title: Role of mitochondrial dysfunction in neurotoxicity of MPP+: partial protection of PC12 cells by acetyl-L-carnitine.
abstract: The damage to the central nervous system that is observed after administration of either methamphetamine (METH) or 1-methyl-4-phenylpyridinium (MPP+), the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is known to be linked to dopamine (DA). The underlying neurotoxicity mechanism for both METH and MPP+ seem to involve free radical formation and impaired mitochondrial function. The MPP+ is thought to selectively kill nigrostriatal dopaminergic neurons by inhibiting mitochondrial complex I, with cell death being attributed to oxidative stress damage to these vulnerable DA neurons. In the present study, MPP+ was shown to significantly inhibit the response to MTT by cultured PC12 cells. This inhibitory action of MPP+ could be partially reversed by the co-incubation of the cells with the acetylated form of carnitine, acetyl-L-carnitine (ALC). Since at least part of the toxic action of MPP+ is related to mitochondrial inhibition, the partial reversal of the inhibition of MTT response by ALC could involve a partial restoration of mitochondrial function. The role carnitine derivatives, such as ALC, play in attenuating MPP+ and METH-evoked toxicity is still under investigation to elucidate the contribution of mitochondrial dysfunction in mechanisms of neurotoxicity.
authors.affiliation: Research and Development, Sigma-tau HealthScience S.p.A., Pomezia 00040, Italy. ashraf.virmani@st-hs.it
authors.forename: Ashraf
authors.initials: A
authors.lastname: Virmani
authors.forename: Franco
authors.initials: F
authors.lastname: Gaetani
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Binienda
authors.forename: Alex
authors.initials: A
authors.lastname: Xu
authors.forename: Helen
authors.initials: H
authors.lastname: Duhart
authors.forename: Syed F
authors.initials: SF
authors.lastname: Ali
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000108:Acetylcarnitine / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats
chemical_list: D018696:Neuroprotective Agents; D000108:Acetylcarnitine; D015655:1-Methyl-4-phenylpyridinium