title: Oxidation of dopamine to aminochrome as a mechanism for neurodegeneration of dopaminergic systems in Parkinson's disease. Possible neuroprotective role of DT-diaphorase.
abstract: Although it is generally accepted that free radicals are involved in the neurodegenerative process occurring in the dopaminergic neurons of the nigro-striatal system in Parkinson's disease, the exact mechanism of neurodegeneration in vivo is still unknown. We propose that the degeneration of dopaminergic nigrostriatal system in this condition may depend on: (a) existence of free dopamine which oxidizes to aminochrome as a consequence of: (i) overproduction of dopamine; (ii) inhibition and/or low expression of synaptic vesicle catecholamine transporter; (iii) inhibition or low expression of monoamine oxidases; (b) one-electron reduction of aminochrome to leukoaminochrome o-semiquinone radical, which induces neurotoxicity, due to inhibition of DT-diaphorase or the existence of a polymorphism with a point mutation (C --> T) in the cDNA 609 expressing an inactive DT-diaphorase. We suggest that DT-diaphorase plays a neuroprotective role in dopaminergic neurons, which is supported by the following observations: (i) Cu-toxicity is dependent on DT-diaphorase inhibition with dicoumarol in RCSN-3 cells derived from the rat substantia nigra; (ii) the cytotoxic effect of monoamine oxidase-A inhibitor amiflamine in RCSN-3 cells is increased by 2.4-fold (p < 0.001) in the presence of the inhibitor of DT-diaphorase, dicoumarol; (iii) concomitant intracerebral administration of manganese (Mn3+) together with the DT-diaphorase inhibitor dicoumarol into the left medial forebrain bundle produced a behavioral pattern characterized by contralateral rotational behavior when the rats were stimulated with apomorphine, in a manner similar to that observed in animals injected unilaterally with 6-hydroxydopamine; (iv) incubation of RCSN-3 cells with salsolinol in the presence of DT-diaphorase inhibitor significantly decreased cell survival by 2.5-fold (p < 0.001).
authors.affiliation: Programme of Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Independencia 1027, Casilla 70000, Santiago 7, Chile.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Graumann
authors.forename: Irmgard
authors.initials: I
authors.lastname: Paris
authors.forename: Pedro
authors.initials: P
authors.lastname: Martinez-Alvarado
authors.forename: Pamela
authors.initials: P
authors.lastname: Rumanque
authors.forename: Carolina
authors.initials: C
authors.lastname: Perez-Pastene
authors.forename: Sergio P
authors.initials: SP
authors.lastname: Cardenas
authors.forename: Pablo
authors.initials: P
authors.lastname: Marin
authors.forename: Fernando
authors.initials: F
authors.lastname: Diaz-Grez
authors.forename: Raul
authors.initials: R
authors.lastname: Caviedes
authors.forename: Pablo
authors.initials: P
authors.lastname: Caviedes
authors.forename: Juan
authors.initials: J
authors.lastname: Segura-Aguilar
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D045563:Indolequinones; D007211:Indoles / Q000378:metabolism* / Q000494:pharmacology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010084:Oxidation-Reduction / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*
chemical_list: D045563:Indolequinones; D007211:Indoles; D018696:Neuroprotective Agents; C091584:aminochrome 1; D016660:NAD(P)H Dehydrogenase (Quinone); D004298:Dopamine