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Abstract The decrease of pyruvate and ketoglutarate dehydrogenase complex activities is the main cause of energy and acetyl-CoA deficits in thiamine deficiency-evoked cholinergic encephalopathies. However, disturbances in pathways of acetyl-CoA metabolism leading to appearance of cholinergic deficits remain unknown. Therefore, the aim of this work was to investigate alterations in concentration and distribution of acetyl-CoA and in acetylcholine metabolism in brain nerve terminals, caused by thiamine deficits. They were induced by the pyrithiamine, a potent inhibitor of thiamine pyrophosphokinase. The thiamine deficit reduced metabolic fluxes through pyruvate and ketoglutarate dehydrogenase steps, yielding deficits of acetyl-CoA in mitochondrial and cytoplasmic compartments of K-depolarized nerve terminals. It also inhibited indirect transport of acetyl-CoA though ATP-citrate lyase pathway being without effect on its direct Ca-dependent transport to synaptoplasm. Resulting suppression of synaptoplasmic acetyl-CoA correlated with inhibition of quantal acetylcholine release (r=0.91, p=0.012). On the other hand, thiamine deficiency activated nonquantal acetylcholine release that was independent of shifts in intraterminal distribution of acetyl-CoA. Choline acetyltransferase activity was not changed by these conditions. These data indicate that divergent alterations in the release of nonquantal and quantal acetylcholine pools from thiamine deficient nerve terminals could be caused by the inhibition of acetyl-CoA and citrate synthesis in their mitochondria. They in turn, caused inhibition of acetyl-CoA transport to the synaptoplasmic compartment through ATP-citrate lyase pathway yielding deficits of cholinergic functions.
Department of Laboratory Medicine,Medical University of Gda?sk, Poland.
This article was published in the following journal.
Name: Journal of neurochemistry
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A hexosiminidase that specifically hydrolyzes terminal non-reducing N-acetyl-D-galactosamine residues in N-acetyl-beta-D-galactosaminides.
An enzyme present in nerve tissue. It catalyzes reversibly the formation of thiamine diphosphate and orthophosphate from thiamine triphosphate. EC 184.108.40.206.
An enzyme that hydrolyzes thiamine pyrophosphate to thiamine monophosphate plus inorganic phosphate. EC 3.6.1.-.
A thiamine antagonist due to its inhibition of thiamine pyrophosphorylation. It is used to produce thiamine deficiency.
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