期刊
JOURNAL OF NEUROCHEMISTRY
卷 115, 期 2, 页码 333-342出版社
WILEY
DOI: 10.1111/j.1471-4159.2010.06919.x
关键词
acetylcholine; acetyl-CoA; brain; nerve terminals; thiamine deficiency
资金
- Ministry of Research and Higher Education [NN 401 2333 33, NN 401 029937]
- Medical University of Gdansk [St-57, W-185]
P>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 non-quantal 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 non-quantal 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.
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