Distinct Mechanisms Underlie Neurotoxin-Mediated Cell Death in Cultured Dopaminergic Neurons

Lotharius, Julie; Dugan, Laura L.; O’Malley, Karen L.

doi:10.1523/jneurosci.19-04-01284.1999

Cited by 380 publications

(316 citation statements)

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“…In particular, 6-OHDA, one of the most commonly used catecholaminergic neurotoxins, is known to produce ROS (Vroegop et al, 1995;Lotharius et al, 1999) and to potently inhibit mitochondrial electron transport chain complexes I and IV (Ogawa et al, 1994;Glinka et al, 1997). Reduced GSH and its precursor NAC are recognized as highly effective antioxidants, and have been shown to protect against neuronal degeneration in the 6-OHDA-challenged rat striatum (Froissard et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Protective effects of fustin, a flavonoid from Rhus verniciflua Stokes, on 6-hydroxydopamine-induced neuronal cell death

Park

Lee²,

Park³

et al. 2007

Exp Mol Med

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Abstract6-Hydroxydopamine (6-OHDA) is a neurotoxin and is commonly used to generate experimental models of Parkinson's disease (PD). In this study, we investigated the signaling molecules involved in the 6-OHDA-induced cell death using a neuronal catecholaminergic cell line (SK-N-SH cells), and the protective effect of fustin, a flavonoid from Rhus verniciflua Stokes, on 6-OHDA-induced neuronal death. 6-OHDA significantly increased levels of reactive oxygen species (ROS), intracellular Ca 2+ ([Ca 2+ ] i ), and p38 phosphorylation. In addition, this ROS increase by 6-OHDA was reduced by pretreatment with N-acetylcysteine (NAC), a free radical scavenger, but not by bis-(o-aminophenoxy)-ethane-N,N,N,Ntetraacetic acid (BAPTA), a Ca 2+ chelator. However, the [Ca 2+ ] i increase induced by 6-OHDA was suppressed by NAC. Moreover, pretreatment with NAC or BAPTA significantly prevented the 6-OHDAinduced increases in p38 phosphorylation, Bax/ Bcl-2 ratio, and caspase-3 activity. Although 6-OHDA-increased phosphorylation of p38 was prevented by NAC or BAPTA, inhibition of p38 by SB203580 did not suppress ROS, Bax/Bcl-2 ratio, or caspase-3 activity increases, and only partially prevented 6-OHDA-induced cell death, thus demonstrating that p38 activation is a component of a signaling pathway leading to the initiation of 6-OHDA-induced cell death, which acts in parallel with an ROS-Ca 2+ -Bcl-2-caspase-3 pathway. Moreover, fustin not only suppressed 6-OHDA-induced cell death in a concentration-dependent manner but also blocked 6-OHDA-induced increases in ROS, [Ca 2+ ] i , Bax/Bcl-2 ratio, caspase-3 activity, and p38 phosphorylation. These results suggest that fustin exerts neuroprotection against 6-OHDA-induced cell death.

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Section: Discussionmentioning

confidence: 99%

Protective effects of fustin, a flavonoid from Rhus verniciflua Stokes, on 6-hydroxydopamine-induced neuronal cell death

Park

Lee²,

Park³

et al. 2007

Exp Mol Med

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“…A body of work has been generated to support the premise that MPP + can directly lead to ROS formation and mitochondrial dysfunction [20,21] . The antioxidants that could modulate ROS level have been shown to reduce apoptotic cell death in the dopaminergic cell lines and the PC12 cells treated with MPP + [22] .…”

Section: Discussionmentioning

confidence: 99%

Protective effect of erythropoietin against 1-methyl-4-phenylpyridinium-induced neurodegenaration in PC12 cells

Shang

Sun

et al. 2007

Neurosci. Bull.

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Objective The neuroprotective effect of erythropoietin (EPO) against 1-methyl-4-phenylpyridinium (MPP + )-induced oxidative stress in cultured PC12 cells, as well as the underlying mechanism, were investigated. Methods PC12 cells impaired by MPP + were used as the cell model of Parkinson's disease. Methyl thiazolyl tetrazolium (MTT) was used to assay the viability of the PC12 cells exposed to gradient concentrations of EPO, and the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay was used to analyze the apoptosis ratio of PC12 cells. The expression of Bcl-2 and Bax in PC12 cells were examined by Western blot, and the reactive oxygen species (ROS), the mitochondrial transmembrane potential and the activity of caspase-3 in each group were detected by spectrofluorometer. Results Treatment of PC12 cells with MPP + caused the loss of cell viability, which may be associated with the elevation in apoptotic rate, the formation of ROS and the disruption of mitochondrial transmembrane potential. It was also shown that MPP + significantly induced the upregulation of Bax/Bcl-2 ratio and the activation of caspase-3. In contrast, EPO significantly reversed these responses and had the maximum protective effect at 1 U/mL. Conclusion The inhibitive effect of EPO on the MPP + -induced cytotoxicity may be ascribed to its anti-oxidative property and anti-apoptotic activity, and EPO may provide a useful therapeutic strategy for treatment of neurodegenerative diseases such as Parkinson's disease.

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“…Hitherto, it has not been clearly defined whether the cell death induced by MPP + is apoptotic and/or necrotic. Contradictory results have been obtained from the treatment with different doses of MPP + in different culture systems [1][2][3][4]. This study, therefore, aims at determining the cell death mechanisms underlying MPP + -induced dopamine neuron degeneration in vivo in a living animal model of Caenorhabditis elegans.…”

Section: Dear Editormentioning

confidence: 99%

Dopamine neuron degeneration induced by MPP+ is independent of CED-4 pathway in Caenorhabditis elegans

2008

Cell Res

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Dear Editor,Parkinson's disease (PD) is a common neurodegenerative disease characterized by progressive loss of dopamine neurons in the substantia nigra, and manifests the cardinal clinical symptoms of resting tremors, rigidity, bradykinesia, hyperkinesias and abnormal posture. In the 1980s a synthetic heroin contaminant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was discovered as a cause of parkinsonism in a group of drug addicts. Since then, mechanisms involved in 1-methyl-4-phenylpyridinium (MPP + )-induced neurotoxicity have been extensively studied in various animal models and cell cultures. MPTP is highly lipophilic and can easily cross the blood-brain barrier and cell membrane. MPTP is metabolized in glial cells by monoamine oxidase type B to its active ionic metabolite MPP + , which is then selectively taken up by dopamine neurons via dopamine transporter (DAT). Hitherto, it has not been clearly defined whether the cell death induced by MPP + is apoptotic and/or necrotic. Contradictory results have been obtained from the treatment with different doses of MPP + in different culture systems [1][2][3][4]. This study, therefore, aims at determining the cell death mechanisms underlying MPP + -induced dopamine neuron degeneration in vivo in a living animal model of Caenorhabditis elegans.C. elegans hermaphrodite contains eight dopamine neurons: four symmetrically arranged cephalic cells (CEPs, two dorsal and two ventral), two bilateral anterior deirids (ADEs) in the head, and two bilateral posterior deirids (PDEs) near the vulva. The processes of dopamine neurons run through the body and tail. Since C. elegans is transparent, using the green fluorescent protein (GFP) attached to the DAT gene promoter (Pdat-1::GFP) we can visualize the bodies and processes of dopamine neurons to study dopamine neuron degeneration in vivo. A number of mutant alleles related to apoptotic cell death and necrotic cell death genes are available in C. elegans, which afford us an opportunity to investigate the relationship between MPP + -induced dopamine neuron degeneration and cell death pathways in vivo using the living animal model.In order to investigate MPP + -induced neurotoxicity in dopamine neurons of C. elegans in vivo, we synchronized Pdat-1::GFP reporter strain BZ555 at L1 stage and incubated the worms in various concentrations of MPP + (from 0.25 to 1.0 mM) and observed the GFP-labeled dopamine neurons 24, 48, and 72 h after MPP + treatment. Dramatic changes of GFP fluorescence in dopamine neurons were detected in MPP + -treated worms, but not in vehicle-treated worms. By 24 h after MPP + treatment, the GFP signal of CEP and ADE dendrites was significantly reduced or lost with retention of GFP in cell soma ( Figure 1A-i, ii, iii). In addition, blebbing along the CEP and ADE processes and swelling in the dopamine cell bodies were observed in some worms ( Figure 1A-ii). By 48 h, GFP was completely lost in a part of dopamine neurons. By 72 h after incubation with 0.5 mM MPP + , we found that a few of the worms surv...

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Distinct Mechanisms Underlie Neurotoxin-Mediated Cell Death in Cultured Dopaminergic Neurons

Cited by 380 publications

References 40 publications

Protective effects of fustin, a flavonoid from Rhus verniciflua Stokes, on 6-hydroxydopamine-induced neuronal cell death

Protective effects of fustin, a flavonoid from Rhus verniciflua Stokes, on 6-hydroxydopamine-induced neuronal cell death

Protective effect of erythropoietin against 1-methyl-4-phenylpyridinium-induced neurodegenaration in PC12 cells

Dopamine neuron degeneration induced by MPP+ is independent of CED-4 pathway in Caenorhabditis elegans

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