Chronic intrastriatal injection of the excitatory amino acid receptor antagonist l-kynurenic acid in rat produces selective neuron sparing lesions

Heritable neurodegenerative diseases may be associated with one or more endogenous neurotoxins whose actions on neurons lead to the degenerative changes. One metabolite of tryptophan, the amino acid l-kynurenic acid ( l-KYN), was chronically injected into the striatum of the male rat to test its potential as an endogenous neurotoxin. l-KYN, at concentrations of approximately five times its normal brain levels, produced a large lesion with relative selective neuron sparing. The l-KYN-induced lesion presented three concentric regions: a central necrotic zone, a thin pyknotic zone, and an outermost spongiose zone. The number of GABA-ergic neurons were markedly reduced (∼76%), while cholinesterase-positive neurons were also lost. The NADPH diaphorase-positive neurons were the most resistant to l-KYN neurotoxicity and were spread throughout the spongiose zone. The brain levels of l-KYN are abnormal in patients with the neurodegenerative disorder Huntington's disease and as a neurotoxin l-KYN may play a role in the etiology of this disease. Of further significance, the fact that l-KYN is neurotoxic contraindicates the use of this excitatory amino acid receptor antagonist as a therapeutic agent in the treatment of neurodegenerative disorders.