PROTECTION AGAINST QUINOLINIC ACID-MEDIATED EXCITOTOXICITY IN NIGROSTRIATAL DOPAMINERGIC-NEURONS BY ENDOGENOUS KYNURENIC ACID

Endogenous excitotoxins have been implicated in the degeneration of do paminergic neurons in the substantia nigra compacta of patients with P arkinson's disease. One such agent quinolinic acid is an endogenous ex citatory amino acid receptor agonist. This study examined whether an i ncreased level of endogenous kynurenic acid, an excitatory amino acid receptor antagonist, can protect nigrostriatal dopamine neurons agains t quinolinic acid-induced excitotoxic damage. Nigral infusion of quino linic acid (60 nmoles) or N-methyl-D- aspartate (15 nmoles) produced a significant depletion in striatal tyrosine hydroxylase activity, a bi ochemical marker for dopaminergic neurons. Three hours following the i ntraventricular infusion of nicotinylalanine (5.6 nmoles), an agent th at inhibits kynureninase and kynurenine hydroxylase activity, when com bined with kynurenine (450 mg/kg i.p.), the precursor of kynurenic aci d, and probenecid (200 mg/kg i.p.), an inhibitor of organic acid trans port, the kynurenic acid in the whole brain and substantia nigra was i ncreased 3.3-fold and 1.5-fold respectively when compared to rats that received saline, probenecid and kynurenine. This elevation in endogen ous kynurenic acid prevented the quinolinic acid-induced reduction in striatal tyrosine hydroxylase. However, 9 h following the administrati on of nicotinylalanine with kynurenine and probenecid, a time when who le brain kynurenic acid levels had decreased 12-fold, quinolinic acid injections produced a significant depletion in striatal tyrosine hydro xylase. Intranigral infusion of quinolinic acid in rats that received saline with kynurenine and probenecid resulted in a significant deplet ion of ipsilateral striatal tyrosine hydroxylase. Administration of ni cotinylalanine in combination with kynurenine and probenecid also bloc ked N-methyl-D-aspartate-induced depletion of tyrosine hydroxylase. Ty rosine hydroxylase immunohistochemical assessment of the substantia ni gra confirmed quinolinic acid-induced neuronal cell loss and the abili ty of nicotinylalanine in combination with kynurenine and probenecid t o protect neurons from quinolinic acid-induced toxicity. The present s tudy demonstrates that increases in endogenous kynurenic acid can prev ent the loss of nigrostriatal dopaminergic neurons resulting from a fo cal infusion of quinolinic acid or N-methyl-D-aspartate. The strategy of neuronal protection by increasing the brain kynurenic acid may be u seful in retarding cell loss in Parkinson's disease and other neurodeg enerative diseases where excitotoxic mechanisms have been implicated. (C) 1997 IBRO. Published by Elsevier Science Ltd.