Pretreatment with L-kynurenine, the precursor to the excitatory amino acid antagonist kynurenic acid, suppresses epileptiform activity in combined entorhinal/hippocampal slices.

ABSTRACT

The kynurenine pathway converts tryptophan into various compounds, including L-kynurenine, which in turn can be converted to the excitatory amino acid receptor antagonist kynurenic acid. The hypothesis that endogenously-produced kynurenic acid could have physiological effects was tested in combined entorhinal/hippocampal slices from adult rats. Specifically, perfusion with L-kynurenine (1 mM) was examined for its ability to suppress epileptiform activity produced by subsequent perfusion with buffer lacking added magnesium (nominal 0 mM magnesium buffer). Importantly, treatment with L-kynurenine did not appear to have depressant effects in itself, but it prevented spontaneous epileptiform activity in all 64 slices subsequently perfused with 0 mM magnesium buffer. In contrast, 45 slices that were not pretreated with L-kynurenine exhibited spontaneous epileptiform activity. These data support the hypothesis that endogenously-produced kynurenic acid can be produced and released in brain slices, where it can suppress excitatory activity in an "anticonvulsant' manner. Therefore, manipulation of the kynurenine pathway might constitute a useful new direction for anticonvulsant drug development.