Acetyl-L-carnitine prevents total body hydroxyl free radical and uric acid production induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the rat.
Acetyl-L-carnitine (ALCAR) is intimately involved in the transport of long chain fatty acids across the inner mitochondrial membrane during oxidative phosphorylation. ALCAR also has been reported to attenuate the occurrence of parkinsonian symptoms associated with 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) in vivo, and protects in vitro against the toxicity of the neurotoxic 1-methyl-4-phenylpyridinium (MPP+) metabolite of MPTP. The mechanism for these protective effects remains unclear. ALCAR may attenuate hydroxyl (HO*) free radical production in the MPTP/MPP+ neurotoxic pathway through several mechanisms. Most studies on MPTP/MPP+ toxicity and protection by ALCAR have focused on in vivo brain chemistry and in vitro neuronal culture studies. The present study investigates the attenuative effects of ALCAR on whole body oxidative stress markers in the urine of rats treated with MPTP. In a first study, ALCAR totally prevented the MPTP-induced formation of HO* measured by salicylate radical trapping. In a second study, the production of uric acid after MPTP administration-a measure of oxidative stress mediated through xanthine oxidase-was also prevented by ALCAR. Because ALCAR is unlikely to be a potent radical scavenger, these studies suggest that ALCAR protects against MPTP/MPP+-mediated oxidative stress through other mechanisms. We speculate that ALCAR may operate through interference with organic cation transporters such as OCTN2 and/or carnitine-acylcarnitine translocase (CACT), based partly on the above findings and on semi-empirical electronic similarity calculations on ALCAR, MPP+, and two other substrates for these transporters.
Loots
Du Toit
DT
Department of Biochemistry, North West University, Potchefstroom 2520, South Africa.
Mienie
Lodewyk J
LJ
Bergh
Jacobus J
JJ
Van der Schyf
Cornelis J
CJ
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors*; D000108:Acetylcarnitine / Q000494:pharmacology*; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D008401:Gas Chromatography-Mass Spectrometry; D017665:Hydroxyl Radical / Q000378:metabolism; D020267:MPTP Poisoning / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014527:Uric Acid / Q000652:urine
D015415:Biomarkers; D020011:Protective Agents; D014527:Uric Acid; D017665:Hydroxyl Radical; D000108:Acetylcarnitine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine