Acute and long-term effects of intracerebroventricular administration of α-ketoisocaproic acid on oxidative stress parameters and cognitive and noncognitive behaviors.

ABSTRACT

Maple Syrup Urine Disease (MSUD) is biochemically characterized by elevated levels of leucine, isoleucine and valine, as well as their corresponding transaminated branched-chain α-keto acids in tissue and biological fluids. Neurological symptoms and cerebral abnormalities, whose mechanisms are still unknown, are typical of this metabolic disorder. In the present study, we evaluated the early effects (1 h after injection) and long-term effects (15 days after injection) of a single intracerebroventricular administration of α-ketoisocaproic acid (KIC) on oxidative stress parameters and cognitive and noncognitive behaviors. Our results showed that KIC induced early and long-term effects; we found an increase in TBARS levels, protein carbonyl content and DNA damage in the hippocampus, striatum and cerebral cortex both one hour and 15 days after KIC administration. Moreover, SOD activity increased in the hippocampus and striatum one hour after injection, whereas after 15 days, SOD activity decreased only in the striatum. On the other hand, KIC significantly decreased CAT activity in the striatum one hour after injection, but 15 days after KIC administration, we found a decrease in CAT activity in the hippocampus and striatum. Finally, we showed that long-term cognitive deficits follow the oxidative damage; KIC induced impaired habituation memory and long-term memory impairment. From the biochemical and behavioral findings, it we presume that KIC provokes oxidative damage, and the persistence of brain oxidative stress is associated with long-term memory impairment and prepulse inhibition.