Protection against quinolinic acid-mediated excitotoxicity in nigrostriatal dopaminergic neurons by endogenous kynurenic acid

Neuroscience
A F MirandaK Jhamandas

Abstract

Endogenous excitotoxins have been implicated in the degeneration of dopaminergic neurons in the substantia nigra compacta of patients with Parkinson's disease. One such agent quinolinic acid is an endogenous excitatory amino acid receptor agonist. This study examined whether an increased level of endogenous kynurenic acid, an excitatory amino acid receptor antagonist, can protect nigrostriatal dopamine neurons against quinolinic acid-induced excitotoxic damage. Nigral infusion of quinolinic acid (60 nmoles) or N-methyl-D- aspartate (15 nmoles) produced a significant depletion in striatal tyrosine hydroxylase activity, a biochemical marker for dopaminergic neurons. Three hours following the intraventricular infusion of nicotinylalanine (5.6 nmoles), an agent that inhibits kynureninase and kynurenine hydroxylase activity, when combined with kynurenine (450 mg/kg i.p.), the precursor of kynurenic acid, and probenecid (200 mg/kg i.p.), an inhibitor of organic acid transport, the kynurenic acid in the whole brain and substantia nigra was increased 3.3-fold and 1.5-fold respectively when compared to rats that received saline, probenecid and kynurenine. This elevation in endogenous kynurenic acid prevented the quinolinic acid-induced ...Continue Reading

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