Disruption of brain redox homeostasis by acute intracerebral accumulation of α-ketoisocaproic acid in neonatal rats

Background: Maple syrup urine disease (MSUD) is caused by deficiency of branched-chain a-keto acid dehydrogenase complex activity, resulting in tissue accumulation of the branched-chain amino acids (BCAA) and their respective branched-chain a-keto acids (BCKA), particularly leucine and α-ketoisocaproic acid (KIC). Patients usually manifest acute episodes of encephalopathy with seizures, coma, and life-threatening cerebral edema in the first weeks of life. Since the neurotoxic mechanisms of these metabolites are still under debate, the present work investigated the ex vivo effects of an acute accumulation of KIC in brain of neonatal rats on redox homeostasis and mitochondrial respiration. Methods: One-day old rats were submitted to an intracerebroventricular injection of phosphate buffered saline (control) or KIC (1 mmol/g). Cerebral cortex and striatum were obtained 6 hours after injection to measure redox homeostasis, whereas the mitochondrial respiratory parameters were determined in cerebral cortex 1 hour after injection. Results: KIC treatment disturbed redox homeostasis in the cerebral cortex and striatum, as observed by increased 2’,7’-dichlorofluorescein oxidation (reactive oxygen species generation), malondialdehyde levels (lipid oxidative damage) and carbonyl formation (protein oxidative damage), besides impairing the antioxidant defenses (decreased concentrations of reduced glutathione and alterations of glutathione peroxidase, glutathione reductase and superoxide dismutase activities). In contrast, KIC did not change the respiratory parameters, suggesting that energy homeostasis was not affected. Discussion/Conclusion: It is assumed that disruption of redox homeostasis caused by acute intracerebral accumulation of KIC in the neonatal period may be a relevant pathomechanism involved in the neurological damage characteristic of MSUD patients particularly during crises of metabolic decompensation.

Financial support: PROPESQ/UFRGS, FAPERGS, INCT and CNPq.