Preferential resistance of dopaminergic neurons to glutathione depletion in a reconstituted nigrostriatal system

Nakamura, Ken; Won, Lisa; Heller, Alfred; Kang, Un Jung

doi:10.1016/s0006-8993(00)02425-2

Cited by 11 publications

(18 citation statements)

References 44 publications

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“…Although NAC does not alter PCB-induced depletion of tissue DA, it does protect against depletion of GABA suggesting that PCB-induced increases in oxidative stress lead to reductions in GABA concentrations. Indeed, using either a similar organotypic culture technique (Gramsbergen et al, 2002) or a dissociated cell culture model (Nakamura et al, 2000), depletion of GSH content with L-buthionine sulfoximine (BSO), depleted tissue GABA content and increased GABA neuronal death prior to any observed reductions in DA or the loss of DA neurons.…”

Section: Discussionmentioning

confidence: 99%

Polychlorinated biphenyl-induced oxidative stress in organotypic co-cultures: Experimental dopamine depletion prevents reductions in GABA

Lyng

Seegal

2008

NeuroToxicology

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Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that have been demonstrated to be toxic to the dopamine (DA) systems of the central nervous system. One proposed mechanism for PCB-induced DA neurotoxicity is inhibition of the vesicular monoamine transporter (VMAT); such inhibition results in increased levels of unsequestered DA and DA metabolism leading to oxidative stress. We have used an organotypic co-culture system of developing rat striatum and ventral mesencephalon (VM) to determine whether alterations in the vesicular storage of DA, resulting from PCB exposure and consequent induction of oxidative stress, leads to GABA and DA neuronal dysfunction. 24 hr exposure to an environmentally relevant mixture of PCBs reduced tissue DA and GABA concentrations, increased medium levels of DA and measures of oxidative stress in both the striatum and VM. Alterations in neurochemistry and increases in measures of oxidative stress were blocked in the presence of n-acetylcysteine (NAC). Although NAC treatment did not alter PCB-induced changes in DA neurochemistry, it did protect against reductions in GABA concentration. To determine whether alterations in the vesicular storage of DA were responsible for PCB-induced oxidative stress and consequent reductions in GABA levels, we depleted DA from the co-cultures using α-methyl-p-tyrosine (AMPT). AMPT reduced striatal and VM DA levels by 90% and 70%, respectively. PCB exposure, following DA depletion, neither increased levels of oxidative stress nor resulted in GABA depletion. These results suggest that PCB-induced alterations in the vesicular storage of DA, resulting in increased levels of unsequestered DA, leads to increased oxidative stress, depletion of tissue glutathione, and consequent reductions in tissue GABA concentrations.

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Section: Discussionmentioning

confidence: 99%

Polychlorinated biphenyl-induced oxidative stress in organotypic co-cultures: Experimental dopamine depletion prevents reductions in GABA

Lyng

Seegal

2008

NeuroToxicology

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“…Each of these compounds decreases BH 4 to less than 5% of control levels in cell lines (30). In mesencephalic neurons, DAHP and NAS in combination decrease BH 4 levels to about 16% of control (15). BH 4 depletion increased superoxide in dopaminergic neurons without affecting superoxide in nondopaminergic neurons (n ϭ 20 and 316, respectively).…”

Section: Bh 4 Decreases Superoxide In Primary Mesencephalicmentioning

confidence: 92%

“…Mesencephalic Cultures-Cultures were prepared as described previously (15). Briefly, timed pregnant Harlan Sprague-Dawley rats were purchased from Harlan Sprague-Dawley (Madison, WI).…”

Section: Methodsmentioning

confidence: 99%

“…Although these findings suggest that dopaminergic neurons are susceptible to oxidative stress, studies in vivo have not observed dopaminergic neuronal death following the oxidative stress generated by glutathione depletion (11)(12)(13). Furthermore, mesencephalic dopaminergic neurons in primary monolayer (14) and reaggregate (15) cultures are less susceptible to the toxicity of glutathione depletion than nondopaminergic neurons.…”

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confidence: 94%

“…Recently, BH 4 has also been found to decrease superoxide formed by xanthine/xanthine oxidase (16), a macrophage/phorbol myristate acetate reaction system (17), and by NOS (18,19), and to protect against a variety of oxidative stressors (20 -23). BH 4 also mediates the marked preferential resistance of dopaminergic neurons to glutathione depletion (15). Therefore, BH 4 may provide dopaminergic neurons with an additional pathway for the metabolism of reactive oxygen species (ROS).…”

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confidence: 99%

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Tetrahydrobiopterin Scavenges Superoxide in Dopaminergic Neurons

Nakamura¹,

Bindokas²,

Kowlessur³

et al. 2001

Journal of Biological Chemistry

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Increased oxidative stresses are implicated in the pathogenesis of Parkinson's disease, and dopaminergic neurons may be intrinsically susceptible to oxidative damage. However, the selective presence of tetrahydrobiopterin (BH 4 ) makes dopaminergic neurons more resistant to oxidative stress caused by glutathione depletion. To further investigate the mechanisms of BH 4 protection, we examined the effects of BH 4 on superoxide levels in individual living mesencephalic neurons. Dopaminergic neurons have intrinsically lower levels of superoxide than nondopaminergic neurons. In addition, inhibiting BH 4 synthesis increased superoxide in dopaminergic neurons, while BH 4 supplementation decreased superoxide in nondopaminergic cells. BH 4 is also a cofactor in catecholamine and NO production. In order to exclude the possibility that the antioxidant effects of BH 4 are mediated by dopamine and NO, we used fibroblasts in which neither catecholamine nor NO production occurs. In fibroblasts, BH 4 decreased baseline reactive oxygen species, and attenuated reactive oxygen species increase by rotenone and antimycin A. Physiologic concentrations of BH 4 directly scavenged superoxide generated by potassium superoxide in vitro. We hypothesize that BH 4 protects dopaminergic neurons from ordinary oxidative stresses generated by dopamine and its metabolites and that environmental insults or genetic defects may disrupt this intrinsic capacity of dopaminergic neurons and contribute to their degeneration in Parkinson's disease. Parkinson's disease (PD)1 is characterized by the selective degeneration of dopaminergic neurons in the substantia nigra (SN) pars compacta. While the etiology and pathogenesis of this cell death in most cases of PD remain unknown, it has been widely hypothesized that increased oxidative stress and mitochondrial dysfunction contribute to dopaminergic neuronal degeneration. Autopsy studies have noted numerous abnormalities indicative of increased oxidative damage in the SN (1-5).In particular, decreased glutathione in the SN has been found in autopsy brains from individuals with incidental Lewy bodies, presumed to represent presymptomatic PD (6). In addition, mitochondrial complex I activity is also decreased in the SN of PD patients (7, 8), and complex I inhibition can increase the formation of reactive oxygen species (9, 10). Although these findings suggest that dopaminergic neurons are susceptible to oxidative stress, studies in vivo have not observed dopaminergic neuronal death following the oxidative stress generated by glutathione depletion (11-13). Furthermore, mesencephalic dopaminergic neurons in primary monolayer (14) and reaggregate (15) cultures are less susceptible to the toxicity of glutathione depletion than nondopaminergic neurons.To explain this unanticipated resistance of dopaminergic neurons to oxidative stress, we hypothesized that dopaminergic neurons may contain additional antioxidants for the metabolism of ROS. One candidate is tetrahydrobiopterin (BH 4 ), which is present abundantly in do...

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Edaravone Protects Neurons in the Rat Substantia Nigra Against 6-Hydroxydopamine-Induced Oxidative Stress Damage

Liu

Shao

et al. 2014

Cell Biochem Biophys

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To investigate the mechanism of the neuroprotective effect of edaravone in substantia nigra (SN) of the 6-OHDA-induced rat model of Parkinson's disease. Animal model of Parkinson's disease was induced in male Sprague-Dawley rats by injecting 6-OHDA into the left medial forebrain bundle. Subsequently, rats were intraperitoneally injected with 0.3, 1, or 3 mg/kg of edaravone for 14 days or with 3 mg/kg edaravone for 14 days followed by 14 days of no treatment. We evaluated the effect of edaravone on the rotational and normal behavior of the rats, and on the number of tyrosine hydroxylase (TH)-positive cells, the amount of Nissl bodies, and the levels of glutathione (GSH), and malondialdehyde (MDA) in the SN. Edaravone treatment at 3 mg/kg significantly reduced apomorphine-induced rotational behavior (P < 0.01), improved the spontaneous behavior, prevented the decrease in the levels of TH-positive cells, Nissl bodies and GSH, and inhibited the increase in the levels of MDA (P < 0.05) in SN of rats with 6-OHDA-induced PD. Edaravone exerted a long-term neuroprotective effects in 6-OHDA-induced PD animal model by attenuating changes in the levels of GSH and MDA in SN, caused by oxidative stress. Edaravone prevented 6-OHDA-induced behavioral changes and de-pigmentation of SN that results from the loss of dopaminergic neurons.

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Preferential resistance of dopaminergic neurons to glutathione depletion in a reconstituted nigrostriatal system

Cited by 11 publications

References 44 publications

Polychlorinated biphenyl-induced oxidative stress in organotypic co-cultures: Experimental dopamine depletion prevents reductions in GABA

Polychlorinated biphenyl-induced oxidative stress in organotypic co-cultures: Experimental dopamine depletion prevents reductions in GABA

Tetrahydrobiopterin Scavenges Superoxide in Dopaminergic Neurons

Edaravone Protects Neurons in the Rat Substantia Nigra Against 6-Hydroxydopamine-Induced Oxidative Stress Damage

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