In Vivo Intracerebral Administration of α-Ketoisocaproic Acid to Neonate Rats Disrupts Brain Redox Homeostasis and Promotes Neuronal Death, Glial Reactivity, and Myelination Injury.

Maple syrup urine disease (MSUD) is caused by severe deficiency of branched-chain α-keto acid dehydrogenase complex activity, resulting in tissue accumulation of branched-chain α-keto acids and amino acids, particularly α-ketoisocaproic acid (KIC) and leucine. Affected patients regularly manifest with acute episodes of encephalopathy including seizures, coma, and potentially fatal brain edema during the newborn period. The present work investigated the ex vivo effects of a single intracerebroventricular injection of KIC to neonate rats on redox homeostasis and neurochemical markers of neuronal viability (neuronal nuclear protein (NeuN)), astrogliosis (glial fibrillary acidic protein (GFAP)), and myelination (myelin basic protein (MBP) and 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase)) in the cerebral cortex and striatum. KIC significantly disturbed redox homeostasis in these brain structures 6 h after injection, 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 (diminished levels of reduced glutathione and altered glutathione peroxidase, glutathione reductase, and superoxide dismutase activities) in both cerebral structures. Noteworthy, the antioxidants N-acetylcysteine and melatonin attenuated or normalized most of the KIC-induced effects on redox homeostasis. Furthermore, a reduction of NeuN, MBP, and CNPase, and an increase of GFAP levels were observed at postnatal day 15, suggesting neuronal loss, myelination injury, and astrocyte reactivity, respectively. Our data indicate that disruption of redox homeostasis, associated with neural damage caused by acute intracerebral accumulation of KIC in the neonatal period may contribute to the neuropathology characteristic of MSUD patients.