Chronic postnatal administration of methylmalonic acid provokes a decrease of myelin content and ganglioside N-acetylneuraminic acid concentration in cerebrum of young rats

Levels of methylmalonic acid (MMA) comparable to those of human methylmalonic acidemia were achieved in blood (2-2.5 mmol/l) and brain (1.35 æmol/g) of rats by administering buffered MMA, pH 7.4, subcutaneously twice a day from the 5th to the 28th day of life. MMA doses ranged from 0.76 to 1.67 æmol/g as a function of animal age. Control rats were treated with saline in the same volumes. The animals were sacrificed by decapitation on the 28th day of age. Blood was taken and the brain was rapidly removed. Medulla, pons, the olfactory lobes and cerebellum were discarded and the rest of the brain ("cerebrum") was isolated. Body and "cerebrum" weight were measured, as well as the cholesterol and triglyceride concentrations in blood and the content of myelin, total lipids, and the concentrations of the lipid fractions (cholesterol, glycerolipids, phospholipids and ganglioside N-acetylneuraminic acid (ganglioside-NANA)) in the "cerebrum". Chronic MMA administration had no effect on body or "cerebrum" weight, suggesting that the metabolites per se neither affect the appetite of the rats nor cause malnutrition. In contrast, MMA caused a significant reduction of plasma triglycerides, but not of plasma cholesterol levels. A significant diminution of myelin content and of ganglioside-NANA concentration was also observed in the "cerebrum". We propose that the reduction of myelin content and ganglioside-NANA caused by MMA may be related to the delayed myelination/cerebral atrophy and neurological dysfunction found in methylmalonic acidemic children

Effects of postnatal methylmalonate administration on neurobehavioral development of rats

Administration of methylmalonic acid in rats has been used as a model for methylmalonicacidemia in humans. Nestling Wistar rats of both sexes received 5 injections daily at 3-h intervals (starting at 7:30 a.m.) of saline or methylmalonic acid (MMA, 10 mg/ml) in a volume of 9 microliters/g body weight per injection subcutaneously in the lumbar region from the 5th to the 9th day of life and 11 microliters/g from day 10 to 14. Growth and neuromotor development were assessed by monitoring the following parameters daily in 54 rats: body weight, ear unfolding, incisor eruption, eye opening, righting, palmar grasp, negative geotaxis, cliff avoidance, free-fall righting and startle reflex. The only statistically significant effects of MMA administration were on the day of appearance of the free-fall righting reflex: MMA, 12.44 +/- 1.55 vs 11.0 +/- 0.39 days for saline control (P < 0.05, by two-way ANOVA) and a significant decrease in weight (P < 0.05, by ANOVA with repeated measures). The results suggest that chronic MMA administration to rats has a selective effect on neuromotor development

Effect of postnatal methylmalonate administration on adult rat behavior

Methylmalonate (MMA) levels (2.0-2.5 mM) comparable to those of human methylmalonic acidemia were achieved in blood of young rats from the 5th to the 25th day of life by of life by injecting the drug subcutaneously twice a day with an interval of 8h. MMA doses ranged from 0.76 to 1.69 *mol/g body weight as a function of animal age. MMA-treated rats had normal body and brain weights. Behavioral studies using aversive and nonaversive tasks were performaed at 60 days of life. Motor activity was similar in MMA-treated and saline-treated controls. No differences in performance between these groups were identified in the shuttle-avoidance responses and in the inhibitory avoidance tasks. However, MMA-injected rats escaped footshock faster than the controls (1.22 ñ 0.11 vs 1.76 ñ 0.14 (mean ñ SEM) for 24 rats in each group (P<0.01)) suggesting that they may be hyperreactive to this stimulus. In the open field, a nonaversive behavior task, MMA-injected rats, in contrast to control rats, presented no habituation. Our results suggest that MMA by itself may impair central nervous system function, causing minor disabilities which result in specific learning deficiencies