Inhibition of DT-Diaphorase potentiates thein vivo neurotoxic effect of intranigral injection of salsolinol in rats

Dı́az-Véliz, Gabriela; Mora, Sergio; Lungenstrass, H.; Segura‐Aguilar, Juan

doi:10.1007/bf03033183

Cited by 14 publications

(9 citation statements)

References 11 publications

(10 reference statements)

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“…This redox cycling results in (i) the depletion of NADH, which is required to produce ATP synthesis in the mitochondria; (ii) depletion of NADPH, required to keep GSH in the reduced state, necessary to exert its antioxidant action; (iii) depletion of oxygen, required for ATP synthesis in the mitochondria; (iv) formation of superoxide radicals, which spontaneously or enzymatically generate hydrogen peroxide, the precursor of hydroxyl radicals. Leucoaminochrome-o-semiquinone radical is highly neurotoxic in cells and rats, and it has been proposed as an endogenous neurotoxin which induces neurodegeneration of dopaminergic neurons in PD (Paris et al, 2001;2005a-g;SeguraAguilar et al, 2001;Arriagada et al, 2004;Diaz-Veliz et al, 2004a,b, Fuentes-Bravo et al, 2005Lozano-Gonzalez et al, 2005). Aminochrome also induces toxicity in astrocytes ; and (iv) Aminochrome can be reduced with two-electrons to leukoaminochrome, catalyzed by DT-diaphorase (FIG.…”

Section: Aminochrome As An Endogenous Neurotoxinmentioning

confidence: 94%

Aminochrome as a preclinical experimental model to study degeneration of dopaminergic neurons in Parkinson’s disease

et al. 2007

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Four decades after L-dopa introduction to PD therapy, the cause of Parkinson's disease (PD) remains unknown despite the intensive research and the discovery of a number of gene mutations and deletions in the pathogenesis of familial PD. Different model neurotoxins have been used as preclinical experimental models to study the neurodegenerative process in PD, such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and rotenone. The lack of success in identifying the molecular mechanism for the degenerative process in PD opens the question whether the current preclinical experimental models are suitable to understand the degeneration of neuromelanin-containing dopaminergic neurons in PD. We propose aminochrome as a model neurotoxin to study the neurodegenerative processes occurring in neuromelanin-containing dopaminergic neurons in PD. Aminochrome is an endogenous compound formed during dopamine oxidation and it is the precursor of neuromelanin, a substance whose formation is a normal process in mesencephalic dopaminergic neurons. However, aminochrome itself can induce neurotoxicity under certain aberrant conditions such as (i) one-electron reduction of aminochrome catalyzed by flavoenzymes to leukoaminochrome o-semiquinone radical, which is a highly reactive neurotoxin; or (ii) the formation of aminochrome adducts with alpha-synuclein, enhancing and stabilizing the formation of neurotoxic protofibrils. These two neurotoxic pathways of aminochrome are prevented by DT-diaphorase, an enzyme that effectively reduces aminochrome with two-electrons preventing both aminochrome one-electron reduction or formation alpha synuclein protofibrils. We propose to use aminochrome as a preclinical experimental model to study the neurodegenerative process of neuromelanin containing dopaminergic neurons in PD.

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Section: Aminochrome As An Endogenous Neurotoxinmentioning

confidence: 94%

Aminochrome as a preclinical experimental model to study degeneration of dopaminergic neurons in Parkinson’s disease

et al. 2007

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“…Each rat was placed in a plexiglass cage (30 × 30 × 30 cm), and spontaneous locomotor activity and rearing were monitored during a period of 30 min and evaluated as described previously [ 43 ]. The floor of the cage was an activity platform (Lafayette Instrument Co., Lafayette, IN, USA) connected to an electromechanical counter.…”

Section: Methodsmentioning

confidence: 99%

Prenatal Stress Down-Regulates Reelin Expression by Methylation of Its Promoter and Induces Adult Behavioral Impairments in Rats

et al. 2015

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Prenatal stress causes predisposition to cognitive and emotional disturbances and is a risk factor towards the development of neuropsychiatric conditions like depression, bipolar disorders and schizophrenia. The extracellular protein Reelin, expressed by Cajal-Retzius cells during cortical development, plays critical roles on cortical lamination and synaptic maturation, and its deregulation has been associated with maladaptive conditions. In the present study, we address the effect of prenatal restraint stress (PNS) upon Reelin expression and signaling in pregnant rats during the last 10 days of pregnancy. Animals from one group, including control and PNS exposed fetuses, were sacrificed and analyzed using immunohistochemical, biochemical, cell biology and molecular biology approaches. We scored changes in the expression of Reelin, its signaling pathway and in the methylation of its promoter. A second group included control and PNS exposed animals maintained until young adulthood for behavioral studies. Using the optical dissector, we show decreased numbers of Reelin-positive neurons in cortical layer I of PNS exposed animals. In addition, neurons from PNS exposed animals display decreased Reelin expression that is paralleled by changes in components of the Reelin-signaling cascade, both in vivo and in vitro. Furthermore, PNS induced changes in the DNA methylation levels of the Reelin promoter in culture and in histological samples. PNS adult rats display excessive spontaneous locomotor activity, high anxiety levels and problems of learning and memory consolidation. No significant visuo-spatial memory impairment was detected on the Morris water maze. These results highlight the effects of prenatal stress on the Cajal-Retzius neuronal population, and the persistence of behavioral consequences using this treatment in adults, thereby supporting a relevant role of PNS in the genesis of neuropsychiatric diseases. We also propose an in vitro model that can yield new insights on the molecular mechanisms behind the effects of prenatal stress.

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“…The entire experimental model for Parkinson's disease used exogenous neurotoxins such as 6-hydroxydopamine [111], MPTP [112], paraquat [113], rotenone [114] and dithiocarbamates [115]. Most likely, the degeneration of dopaminergic neurons containing neuromelanin is primarily dependent on an endogenous neurotoxin(s), such as (i) the o-quinones (dopamine o-quinone, aminochrome and 5,6-indolequinone) generated during dopamine oxidation; (ii) 3,4-dihydroxyphenylacetaldehyde generated by the oxidative deamination of dopamine catalyzed by MAO [116]; (iii) salsolinol, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, the condensation product of dopamine with aldehyde [86]. It is plausible that certain genetic polymorphisms will potentiate the effect of endogenous neurotoxins.…”

Section: Discussionmentioning

confidence: 99%

“…The depletion of NADPH results in a decrease in reduced glutathione because NADPH is required for the enzymatic reduction of glutathione. Several reports demonstrate that the one-electron reduction of aminochrome is a neurotoxic reaction both in cell cultures and in vivo [27,28,32,33,54,[56][57][58][59][60][61][62][81][82][83][84][85][86].…”

Section: One-electron Reductionmentioning

confidence: 99%

Molecular and Neurochemical Mechanisms Dopamine Oxidation To O-Quinones in Parkinson’s Disease Pathogenesis

Muñoz

Meléndez

Paris

et al. 2015

Current Topics in Neurotoxicity

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Four decades after L-dopa was introduced as a therapy for Parkinson's disease, it is still the gold standard for Parkinson's pharmacological treatment because no new drug has been discovered. This is due to the ambiguity regarding the molecular mechanisms responsible for the degeneration of dopaminergic neurons containing neuromelanin in the substantia nigra, which induces the motor symptoms of Parkinson's disease. The question is to identify the mechanisms underlying the neurodegenerative process of Parkinson's disease initiated years before the motor symptoms are evident, through pre-motor symptoms. The possible role of an exogenous environmental neurotoxin has been proposed. However, MPTP generates severe Parkinsonism in just 3 days, in contrast with idiopathic Parkinson's disease, which occurs after years of slow degeneration. The discovery of proteins (such as alpha synuclein and parkin) associated with the familial form of the disease opened new lines of basic research, resulting in a general agreement that five mechanisms are involved in the degeneration of dopaminergic neurons containing neuromelanin: protein degradation dysfunction, mitochondrial dysfunction, alpha synuclein aggregation, oxidative stress and neuroinflammation. Dopamine oxidation sequentially generates dopamine o-quinone, aminochrome, 5,6-indolequinone and finally, neuromelanin. These o-quinones have been reported to be directly involved in four of

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Inhibition of DT-Diaphorase potentiates thein vivo neurotoxic effect of intranigral injection of salsolinol in rats

Cited by 14 publications

References 11 publications

Aminochrome as a preclinical experimental model to study degeneration of dopaminergic neurons in Parkinson’s disease

Aminochrome as a preclinical experimental model to study degeneration of dopaminergic neurons in Parkinson’s disease

Prenatal Stress Down-Regulates Reelin Expression by Methylation of Its Promoter and Induces Adult Behavioral Impairments in Rats

Molecular and Neurochemical Mechanisms Dopamine Oxidation To O-Quinones in Parkinson’s Disease Pathogenesis

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