title: MPP(+)-induced degeneration is potentiated by dicoumarol in cultures of the RCSN-3 dopaminergic cell line. Implications of neuromelanin in oxidative metabolism of dopamine neurotoxicity.
abstract: We have tested the idea that oxidative metabolism of dopamine may be involved in MPTP toxicity using the RCSN-3 cell line derived from the substantia nigra of an adult rat. Treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (10 microM), MPTP combined with 40 microM dicoumarol (an inhibitor of DT-diaphorase) and dicoumarol alone, did not induce toxicity in RCSN-3 cells after 72 h incubation. The lack of toxicity in MPTP-treated RCSN-3 cells may be explained by the fact that they are unable to metabolize MPTP to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium ion (MPP+ as determined by HPLC. Incubation for 72 h with 100 microM MPP+ induced a 6.6 +/- 1.4% cell death of RCSN-3 cells compared to 3.5 +/- 0.4 observed in control cells. However, when the cells were treated with 100 microM MPP+ and 40 microM dicoumarol, cell death increased 4-fold compared to that of cells treated solely with MPP+ (27 +/- 2%; P<0.001). Under these conditions, a significant increase in DNA fragmentation (3-fold compared to MPP+ alone; P<0.01) and in calpain activation (P<0.05 compared to control) was evident. The inhibition of DT-diaphorase by dicoumarol supports the idea that oxidative metabolism of dopamine is involved in MPP+ toxicity in RCSN-3 cells.
authors.affiliation: Experimental Neurology and Neurosurgery, Department of Human Anatomy and Psychobiology, School of Medicine, University of Murcia, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Aguilar Hernández
authors.forename: M J
authors.initials: MJ
authors.lastname: Sánchez De Las Matas
authors.forename: C
authors.initials: C
authors.lastname: Arriagada
authors.forename: C
authors.initials: C
authors.lastname: Barcia
authors.forename: P
authors.initials: P
authors.lastname: Caviedes
authors.forename: M T
authors.initials: MT
authors.lastname: Herrero
authors.forename: J
authors.initials: J
authors.lastname: Segura-Aguilar
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism; D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D002154:Calpain / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D053938:DNA Fragmentation / Q000187:drug effects; D001728:Dicumarol / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D015259:Dopamine Agents / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008543:Melanins / Q000502:physiology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology; D010084:Oxidation-Reduction; D051381:Rats
chemical_list: D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D008543:Melanins; C014121:neuromelanin; D001728:Dicumarol; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D016660:NAD(P)H Dehydrogenase (Quinone); D002154:Calpain; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine