2-IMINOTHIAZOLIDINE-4-CARBOXYLIC ACID PRODUCES HIPPOCAMPAL CA1 LESIONS INDEPENDENT OF SEIZURE EXCITATION AND GLUTAMATE-RECEPTOR ACTIVATION

We previously demonstrated that 2-iminothiazolidine-4-carboxylic acid (2-ICA) formed by cyanide reacting with cysteine, caused glutamate ant agonist-sensitive seizures when injected i.c.v. (intracerebroventricul ar) in mice and produced hippocampal CA1 damage following i.c.v. infus ion in rats. In this study, the ability of either 2-ICA, glutamate, pr oline or NMDA (N-methyl-D-aspartate) injected i.c.v. to produce hippoc ampal lesions sensitive to glutamate antagonists was compared in mice. Hippocampal CA1 damage was observed 5-days following either a seizure (3.2 mu mol) or subseizure (1.0 mu mol) dose of 2-ICA. Glutamate (3.2 mu mol) or proline (10 mu mol) also produced hippocampal damage; glut amate damage was primarily to the CA1 subfield, whereas proline damage d neurons throughout the entire hippocampal formation. NMDA (3.2 nmol) caused seizure activity in all animals with a 50% lethality. No hippo campal damage was observed in surviving mice. Neither MK-801 (dizocilp ine maleate) nor CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) pretreatm ent prevented hippocampal lesions produced by 2-ICA. In contrast, MK-8 01 significantly reduced the frequency of mice displaying glutamate hi ppocampal lesions, but failed to block seizures produced by glutamate. MK-801 also protected neurons in the CA2-3 zone and the dentate gyrus , but not in the CA1 region of proline-injected mice. Finally, pretrea tment with the mixed metabotropic glutamate receptor (mGluR)1/mGluR2 a ntagonist-agonist (S)-4-carboxy-3-hydroxyphenylglycine (CHPG) prevente d hippocampal damage produced by the mGluR1 agonist (RS)-3,5-dihydroxy phenylglycine (DHPG), but did not protect against 2-ICA hippocampal le sions. These results show that 2-ICA hippocampal CA1 damage is not med iated through ionotropic or metabotropic glutamate receptors. 2-ICA hi ppocampal damage may represent a neurotoxicity that is distinct from e xcitotoxic-mediated cell death. (C) 1997 Intox Press, Inc.