Nerve cell death and gliosis in the limbic system are neuropathological hallmarks of temporal lobe epilepsy (TLE). This neuronal loss is initially caused by prolonged seizure activity and eventually results in recurrent, spontaneous seizures, i.e. chronic epilepsy. The mechanisms responsible for chronic epilepsy have been central themes of this project for many years. The proposed studies build on a concept that was developed during the past grant period. These data suggest that kynurenic acid (KYNA), an astrocyte-derived, endogenous antagonist of N-methyl-D-aspartate (NMDA) and alpha7 nicotinic acetylcholine (alpha7 nACh) receptors, is an anti-epileptic factor that is particularly effective in the entorhinal cortex (EC), a limbic brain region that is increasingly recognized as a """"""""hot spot"""""""" in TLE. Up-regulation of brain KYNA levels results in a substantial reduction in seizure frequency in chronically epileptic rats. The planned studies will examine the role of KYNA in chronic epilepsy, using electrophysiological and biochemical methods in vivo and in vitro. In addition, novel pharmacological agents that use astrocytes for the focal delivery of KYNA will be examined. Two established rat models of chronic epilepsy will be used for hypothesis testing.
Specific Aim 1 will test the hypothesis that an increase in the endogenous production of KYNA significantly reduces seizure frequency in animals exhibiting recurrent, spontaneous seizures. These in vivo studies will also evaluate whether the anti-epileptic efficacy of elevated KYNA is caused by an action at both NMDA and alpha7 nACh receptors, and whether KYNA preferentially targets the EC to effect seizure reduction;
Specific Aim 2 will assess the regulation of cerebral KYNA in epileptic tissue in vitro. The regulatory mechanisms that normally control brain kynurenine pathway metabolism and function are impaired in chronic epilepsy. These studies are designed to uncover the cellular and molecular mechanisms that account for abnormal KYNA formation in epileptic tissue;
Specific Aim 3 will examine the role of KYNA in epileptogenesis and epilepsy by electrophysiological means in vitro. Combined extracellular and intracellular recordings will be used to reveal the mechanisms underlying the hyperexcitability of entorhinal neurons, and the reason for their exquisite sensitivity to KYNA, in chronic epilepsy. Taken together, these studies will a) provide a comprehensive assessment of the role of KYNA in chronic epilepsy; b) contribute to our understanding of the role of the EC in chronic seizure phenomena and c) introduce a new therapeutic strategy which may offer advantages for the treatment of TLE.
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