Chronic postnatal administration of methylmalonic acid provokes a decreaseof myelin content and ganglioside N-acetylneuraminic acid concentration incerebrum of young rats

Levels of methylmalonic acid (MMA) comparable to those of human methylmalon ic acidemia were achieved in blood (2-2.5 mmol/l) and brain (1.35 mu mol/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 mu mol/g as a function of animal age, Control rats were treated with saline i n 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, po ns, the olfactory lobes and cerebellum were discarded and the rest of the b rain ("cerebrum") was isolated. Body and "cerebrum" weight were measured, a s well as the cholesterol and triglyceride concentrations in blood and the content of myelin, total lipids, and the concentrations of the lipid fracti ons (cholesterol, glycerolipids, phospholipids and ganglioside N-acetylneur aminic acid (ganglioside-NANA)) in the "cerebrum", Chronic MMA administrati on had no effect on body or "cerebrum" weight. suggesting that the metaboli tes per se neither affect the appetite of the rats nor cause malnutrition, In contrast, MMA caused a significant reduction of plasma triglycerides, bu t not of plasma cholesterol levels. A significant diminution of myelin cont ent and of ganglioside-NANA concentration was also observed in the "cerebru m". We propose that the reduction of myelin content and ganglioside-NANA ca used by MMA may be related to the delayed myelination/ cerebral atrophy and neurological dysfunction found in methylmalonic acidemic children.