SYSTEMIC ADMINISTRATION OF KAINATE INDUCES MARKED INCREASES OF ENDOGENOUS KYNURENIC ACID IN VARIOUS BRAIN-REGIONS AND PLASMA OF RATS

The endogenous neuroinhibitory and neuroprotective excitatory amino ac id receptor antagonist kynurenic acid has been hypothetically linked t o the pathogenesis of epilepsy and several other brain disorders. In t he present study, alterations in kynurenic acid levels were examined i n the kainate model of temporal lobe epilepsy. Kainate was systemicall y injected in rats at a dose (10 mg/kg s.c.) which induces a character istic behavioural syndrome with stereotypies and focal (limbic) and ge neralized seizures, eventually progressing into severe status epilepti cus. Kynurenic acid was determined 3 h after kainate injection in vari ous brain regions (olfactory bulb, frontal cortex, piriform cortex, am ygdala, hippocampus, nucleus accumbens, caudate/putamen, thalamus, sup erior and inferior colliculus, pens and medulla, and cerebellar cortex ) and in plasma, using a sensitive high-performance liquid chromatogra phic method. When data were analysed irrespective of individual seizur e severity, significant increases in kynurenic acid were determined in all brain regions examined except the hippocampus, nucleus accumbens and poms/medulla. The most marked (200-500%) increases above controls were seen in the piriform cortex, amygdala, and cerebellar cortex. Fur thermore, a significant kynurenic acid increase of about 200% above co ntrol was determined in plasma. When kynurenic acid levels were determ ined in subgroups of rats with different behavioural alterations in re sponse to kainate, the most marked kynurenic acid increases were seen in subgroups with status epilepticus. Rats which only developed mild ( focal) seizures or stereotyped behaviours (wet dog shakes) also exhibi ted significantly increased kynurenic acid levels, thus indicating tha t the increase in kynurenic acid in response to kainate was not solely due to sustained convulsive seizure activity. Whereas it was previous ly proposed that kynurenic acid is involved only in later stages of se izure disorders, the present data demonstrate that marked increases in central and peripheral kynurenic acid levels occur early after the on set of neuroexcitation, at least in the kainate model.