Abstract
Background: Smoking-derived nicotine (N) and oral contraceptives (OC) are known to synergistically magnify the risk and severity of cerebral ischemia in females. The underlying pathological mechanism remains elusive. Our studies have shown that N toxicity is exacerbated by OC via altered mitochondrial function, which involved a defect in activity of cytochrome c oxidase, the terminal enzyme of the electron transport chain. However, the effects of impaired mitochondrial function on brain metabolism remain to be investigated. To understand the impact in brain metabolisms, in the current study we investigated the global metabolomic profile of brains of adolescent and adult female rats exposed to N +/- OC. Methods: Six and twelve weeks old Sprague-Dawley female rats were randomly (n = 8/group) exposed to either saline, N (4.5 mg/kg) +/- OC for 16-21 days. At the end of the treatment, brain tissue was harvested for metabolomic analysis (performed by Metabolon Inc.) The metabolomic profile was complemented with western blot analysis and enzyme activity measurements. Results: Pathway enrichment analysis showed significant changes in energy metabolism (glycolysis and TCA cycle) and neurotransmitters in both adolescent and adult rats exposed to N, OC and N+OC in relation to saline treatment. The changes were more pronounced in adolescent rats with a significant decrease in glucose, glucose 6-phosphate, fructose-6-phosphate along with a significant increase in pyruvate in N and N+OC exposed groups when compared to saline (p<0.05), suggesting alterations in the glycolytic pathway. Western blot analyses of glycolytic enzymes support the observed metabolic changes. Conclusion: Nicotine and N+OC exposure increased brain glycolysis in an age-dependent manner. Since glucose metabolism is critical for brain physiology, altered glycolysis deteriorates neural function thus exacerbating ischemic brain damage. Moreover, significant decrease in the neuroactive peptide GABA was observed in young female rats treated with N+OC when compared to saline group. Discerning the exact effects of N +/- OC on overall brain metabolism and the molecular mechanisms affecting mitochondrial function at different ages will open a new window for future therapeutic intervention.
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