Measuring human brain GABA in vivo: effects of GABA-transaminase inhibition with vigabatrin.
Gamma-aminobutyric acid (GABA) plays a pivotal role in suppressing the origin and spread of seizure activity. Low occipital lobe GABA was associated with poor seizure control in patients with complex partial seizures. Vigabatrin irreversibly inhibits GABA-transaminase, raising brain and cerebrospinal fluid (CSF) GABA concentrations. The effect of vigabatrin on occipital lobe GABA concentrations was measured by in vivo nuclear magnetic-resonance spectroscopy. Using a single oral dose of vigabatrin, the rate of GABA synthesis in human brain was estimated at 17% of the Krebs cycle rate. As the daily dose of vigabatrin was increased to up to 3 g, the fractional elevation of brain GABA was similar to CSF increase. Doubling the daily dose from 3 to 6 g failed to increase brain GABA further. Increased GABA concentrations appear to reduce GABA synthesis in humans as it does in animals. With traditional antiepileptic drugs, remission of the seizure disorder was associated with normal GABA levels. With vigabatrin, elevated CSF and brain GABA was associated with improved seizure control. Vigabatrin enhances the vesicular and nonvesicular release of GABA. The release of GABA during seizures may be mediated in part by transporter reversal that may serve as an important protective mechanism. During a seizure, this mechanism may be critical in stopping the seizure or preventing its spread.
Petroff
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Department of Neurology, Yale University, New Haven, CT 06520, USA.
Rothman
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D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors*; D000085:Acetates / Q000627:therapeutic use; D000588:Amines; D000927:Anticonvulsants / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001923:Brain Chemistry; D003509:Cyclohexanecarboxylic Acids; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004827:Epilepsy / Q000188:drug therapy; D000077206:Gabapentin; D006801:Humans; D008959:Models, Neurological; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000627:therapeutic use
D000085:Acetates; D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D004791:Enzyme Inhibitors; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin