Effect of pyrithiamine treatment and subsequent thiamine rehabilitation on regional cerebral amino acids and thiamine-dependent enzymes.
Pyrithiamine-induced thiamine-deficiency encephalopathy in the rat shows many neuropathological and biochemical similarities to Wernicke's encephalopathy in humans. Treatment of rats with pyrithiamine resulted in moderate reductions of glutamate in thalamus and pons and in generalized severe reductions of aspartate in pons (by 89%, p less than 0.01), thalamus (by 83%, p less than 0.01), cerebellum (by 53%, p less than 0.01), and cerebral cortex (by 33%, p less than 0.05). Alanine concentrations were concomitantly increased. Activities of the thiamine-dependent enzyme alpha-ketoglutarate dehydrogenase (alpha KGDH) were decreased in parallel with the aspartate decreases; pyruvate dehydrogenase complex activities were unchanged in all brain regions. Following thiamine administration to symptomatic pyrithiamine-treated rats, neurological symptoms were reversed and concentrations of glutamate, aspartate, and alanine, as well as alpha KGDH activities, were restored to normal in cerebral cortex and pons. Aspartate levels and alpha KGDH activities remained below normal values, however, in thalamus. Thus, pyrithiamine treatment leads to reductions of cerebral alpha KGDH and (1) decreased glucose (pyruvate) oxidation resulting in accumulation of alanine and (2) decreased brain content of glutamate and aspartate. Such changes may be of key significance in the pathophysiology of the reversible and irreversible signs of Wernicke's encephalopathy in humans.
Butterworth
R F
RF
Laboratory of Neurochemistry, André-Viallet Clinical Research Centre, Hôpital Saint-Luc University of Montreal, Quebec, Canada.
Héroux
M
M
D000409:Alanine / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D001927:Brain Diseases / Q000209:etiology; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism*; D007658:Ketone Oxidoreductases / Q000378:metabolism*; D008297:Male; D011726:Pyridinium Compounds / Q000494:pharmacology*; D011745:Pyrithiamine / Q000494:pharmacology*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013831:Thiamine / Q000494:pharmacology*; D013832:Thiamine Deficiency / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy
D000596:Amino Acids; D005971:Glutamates; D011726:Pyridinium Compounds; D011768:Pyruvate Dehydrogenase Complex; D001224:Aspartic Acid; D018698:Glutamic Acid; D011745:Pyrithiamine; D007658:Ketone Oxidoreductases; D007655:Ketoglutarate Dehydrogenase Complex; D000409:Alanine; D013831:Thiamine