Effect of dichloroacetate on acetyl-CoA content and acetylcholine synthesis in rat brain synaptosomes.
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 Ca(2+)-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 Ca(2+)-stimulated synaptosomes, the dichloroacetate overcame suppressive effects of (-)hydroxycitrate on the level of synaptoplasmic acetyl-CoA and acetylcholine synthesis, but not on citrate cleavage. 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 pathway.
Szutowicz
A
A
Department of Clinical Biochemistry, Gdańsk School of Medicine, Poland.
Bielarczyk
H
H
Skulimowska
H
H
D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000109:Acetylcholine / Q000096:biosynthesis*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009411:Nerve Endings / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D011773:Pyruvates / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism
D011773:Pyruvates; D000105:Acetyl Coenzyme A; D003999:Dichloroacetic Acid; D000109:Acetylcholine