Acetylcholine thiamin deficiency

Barclay LL, Gibson GE, and Blass JP (1981) Impairment of behavior and acetylcholine metaboUsm in thiamine deficiency./oMf/tal of Pharmacology and Experimental Therapeutics 217, 537-43. 

An inherited pyruvate dehydrogenase deficiency, a thiamine deficiency, or hypoxia deprives the brain of a source of acetyl CoA for acetylcholine synthesis, as well as a source of acetyl CoA for ATP generation from the TCA cycle. 

Barclay, L. L., et al., 1981a. Impairment of behavior and acetylcholine metabolism in thiamine deficiency. J Pharmacol Exp Then 217, 537-543. 

With such an extensive knowledge base, what is the present state of our understanding of the mechanisms of this disorder Not unexpectedly, initial studies, primarily in experimental animal models, focused on the known metabolic pathways which involve thiamine. Indeed, the classical studies of Peters in 1930 (Peters, 1969) showed lactate accumulation in the brainstem of thiamine deficient birds with normalization of this in vitro when thiamine was added to the tissue. This led to the concept of the biochemical lesion of the brain in thiamine deficiency. The enzymes which depend on thiamine are shown in Fig. 14.1. They are transketolase, pyruvate and a-ketoglutarate dehydrogenase. Transketolase is involved in the pentose phosphate pathway needed to form nucleic acids and membrane lipids, including myelin. The ketoacid dehydrogenases are key enzymes of the Krebs cycle needed for energy (ATP) synthesis and also to form acetylcholine via Acetyl CoA synthesis. Decrease in activity of this cycle would result in anaerobic metabolism and lead to lactate formation (i.e., tissue acidosis) (Fig. 14.1). 

Data on the role of acetylcholine deficit in thiamine deficiency are conflicting, but most recent studies do not favor a significant decrease in the synthesis of this neurotransmitter (Hazell et al, 1998 Vorhees et al, 1977). This would be consistent with normal pyruvate dehydrogenase activity in experimental thiamine deficiency, which should not, therefore, result in a lower Acetyl CoA level as a precursor to acetylcholine. 

Heinrich, C.P., Stadler, H., and Weiser, H., 1973. The effect of thiamine deficiency on the acetylcoenzymeA and acetylcholine levels in the rat brain. Journal of Neurochemistry. 21 1273-1281. 

Jankowska-Kulawy, A., Bielarczyk, H., Pawelczyk, T., Wroblewska, M., and Szutowicz A., 2010. Acetyl-CoA and acetylcholine metabolism in nerve terminal compartment of thiamine deficient rat brain. Journal of Neurochemistry. 115 333-342. 

Reynolds, S.F., and Blass, J.P., 1975. Normal levels of acetyl coenzyme A and of acetylcholine in the brains of thiamin-deficient rats. Journal of neurochemistry. 24 183-186. 

Thiamin potentiates CNS effects of acetylcholine. improved cognitive functioning in patients with Alzheimer s or age-related memory loss taking 3-8g/day. chronic thiamin diphosphate deficiency may contribute to cognitive impairment in Alzheimer"s Diseas. 

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