Long-term neurobehavioral and histological damage in brain of mice induced by l-cysteine

Abstract

We investigated whether structural central neural damage and long-term neurobehavioral deficits after l-cysteine ( l-Cys) administration in mice is caused by hypoglycemia. Neonatal ICR mice were injected subcutaneously with l-Cys (0.5–1.5 mg/g body weight [BW]) or saline (control). Blood glucose was measured. At 50 days of age, mice were introduced individually into an eight-arm maze for evaluation of spatial memory (hippocampal-related behavior). Times for visiting all eight arms and number of entries until completion of the eight-arm visits (maze criteria) were measured. The test was repeated once daily for 5 days. In situ terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay was used for detection of brain damage. As early as 20 min and up to 2 h postinjection, animals treated with l-Cys doses higher than 1.2 mg/g BW developed hypoglycemia and looked ill. Several animals convulsed. Long-term survivors required more time, in a dose-dependent manner, to assimilate the structure of the maze, and animals treated with l-Cys (1.5 mg/g BW) exhibited TUNEL-positive changes in the hippocampal regions. All these changes were reversible by coadministration of glucose. We conclude that l-Cys injection can cause pronounced hypoglycemia associated with long-term neurobehavioral changes and central neural damage in mice. Since l-Cys is chemically different from the other excitatory amino acids (glutamate and aspartate), the long-reported l-Cys-mediated neurotoxicity may be connected to its hypoglycemic effect.