Pretreatment with L-kynurenine, the precursor to the excitatory amino acid antagonist kynurenic acid, suppresses epileptiform activity in combined entorhinal/hippocampal slices.
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.
Scharfman
H E
HE
Neurology Research Center, Helen Hayes Hospital, West Haverstraw, NY 10993-1195, USA. hes5@cunixf.cc.columbia.edu
Ofer
A
A
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D002021:Buffers; D004594:Electrophysiology; D018728:Entorhinal Cortex / Q000503:physiopathology*; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy*; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000503:physiopathology*; D007736:Kynurenic Acid / Q000378:metabolism; D007737:Kynurenine / Q000494:pharmacology*; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D009924:Organ Culture Techniques; D011498:Protein Precursors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000927:Anticonvulsants; D002021:Buffers; D018691:Excitatory Amino Acid Antagonists; D011498:Protein Precursors; D007737:Kynurenine; D007736:Kynurenic Acid; D008274:Magnesium