Ascorbic acid prevents water maze behavioral deficits caused by early postnatal methylmalonic acid administration in the rat

Methylmalonic acidemia consists of a group of inherited neurometabolic disorders biochemically characterized by accumulation of methylmalonic acid (MA) and clinically by progressive neurological deterioration whose pathophysiology is not yet fully established. In the present study we investigated the effect of chronic administration (from the 5th to the 28th day of life) of methylmalonic acid (MA) on the performance of adult rats in the Morris water maze task. MA doses ranged from 0.72 to 1.67 μmol/g of body weight as a function of animal age; control rats were treated with the same volume of saline. Chronic postnatal MA treatment had no effect on body weight and in the acquisition of adult rats in the water maze task. However, administration of MA provoked long lasting reversal learning impairment in this task. Motor activity, evaluated by the swim speed in the maze, was not altered by MA administration, indicating no deficit of locomotor activity in rats injected with the metabolite. We also determined the effect of ascorbic acid administered alone or combined with MA on the same behavioral parameters in order to test whether free radicals might be responsible for the behavioral changes observed in MA-treated animals. Ascorbic acid was able to prevent the behavioral alterations provoked by MA. Moreover, the in vitro exposure of hippocampal and striatal preparations to MA revealed that the acid significantly reduced total radical-trapping antioxidant potential (TRAP) and total antioxidant reactivity (TAR) in the striatum, but not in the hippocampus. Furthermore, MA increased the thiobarbituric acid–reactive substances (TBA–RS) measurement in both structures. These data indicate that oxidative stress might be involved in the neuropathology of methylmalonic acidemia and that early MA administration induces long-lasting behavioral deficits, which are possibly caused by oxygen reactive species generation.