Chronic
thiamine deprivation in the rat leads to selective neuropathological damage to pontine structures. Onset of neurological symptoms of
thiamine deprivation (
ataxia, loss of righting reflex) was accompanied by selective decreases (of the order of 30%) in the activity of
alpha-ketoglutarate dehydrogenase (alpha KGDH) in lateral vestibular nucleus and hypothalamus.
Enzyme activities were decreased to a lesser extent in medulla oblongata, striatum and hippocampus and were unchanged in other brain structures. No changes in alpha KGDH occurred prior to the onset of neurological signs of
thiamine deprivation. Administration of the central
thiamine antagonist,
pyrithiamine, results within 3 weeks in loss of righting reflex and convulsions and in more widespread neuropathological changes than those observed following
thiamine deprivation. alpha KGDH activities were found to be substantially diminished in all brain regions studied following
pyrithiamine treatment with most severe changes occurring in brain regions found to be vulnerable to
pyrithiamine (lateral vestibular nucleus, hypothalamus, midbrain, medulla-pons). In some cases, alpha KGDH changes preceded the appearance of neurological symptoms of
pyrithiamine treatment. Such decreases in alpha KGDH may explain previous findings of region-selective changes in energy metabolism and of decreased synthesis of
glucose-derived
neurotransmitters (
acetylcholine,
GABA,
glutamate) in
pyrithiamine-treated rat brain.
Thiamine administration to symptomatic
pyrithiamine treated rats resulted in reversal of neurological signs of
encephalopathy and in normalisation of defective alpha KGDH activity in all brain regions. These findings suggest that the reversible neurological symptoms associated with
Wernicke's Encephalopathy in man likely result from region-selective impairment of alpha KGDH.