Kynurenergic manipulations influence excitatory synaptic function and excitotoxic vulnerability in the rat hippocampus in vivo

Competing enzymatic mechanisms degrade the tryptophan metabolite L-kynureni ne to kynurenate, an inhibitory and neuroprotective compound, and to the ne urotoxins 3-hydroxykynurenine and quinolinate. Kynurenine 3-hydroxylase inh ibitors such as PNU 156561 shift metabolism towards enhanced kynurenate pro duction, and this effect may underlie the recently discovered anticonvulsan t and neuroprotective efficacy of these drugs. Using electrophysiological a nd neurotoxicological endpoints, we now used PNU 156561 as a tool to examin e the functional interplay of kynurenate, 3-hydroxykynurenine and quinolina te in the rat hippocampus in vivo. First, population spike amplitude in are a CAI and the extent of quinolinate-induced excitotoxic neurodegeneration w ere studied in animals receiving acute or prolonged intravenous infusions o f L-kynurenine, PNU 156561, (L-kynurenine + PNU 156561) or kynurenate. Only the latter two treatments, but not L-kynurenine or PNU 156561 alone, cause d substantial inhibition of evoked responses in area CA1, and only prolonge d (3 h) infusion of(L-kynurenine + PNU 156561) or kynurenate was neuroprote ctive. Biochemical analyses in separate animals revealed that the levels of kynurenate attained in both blood and brain (hippocampus) were essentially identical in rats receiving extended infusions of L-kynurenine alone or (L -kynurenine + PNU 156561) (4 and 7 mu M, respectively, after an infusion of 90 or 180 min). However, addition of the kynurenine 3-hydroxylase inhibito r resulted in a significant decrement in the formation of 3-hydroxykynureni ne and quinolinate in both blood and brain. These data suggest that the ratio between kynurenate and 3-hydroxykynurenin e and/or quinolinate in the brain is a critical determinant of neuronal exc itability and viability. The anticonvulsant and neuroprotective potency of kynurenine 3-hydroxylase inhibitors may therefore be due to the drugs' dual action on both branches of the kynurenine pathway of tryptophan degradatio n. (C) 2000 IBRO. Published by Elsevier Science Ltd.