DECREASED METABOLISM IN VIVO OF GLUCOSE INTO AMINO ACIDS OF THE BRAIN OF THIAMINE‐DEFICIENT RATS AFTER TREATMENT WITH PYRITHIAMINE

Abstract

Abstract— Thiamine deficiency produced by administration of pyrithiamine to rats maintained on a thiamine‐deficient diet resulted in a marked disturbance in amino acid and glucose levels of the brain. In the two pyrithiamine‐treated groups of rats (Expt. A and Expt. B) there was a significant decrease in the levels of glutamate (23%, 9%) and aspartate (42%, 57%), and an increase in the levels of glycine (26%, 27%) in the brain, irrespective of whether the animals showed signs of paralysis (Expt. A) or not (Expt. B). as a result of thiamine deficiency. A significant decrease in the levels of γ‐aminobutyrate (22%) and serine (28%) in the brain was also observed in those pyrithiamine‐treated rats which showed signs of paralysis (Expt. A). Threonine content increased by 57% in Expt. A and 40% in Expt. B in the brain of pyrithiamine‐treated rats, but these changes were not statistically significant. The utilization of [U‐14C]glucose into amino acids decreased and accumulation of glucose and [U‐14C]glucose increased significantly in the brain after injection of [U‐14C]glucose to pyrithiamine‐treated rats which showed abnormal neurological symptoms (Expt. A). The decrease in 14C‐content of amino acids was due to decreased conversion of [U‐14C]glucose into alanine, glutamate, glutamine, aspartate and γ‐aminobutyrate. The flux of [14C]glutamate into glutamine and γ‐aminobutyrate also decreased significantly only in the brain of animals paralysed on treatment with pyrithiamine. The decrease in the labelling of, amino acids was attributed to a decrease in the activities of pyruvate dehydrogenase and α‐oxoglutarate dehydrogenase in the brain of pyrithiamine‐treated rats. The measurement of specific radioactivity of glucose, glucose‐6‐phosphate and lactate also indicated a decrease in the activities of glycolytic enzymes in the brain of pyrithiamine‐treated animals in Expt. A only. It was suggested that an alteration in the rate of oxidation in vivo of pyruvate in the brain of thiamine‐deficient rats is controlled by the glycolytic enzymes, probably at the hexokinase level. The lack of neurotoxic effect and absence of significant decrease in the metabolism of [U‐14C]glucose in the brain of pyrithiamine‐treated animals in Expt. B were probably due to the fact that animals in Expt. B were older and weighed more than those in Expt. A, both at the start and the termination of the experiments.

Protective effects of the glutamate antagonist MK-801 on pyrithiamine- induced lesions and amino acid changes in rat brain

“…The present study demonstrates a temporal course and regional specificity to previous reports of thiamine deficiency induced amino acid changes (Gaitonde et al, 1975;Butter-worth et al, 1979;Hamel et al, 1979;Plaitakis et al, 1979;Butterworth and Heroux, 1989). Marked reductions of total aspartate and glutamate closely paralled the pathological changes.…”

Region‐selective alterations of glucose oxidation and amino acid synthesis in the thiamine‐deficient rat brain: a re‐evaluation using 1H/13C nuclear magnetic resonance spectroscopy

“…Region‐selective alterations in cerebral amino acids have been well‐documented in experimental animal models of thiamine deficiency (Gaitonde et al. 1975; Butterworth et al.…”

“…is a key mitochondrial enzyme regulating oxidative (pyruvate) metabolism and, like α‐KGDH, is thiamine‐dependent. However, previous biochemical studies have revealed that, unlike α‐KGDH, activities of PDH are unchanged in brain in thiamine deficiency (Gaitonde et al. 1975; Butterworth et al.…”

Glutamate: its role in learning, memory, and the aging brain

“…A reduction in levels of glutamate and aspartate demonstrated in the brains of neurologically impaired PTD rats (Gaitonde et al 1975;Butterworth et al 1979;Butterworth 1982;Langlais et al 1988) prompted investigation of a possible role for EAA in the pathogenesis of thiamine deficiency encephalopathy. In this regard, Langlais and Mair (1990) treated a group of PTD rats with MK-801 during induction of thiamine deficiency just after the animals developed signs of neurological impairment.…”