Acetyl-L-carnitine cytoprotection against 1-methyl-4-phenylpyridinium toxicity in neuroblastoma cells.
Acetyl-L-carnitine (ALCAR) plays an integral role in the transport of long chain fatty acids across the inner mitochondrial membrane for oxidative phosphorylation. In non-human primates, administration of ALCAR was reported to prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurological injury to the substantia nigra. The present study investigates the effects of ALCAR against the toxicity of 1-methyl-4-phenylpyridinium (MPP(+)), the neurotoxic metabolite of MPTP, in murine brain neuroblastoma cells. MPP(+), a potent mitochondrial toxin, induced a dose-dependent reduction in mitochondrial oxygen consumption and cell viability, corresponding to an accelerated rate of cellular glucose utilization. Treatment with ALCAR, but not L-carnitine, prevented MPP(+) toxicity and partially restored intracellular ATP concentrations, but did not reverse the MPP(+)-induced loss of mitochondrial oxygen consumption. These data indicate that protective effects are independent of oxidative phosphorylation. ALCAR had a substantial glucose sparing effect in both controls and MPP(+)-treated groups, demonstrating a potential role in enhancing glucose utilization through glycolysis. Antagonizing the entry of fatty acids into the mitochondria, with either insulin or malonyl CoA, did not interfere with ALCAR protection against MPP(+). On the contrary, insulin potentiated the protective effects of ALCAR. In conclusion, these data indicate that ALCAR protects against MPP(+) toxicity, independent of mitochondrial oxidative capacity or beta-oxidation of fatty acids. In contrast, the protective effects of ALCAR appear to involve potentiation of energy derived from glucose through anaerobic glycolysis.
Mazzio
Elizabeth
E
College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL 32307, USA.
Yoon
Kyoung J
KJ
Soliman
Karam F A
KF
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D000108:Acetylcarnitine / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection; D004347:Drug Interactions; D005947:Glucose / Q000032:analysis; D019344:Lactic Acid / Q000032:analysis; D051379:Mice; D009447:Neuroblastoma / Q000139:chemically induced / Q000473:pathology; D010101:Oxygen Consumption / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D020011:Protective Agents; D019344:Lactic Acid; D000108:Acetylcarnitine; D000255:Adenosine Triphosphate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D005947:Glucose; D015655:1-Methyl-4-phenylpyridinium