Potentiation of quinolinate-induced hippocampal lesions by inhibition of NO synthesis

Abstract

Low doses of quinolinic acid (QUIN) administered intracerebroventricularly (ICV) to rats produced either no damage or mild to moderate damage in the pyramidal cell layer of the hippocampus and resulted in mild, limbic seizures in the majority of animals treated. The same dose of QUIN following ICV pretreatment with the nitric oxide synthase inhibitor N-nitro-L-arginine (NARG), produced extensive hippocampal lesions with complete loss of the pyramidal layer in 50% of the animals, and moderate damage with total neuronal loss in areas CA1 and CA3 in the remainder of the group. Animals treated with both NARG and QUIN also exhibited a greater incidence of severe convulsive behavior (9/11) and 3 deaths. Pretreatment with the nitric oxide-generating drug molsidomine attenuated the enhanced toxicity observed with combined NARG-QUIN treatment, resulting primarily in no detectable hippocampal damages and mild seizures resembling those produced by QUIN alone. Administration of NARG alone produced neither seizure activity nor histological evidence of neurotoxicity. We conclude that inhibition of nitric oxide production with NARG potentiates the neurotoxicity of quinolinic acid in the rat hippocampus.