MPP+ Downregulates Mitochondrially Encoded Gene Transcripts and Their Activities in Dopaminergic Neuronal Cells: Protective Role of Bcl-2

Kim, Hyun-Eui; Yoon, So Young; Lee, Jung Eun; Choi, Won Seok; Jin, Byung Kwan; OH, T; Markelonis, George J.; Chun, Sang Yearn; Oh, Young J.

doi:10.1006/bbrc.2001.5446

Cited by 19 publications

(12 citation statements)

References 35 publications

(44 reference statements)

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“…However, several studies on BimEL suggest that its proapoptotic property lies mainly in its association with antiapoptotic proteins such as Bcl-2, Bcl-xL, and Bcl-w (2-5) (49). Consistent with this notion, it has been reported that overexpression of Bcl-2 in the dopaminergic cell line MN9D can effectively attenuate cell death under the insult of MPP+ (18,50). Therefore, it is plausible that BimEL may impair the function of antiapoptotic Bcl-2 family proteins through physical association, hence, hindering their role in maintaining normal mitochondrial functions, including calcium buffering, and leading to an increase in cytosolic calcium and calpain activation.…”

Section: Discussionmentioning

confidence: 81%

BimEL up‐regulation potentiates AIF translocation and cell death in response to MPTP

et al. 2005

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This study attempted to elucidate the signaling mechanism underlying dopaminergic cell death in the MPP+ model for Parkinson's disease. In neuronal-differentiated PC12 cells, through the regulation by activated JNK and c-jun, BimEL expression was markedly increased in response to MPP+ treatment, which led to the cell degeneration. In lieu of Smac translocation as seen in other paradigms, up-regulation of BimEL effected an increase in calpain I activity that, in turn, mediated AIF release from the mitochondria. In support, we found that knocking down BimEL expression resulted in a decrease in calpain I activity, as well as AIF release from the mitochondria and cell death. Finally, inhibition of calpain activity mitigated AIF release from the mitochondria and cell death. Under cell-free conditions, activated purified calpain I could induce the release of AIF from isolated mitochondria without the participation of BimEL or activated JNK, suggesting that AIF release is a direct consequence of calpain I activity. In concert, the results suggest a novel signaling pathway for dopaminergic cell degeneration, in which MPP+ induces the up-regulation of BimEL, which in turn potentiates an elevation in calpain I activity that mediates AIF release and cell death in a caspase-independent manner.

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Section: Discussionmentioning

confidence: 81%

BimEL up‐regulation potentiates AIF translocation and cell death in response to MPTP

et al. 2005

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“…Moreover, we confirmed that these drugs did not affect the MPP ϩ -induced cell death in PC12 cells. It has been demonstrated that ROS or a ROSmediated signal plays an essential role in 6-hydroxydopamine-induced but not MPP ϩ -induced cell death in a dopaminergic neuronal cell line (Choi et al, 1999, Kim et al, 2001. Seyfried et al (2000) have suggested that the generation of ROS might not be the primary mechanism of MPP ϩ toxicity in PC12 cells.…”

Section: Discussionmentioning

confidence: 99%

Nonsteroidal Anti-Inflammatory Drugs Potentiate 1-Methyl-4-phenylpyridinium (MPP⁺)-Induced Cell Death by Promoting the Intracellular Accumulation of MPP⁺in PC12 Cells

Morioka

Kumagai²,

Morita³

et al. 2004

J Pharmacol Exp Ther

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In this study, we investigated the effects of nonsteroidal antiinflammatory drugs (NSAIDs) on 1-methyl-4-phenylpyridinium (MPP ϩ )-induced cell death in PC12 cells. Coincubation of PC12 cells with indomethacin, ibuprofen, ketoprofen, or diclofenac, but not aspirin or N- [2-(cyclohexyloxy)-4-nitrophenyl]methanosulfonamide (NS-398), significantly potentiated the MPP ϩ -induced cell death. In contrast, these NSAIDs had no effect on rotenone-induced cell death. The potentiating actions of these NSAIDs were not suppressed by treatment with phenyl-N-butyl-nitrone, a radical scavenger; N-acetyl-L-cysteine, an antioxidant; Ac-DEVD-CHO, a selective caspase-3 inhibitor; or 2-chloro-5-nitro-N-phenylbenzamide (GW9662), a selective antagonist of peroxisome proliferator-activated receptor ␥. Furthermore, we observed that DNA fragmentation, which is one of the hallmarks of apoptosis, was not induced by coincubation with MPP ϩ and NSAIDs. We confirmed that coincubation of PC12 cells with 30 M MPP ϩ and 100 M indomethacin, ibuprofen, ketoprofen, or diclofenac led to a significant increase in the accumulation of intracellular MPP ϩ compared with incubation with 30 M MPP ϩ alone. In addition, these NSAIDs markedly reduced the efflux of MPP ϩ from PC12 cells. (3-(3-(2-(7-Chloro-2-quinolinyl) ethenyl) phenyl ((3-dimethyl amino3oxo-propyl) thio) methyl) propanoic acid (MK 571), which is an inhibitor of multidrug resistance proteins (MRPs), mimicked the NSAIDs-induced effects, increasing cell toxicity and promoting the accumulation of MPP ϩ . Moreover, some types of MRPs' mRNA were detected in PC12 cells. These results suggest that some NSAIDs might cause a significant increase in the intracellular accumulation of MPP ϩ via the suppression of reverse transport by the blockade of MRP, resulting in the potentiation of MPP ϩ -induced cell death.The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes a selective degeneration of nigrostriatal dopaminergic neurons and has been investigated extensively as part of an etiological model for Parkinson's disease (Tipton and Singer, 1993;Blum et al., 2001). The neurotoxic effects in vivo of MPTP are dependent on the conversion to its active metabolite 1-methyl-4-phenylpyridinium (MPP ϩ ) by monoamine oxidase B in glial cells and the uptake into neurons through transporters (Tipton and Singer, 1993;Kitayama et al., 1998). MPP ϩ induces an inhibition of complex I activity of the mitochondrial respiratory chain and cellular ATP depletion and a loss of mitochondrial transmembrane potential, resulting in cell death (Bates et al., 1994).Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their anti-inflammatory, antipyretic, and analgesic properties. The molecular basis for the therapeutic effects of NSAIDs is the ability to inhibit cyclooxygenase (COX) activity and thereby suppress the production of prostaglandins (Vane, 1971). In addition to alleviating inflammaArticle, publication date, and citation information can be found at

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“…Previously, we have shown that the dopaminergic toxins MPP + and 6-OHDA induce distinct cell-death processes in dopaminergic cells (Oh et al 1995;Choi et al 1999a,b;Lotharius et al 1999;Kim et al 2001). To determine whether the overexpression of a-synuclein or its mutants altered these cell death pathways, Syn/WT cells were treated with MPP + , 6-OHDA, the oxidative stress inducer hydrogen peroxide (H 2 O 2 ), and the Alzheimer's disease associated A-b.…”

Section: Overexpression Of A-synuclein Does Not Alter Distinct Toxin-mentioning

confidence: 99%

α‐Synuclein protects naive but not dbcAMP‐treated dopaminergic cell types from 1‐methyl‐4‐phenylpyridinium toxicity

Jensen

Alter

O’Malley

2003

Journal of Neurochemistry

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The pre-synaptic protein, a-synuclein, has been associated with the pathogenesis of Parkinson's disease. The present study indicates that a-synuclein, but not its mutants (A53T, A30P), can protect CNS dopaminergic cells from the parkinsonism-inducing drug 1-methyl-4-phenylpyridinium (MPP + ), whereas it cannot protect from the dopaminergic toxin, 6-hydroxydopamine, hydrogen-peroxide, or the b-amyloid peptide, A-b. Protection from MPP + was directly correlated with the preservation of mitochondrial function. Specifically, a-synuclein rescued cells from MPP + mediated decreases in mitochondrial dehydrogenase activity and loss of ATP levels by utilizing ketosis. It also prevented toxin-induced activation of the creatine kinase/creatine phosphate system. Similarly, a-synuclein protected cells from the complex I inhibitor rotenone and 3-nitroproprionic acid, a complex II inhibitor. Wildtype a-synuclein-mediated neuroprotection and subsequent alterations in energy were not found in dbcAMP-differentiated cells. These results suggest that the normal physiological role for a-synuclein may change during development.

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MPP+ Downregulates Mitochondrially Encoded Gene Transcripts and Their Activities in Dopaminergic Neuronal Cells: Protective Role of Bcl-2

Cited by 19 publications

References 35 publications

BimEL up‐regulation potentiates AIF translocation and cell death in response to MPTP

BimEL up‐regulation potentiates AIF translocation and cell death in response to MPTP

Nonsteroidal Anti-Inflammatory Drugs Potentiate 1-Methyl-4-phenylpyridinium (MPP⁺)-Induced Cell Death by Promoting the Intracellular Accumulation of MPP⁺in PC12 Cells

α‐Synuclein protects naive but not dbcAMP‐treated dopaminergic cell types from 1‐methyl‐4‐phenylpyridinium toxicity

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MPP+ Downregulates Mitochondrially Encoded Gene Transcripts and Their Activities in Dopaminergic Neuronal Cells: Protective Role of Bcl-2

Cited by 19 publications

References 35 publications

BimEL up‐regulation potentiates AIF translocation and cell death in response to MPTP

BimEL up‐regulation potentiates AIF translocation and cell death in response to MPTP

Nonsteroidal Anti-Inflammatory Drugs Potentiate 1-Methyl-4-phenylpyridinium (MPP+)-Induced Cell Death by Promoting the Intracellular Accumulation of MPP+in PC12 Cells

α‐Synuclein protects naive but not dbcAMP‐treated dopaminergic cell types from 1‐methyl‐4‐phenylpyridinium toxicity

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Nonsteroidal Anti-Inflammatory Drugs Potentiate 1-Methyl-4-phenylpyridinium (MPP⁺)-Induced Cell Death by Promoting the Intracellular Accumulation of MPP⁺in PC12 Cells