title: On the Role of DT-Diaphorase Inhibition in Aminochrome-Induced Neurotoxicity In Vivo.
abstract: Dopamine oxidation in the pathway leading to neuromelanin formation generates the ortho-quinone aminochrome, which is potentially neurotoxic but normally rapidly converted by DT-diaphorase to nontoxic leukoaminochrome. However, when administered exogenously into rat striatum, aminochrome is able to produce damage to dopaminergic neurons. Because of a recent report that substantia nigra pars compacta (SNpc) tyrosine hydroxylase (T-OH) levels were unaltered by aminochrome when there was cell shrinkage of dopaminergic neurons along with a reduction in striatal dopamine release, the following study was conducted to more accurately determine the role of DT-diaphorase in aminochrome neurotoxicity. In this study, a low dose of aminochrome (0.8 nmol) with or without the DT-diaphorase inhibitor dicoumarol (0.2 nmol) was injected into the left striatum of rats. Intrastriatal 6-hydroxydopamine (6-OHDA, 32 nmol) was used as a positive neurotoxin control in other rats. Two weeks later, there was significant loss in numbers of T-OH immunoreactive fibers in SNpc, also a loss in cell density in SNpc, and prominent apomorphine (0.5 mg/kg sc)-induced contralateral rotations in rats that had been treated with aminochrome, with aminochrome/dicoumarol, or with 6-OHDA. Findings demonstrate that neurotoxic aminochrome is able to exert neurotoxicity only when DT-diaphorase is suppressed-implying that DT-diaphorase is vital in normally suppressing toxicity of in vivo aminochrome, generated in the pathway towards neuromelanin formation.
authors.affiliation: Molecular & Clinical Pharmacology, Faculty of Medicine, University of Chile, Independencia 1027, Casilla, 70000, Santiago 7, Chile.|Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.
authors.forename: Andrea
authors.initials: A
authors.lastname: Herrera-Soto
authors.affiliation: Molecular & Clinical Pharmacology, Faculty of Medicine, University of Chile, Independencia 1027, Casilla, 70000, Santiago 7, Chile.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Díaz-Veliz
authors.affiliation: Molecular & Clinical Pharmacology, Faculty of Medicine, University of Chile, Independencia 1027, Casilla, 70000, Santiago 7, Chile.
authors.forename: Sergio
authors.initials: S
authors.lastname: Mora
authors.affiliation: Molecular & Clinical Pharmacology, Faculty of Medicine, University of Chile, Independencia 1027, Casilla, 70000, Santiago 7, Chile.
authors.forename: Patricia
authors.initials: P
authors.lastname: Muñoz
authors.affiliation: Laboratorio de Neuroanatomía, Departamento de Anatomía Normal, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Pablo
authors.initials: P
authors.lastname: Henny
authors.affiliation: Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.
authors.forename: Harry W M
authors.initials: HWM
authors.lastname: Steinbusch
authors.affiliation: Molecular & Clinical Pharmacology, Faculty of Medicine, University of Chile, Independencia 1027, Casilla, 70000, Santiago 7, Chile. jsegura@med.uchile.cl.
authors.forename: Juan
authors.initials: J
authors.lastname: Segura-Aguilar
mesh_terms: D000818:Animals; D001728:Dicumarol / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D045563:Indolequinones / Q000633:toxicity*; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D009498:Neurotoxins / Q000633:toxicity*; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013238:Stereotaxic Techniques; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D045563:Indolequinones; D009498:Neurotoxins; C091584:aminochrome 1; D001728:Dicumarol; D014446:Tyrosine 3-Monooxygenase; D016660:NAD(P)H Dehydrogenase (Quinone)
keywords: Aminochrome; DT-diaphorase; Dopamine; Neurodegeneration; Neuroprotection; Neurotoxicity; Substantia nigra