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.