RS-alpha-lipoic acid protects cholinergic cells against sodium nitroprusside and amyloid-beta neurotoxicity through restoration of acetyl-CoA level.
The work presented here verifies the hypothesis that RS-alpha-lipoic acid may exert its cholinoprotective and cholinotrophic activities through the maintenance of appropriate levels of acetyl-CoA in mitochondrial and cytoplasmic compartments of cholinergic neurons. Sodium nitroprusside (SNP) and amyloid-beta decreased pyruvate dehydrogenase, choline acetyltransferase activities, acetyl-CoA content in mitochondria and cytoplasm, as well as increased fraction of non-viable, trypan blue positive cells in cultured differentiated cholinergic SN56 neuroblastoma cells. Lipoic acid totally reversed toxin-evoked suppression of choline acetyltrasferase and pyruvate dehydrogenase activities, as well as mitochondrial and cytoplasmic acetyl-CoA levels, and partially attenuated increase of cell mortality. Significant negative correlations were found between enzyme activities, acetyl-CoA levels and cell mortality in different neurotoxic and neuroprotective conditions employed here. The level of cytoplamic acetyl-CoA correlated with mitochondrial acetyl-CoA, whereas choline acetyltransferase activity followed shifts in cytoplasmic acetyl-CoA. Thus, we conclude that, in cholinergic neurons, particular elements of the pyruvate-acetyl-CoA-acetylcholine pathway form a functional unit responding uniformly to nerotoxic and neuroprotectory conditions.
Bielarczyk
Hanna
H
Department of Laboratory Medicine, Medical University of Gdansk, Gdansk, Poland.
Gul
Sylwia
S
Ronowska
Anna
A
Bizon-Zygmanska
Dorota
D
Pawelczyk
Tadeusz
T
Szutowicz
Andrzej
A
D000105:Acetyl Coenzyme A / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D006801:Humans; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D020030:Nitric Oxide Donors / Q000633:toxicity*; D009599:Nitroprusside / Q000633:toxicity*; D010275:Parasympathetic Nervous System / Q000166:cytology* / Q000187:drug effects; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology*; D014343:Trypan Blue
D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D020030:Nitric Oxide Donors; D011768:Pyruvate Dehydrogenase Complex; D009599:Nitroprusside; D000105:Acetyl Coenzyme A; D008063:Thioctic Acid; D007655:Ketoglutarate Dehydrogenase Complex; D002795:Choline O-Acetyltransferase; D014343:Trypan Blue