The pentylenetetrazole-induced activity in the hippocampus can be inhibited by the conversion of L-kynurenine to kynurenic acid: an in vitro study

The kynurenine pathway converts tryptophan into various compounds, including l-kynurenine, which in turn can be converted into the excitatory amino acid receptor antagonist kynurenic acid. The ionotropic glutamate receptors have been considered to be attractive targets for new anticonvulsants in neurological disorders such as epileptic seizure. This study was designed to examine the conversion of l-kynurenine to kynurenic acid and to investigate the effects of kynurenic acid on pentylenetetrazole-treated rat brain slices, and in parallel to draw attention to the fact that a well-designed in vitro model has many advantages in pharmacological screening. Schaffer collateral stimulation-evoked field EPSPs were recorded from area CA1 of rat hippocampal slices in vitro; drugs were bath-applied. Pretreatment with the kynurenic acid precursor l-kynurenine led to the elimination of the effect of pentylenetetrazole on hippocampal slices in vitro. N-Omega-nitro-l-arginine, which inhibits kynurenine aminotransferase I and II, abolished this neuroprotective effect.This study has furnished the first in vitro electrophysiological evidence that rat brain slices have the enzymatic capacity to convert exogenously administered l-kynurenine (16 μM) to kynurenic acid in an amount sufficient to protect them against pentylenetetrazole (1 mM)-induced hyperexcitability.