Glutamate is the major excitatory and y-aminobutyric acid (GABA) the major inhibitory neurotransmitter in mammalian brain and human cortex. Animal models of epilepsy consistently indicate that GABA synaptic function is decreased in seizure states. Extensive studies in animals have shown that changes in GABA release and metabolism may play an important role in the origin and spread of seizure activity. Although it can be inferred that the clinical benefit reported in the treatment of epilepsy is associated with and attributable to elevation of brain GABA, evidence to show changes in brain GABA levels in man is lacking. Recent advances in nuclear magnetic resonance spectroscopy (NMRS) have permitted the first non-invasive measurements of cerebral GABA in animals and man. Studies of GABA synthesis and catabolism in human cortex will further understanding of this important inhibitory neurotransmitter in human health and disease. We propose to study changes in cerebral GABA and glutamate levels in non-epileptic volunteers and patients with epilepsy. Vigabatrin (y-vinyl-y-amino butyric acid), a GABA- transaminase inhibitor, is one of the most promising new anti-epileptic drugs under development. We propose to study changes in cerebral GABA and glutamate levels in patients with epilepsy as a function of dose and time of vigabatrin administration using NlVlRS. The study has four goals: To measure in vivo cerebral GABA and glutamate levels in non-epileptic and epileptic subjects, to measure cerebral GABA levels in epileptic subjects treated with standard dose and high dose vigabatrin, to measure cerebral GABA levels of epileptic subjects before and after initiation of vigabatrin therapy, and to compare the rate of GABA accumulation following a single dose of vigabatrin with the rate of GABA turnover before and after chronic administration of vigabatrin in a rat model using 13C-labeled glucose.
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