism and relationship to age in the post-stroke brain is elusive.Methods: Using transcriptomic and metabolomics approach, we examined the expression pattern of glucose metabolism pathway specific genes in the naïve and post-stroke brains of 3 month, and 12 month old rats subjected to focal cerebral ischemia by middle cerebral artery occlusion and 2 days re-perfusion. Metabolites were analyzed using Nuclear Magnetic Resonance (NMR) spectroscopy.Results: Our data shows substantial alterations in the glucose metabolism pathway in aged, and particularly in post stroke rat brain. Brains from 12 month old rats showed about 15 fold increase in phosphoenolpyruvate carboxykinase (PCK1), and 2 fold increase in phosphorylase kinase (PHKG1) mRNA as compared to 3 month old rats. In the post-stroke brain, mRNA levels of hexokinase 3 (HK3) was upregulated 9 fold in 3 month old rats. However, HK3 mRNA substantially increased to 26 fold in 12 month old post-stroke brain as compared to control brains. The PCK1 gene was down regulated 2-4 fold in post-stroke brain. Metabolomics studies indicated significant alterations in nucleotide metabolism and decreased antioxidants in the aged brain. Metabolic changes in post-stroke brains included depletion of ADP and AMP, and accumulation of fumarate, O-phospho-ethanolamine, glycerol, glycine, leucine, lysine and malate.Conclusion: Upregulation of PCK1, a key gluconeogenic enzyme may contribute to excess glucose production in aged brain, leading to increased risk of obesity and stroke. The inducible expression of HK3 in post-stroke brain suggests its adaptive role in metabolic responses to stress in the ischemic environment. Overall, HK3 by modulating glycolysis pathway, may lead to metabolic reprogramming in aged and post stroke brain.

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