Reversible alterations of cerebral gamma-aminobutyric acid in pyrithiamine-treated rats: implications for the pathogenesis of Wernicke's encephalopathy.
Treatment of rats with the central thiamine antagonist, pyrithiamine, results in severe neurological symptoms such as loss of righting reflex. Measurement of gamma-aminobutyric acid (GABA) content of brain tissue from symptomatic pyrithiamine-treated (PT) rats revealed significant reductions in thalamus, cerebellum, and pons. GABA content of cerebral cortex, however, was unaltered. Activities of the thiamine-dependent enzyme alpha-ketoglutarate dehydrogenase (alpha KGDH) were reduced in parallel with the GABA changes. On the other hand, activities of the GABA-synthetic enzyme glutamic acid decarboxylase (GAD) remained within normal limits, with the exception of a small but significant decrease in thalamus of symptomatic PT rats. Affinities and densities of high-affinity [3H]muscimol binding sites on crude cerebral membrane preparations from symptomatic PT rats were unchanged. Thiamine administration to symptomatic animals resulted in correction of abnormal righting reflexes and in normalization of decreased GABA levels and reduced alpha KGDH activities in cerebellum and pons. Thalamic GABA levels and alpha KGDH activities, on the other hand, remained significantly lower than normal. These results suggest that the reversible symptoms of pyrithiamine treatment may result from imparied GABA synthesis in cerebellum and pons of these animals. Similar mechanisms may play a role in the pathogenesis of the reversible symptoms of Wernicke's encephalopathy in man.
Héroux
M
M
Laboratory of Neurochemistry, André-Viallet Clinical Research Centre, Hôpital Saint-Luc, (University of Montreal), Quebec, Canada.
Butterworth
R F
RF
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D008297:Male; D009118:Muscimol / Q000378:metabolism; D011149:Pons / Q000187:drug effects / Q000378:metabolism; D011726:Pyridinium Compounds / Q000494:pharmacology*; D011745:Pyrithiamine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism; D014899:Wernicke Encephalopathy / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D011726:Pyridinium Compounds; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D011745:Pyrithiamine; D007655:Ketoglutarate Dehydrogenase Complex; D005968:Glutamate Decarboxylase