Thiamine-deficient
encephalopathy is characterized by morphologic lesions in the brainstem and less extensively in the cerebellum, but the early
neurologic signs reverse rapidly and fully with
thiamine, indicating a metabolic disorder. The suggested causal mechanisms of the
encephalopathy involve two
thiamine-dependent
enzymes: (a) impairment of
pyruvate decarboxylase activity with decreased cerebral energy (
ATP) synthesis, and (b) reduction of
transketolase activity with possible impairment of the hexose monophosphate shunt and subsequent decrease in
NADPH formation. The latter may be important in maintaining
glutathione in a reduced form (GSH), which apparently functions by keeping
enzymes in a reduced (active) conformation. To examine some of these postulated mechanisms, in this study we measured
pyruvate decarboxylase and
transketolase activity,
lactate,
ATP and GSH levels in the cerebral cortex, cerebellum, and brainstem, and
thiamine concentration in whole brain of rats with diet-induced low
thiamine encephalopathy. Pair-fed and normally fed asymptomatic control animals were similarly investigated. To assess the functional importance of some of our results, we repeated the studies in rats, immediately (16-36 hr) after reversal of the neurological signs with
thiamine administration. THE DATA OBTAINED LED TO THE FOLLOWING CONCLUSIONS: (a) Brain contains a substantial reserve of
thiamine in that
thiamine level has to fall to below 20% of normal before the onset of overt
encephalopathy and an increase in brain
thiamine to only 26% of normal results in rapid reversal of
neurologic signs. (b) Both cerebral
transketolase and
pyruvate decarboxylase activities are impaired in low
thiamine encephalopathy and the abnormality in the
pyruvate decarboxylase is reflected in a rise in brain
lactate. These biochemical abnormalities occur primarily in the brainstem and cerebellum, the sites of the morphologic changes. (c) Although the fall in cerebral
transketolase is about twofold greater than that of
pyruvate decarboxylase activity during
encephalopathy, both
enzymes rise on reversal of
neurologic signs and the degree of the
transketolase rise is slight. Accordingly, this study cannot ascertain the relative functional importance of these two pathways in the induction of the
encephalopathy. The data suggest, however, that the depression of
transketolase is not functionally important per se, but may only be an index of some other critical aspect of the hexose monophosphate shunt. (d) The normal cerebral
ATP concentration and small GSH fall during
encephalopathy, with little GSH rise on reversal of
neurologic signs, suggest that a depletion of neither substance is instrumental in inducing
thiamine-deficient
encephalopathy.