• Kynurenines, seizures and neurodegeneration

      McMaster, Owen George; Schwarcz, Robert; Eccles, Christine U., 1952- (1992)
      Separate branches of the kynurenine pathway of tryptophan metabolism produce the excitotoxin quinolinic acid (QUIN) and the anticonvulsant/neuroprotective kynurenic acid (KYNA). An imbalance of these two kynurenine metabolites has been speculatively linked to epilepsy and a number of neurodegenerative disorders such as Ammon's horn sclerosis and Huntington's chorea. This thesis was designed to probe this theory by examining if a relative kynurenic acid deficiency plays a role in animal models of epilepsy and neurodegenerative disease. The kindling model of epilepsy was used to examine if a relationship existed between kynurenic acid and the seizure-prone state. The establishment of the kindled state was not associated with a reduction in KYNA ten days after amygdala kindling was complete. The kainate model of epilepsy was used to examine if seizure activity was associated with changes in kynurenic acid homeostasis. Basal KYNA production remained unchanged 30 minutes after kainate and during the peak of seizure activity, the effects of various buffer constituents remained the same as for control animals. Kynurenine uptake was also unchanged during the peak of the seizure activity. The effects of intrahippocampal injection of aminooxyacetic acid (AOAA), which is known to inhibit KYNA production, were then examined. AOAA injection resulted in seizures and lesions resembling those induced by QUIN. These effects were blocked by the NMDA receptor agonist APH. Gamma acetylenic GABA (GAG), another compound which inhibits KYNA production, was also discovered to produce QUIN-like, axon-sparing, neuropathology in the hippocampus. Susceptibility to GAG lesions depended on the developmental stage of rats examined. These results add to our current understanding of mechanisms underlying seizures and neurodegenerative disorders and suggest that novel mechanisms may play a role in the etiology of these disorders.