Effect of dichloroacetate on acetyl-CoA content and acetylcholine synthesis in rat brain synaptosomes

摘要

In potassium-depolarized synaptosomes Ca2+inhibited oxidation of pyruvate (30) and decreased the level of acetyl-CoA in intrasynaptosomal mitochondria (32). On the other hand, Ca2+facilitated provision of acetyl-CoA to synaptoplasm, since under these condition no change of synaptoplasmic acetyl-CoA and twofold stimulation of acetylcholine synthesis were found. However, in Ca2+-activated synaptosomes both synaptoplasmic acetyl-CoA and acetylcholine synthesis were suppressed by 1 mM (−)hydroxycitrate by 27 and 29, respectively. It was not the case in resting synaptosomes. Dichloroacetate (0.05 mM) partially reversed the inhibitory effect of Ca2+on pyruvate metabolism in synaptosomes and whole brain mitochondria. In Ca2+-stimulated synaptosomes, the dichloroacetate overcame suppressive effects of (−)hydroxycitrate on the level of synaptoplasmic acetyl-CoA and acetylcholine synthesis, but not on citrate clevage. It is concluded that dichloroacetate may improve the metabolism of acetylcholine in activated cholinergic terminals by increasing the production of acetyl-CoA in mitochondria and increasing its provision through the mitochondrial membrane to synaptoplasm by the transport system, independent of the ATP-citrate lyase path