Correlation of aspartate dose, plasma dicarboxylic amino acid concentration, and neuronal necrosis in infant mice

Abstract

Eight-day-old mice were administered aspartate at 0, 1.88, 3.76, 4.89, 5.64 and 7.52 mmol/kg body wt and the degree and extent of neuronal necrosis determined. In addition, plasma aspartate and glutamate concentrations were determined at each aspartate dose. Animals administered aspartate at 0, 1.88 and 3.76 mmol/kg body wt did not develop neuronal necrosis. Hypothalamic neuronal necrosis (7.33 ± 1.52 necrotic neurons/section of maximal damage) was found in 3 of 10 animals administered aspartate at 4.89 mmol/kg body wt. The extent of neuronal necrosis was proportional to dose once a neurotoxic dose of aspartate was reached. All 12 animals administered aspartate at 5.64 mmol/kg body wt developed lesions (49.5 ± 7.2 necrotic neurons/section of maximal damage). Similarly, all 18 mice administered aspartate at 7.52 mmol/kg developed hypothalamic lesions (80.8 ± 17.8 necrotic neurons/section of maximal damage). Infant mice administered the highest dose of aspartate not producing neuronal necrosis (3.76 mmol/kg) had a mean (±S.D.) peak plasma aspartate concentration of 87 ± 23 μmol/dl and a mean peak plasma glutamate concentration of 64±22 μmol/dl. Thus, the toxic threshold for these amino acids must be greater than those values.