Proteasome inhibitor MG-132 induces dopaminergic degeneration in cell culture and animal models

Sun, Faneng; Anantharam, Vellareddy; Zhang, Danhui; Latchoumycandane, Calivarathan; Kanthasamy, Anumantha G.

doi:10.1016/j.neuro.2006.06.006

Cited by 97 publications

(77 citation statements)

References 37 publications

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“…However, there are two previous reports describing the influence of MG-132 on the nigrostriatal pathway [41,49]. According to our knowledge, the current report is the first to estimate the influence of systemic administration of MG-132.…”

Section: Discussionmentioning

confidence: 82%

Original article Nigrostriatal pathway degeneration in rats after intraperitoneal administration of proteasome inhibitor MG-132

Wójcik

Spodnik²,

Spodnik³

et al. 2014

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Section: Discussionmentioning

confidence: 82%

Original article Nigrostriatal pathway degeneration in rats after intraperitoneal administration of proteasome inhibitor MG-132

Wójcik

Spodnik²,

Spodnik³

et al. 2014

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“…We recently established that N27 cells are a superior cell culture model for studying dopaminergic neurodegeneration, compared to PC12 and SH-SY5Y cells, because N27 cells are derived from the mesencephalon, a brain region directly affected by Parkinson's disease, and they represent a homogenous population of tyrosine hydroxylase-positive cells with functional characteristics resembling dopaminergic neurons (Anantharam et al, 2002;Kaul et al, 2003;Yang et al, 2004;Kaul et al, 2005b;Kanthasamy et al, 2006;Sun et al, 2006). We showed that MPP + treatment in N27 cells induces acute generation of ROS in a time-and dosedependent manner (Kaul et al, 2003;Kaul et al, 2005a), and that ROS generation precedes changes in mitochondrial membrane potential or cytochrome C release.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological inhibition of neuronal NADPH oxidase protects against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in mesencephalic dopaminergic neuronal cells

et al. 2007

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Oxidative stress is widely recognized as a key mediator of degenerative processes in Parkinson's disease (PD). Recently, we demonstrated that the dopaminergic toxin MPP + initiates oxidative stress to cause caspase-3-dependent apoptotic cell death in mesencephalic dopaminergic neuronal (N27) cells. In this study, we determined the source of reactive oxygen species (ROS) produced during MPP + -induced apoptotic cell death. In addition to mitochondria, plasma membrane NADPH oxidase is considered a major producer of ROS inside the cell. Here, we show that N27 cells express key NADPH oxidase subunits gp91 phox and p67 phox . We used structurally diverse NADPH oxidase inhibitors, aminoethyl-benzenesulfonylfluoride (AEBSF, 100-1000 μM), apocynin (100-1000 μM), and diphenylene iodonium (DPI, 3-30 μM), to inhibit intrinsic NADPH oxidase activity in N27 cells. Flow cytometric analysis using the ROS-sensitive dye hydroethidine revealed that AEBSF blocked 300 μM MPP + -induced ROS production for over 45 min in N27 cells, in a dose-dependent manner. Further treatment with DPI, apocynin, and SOD also blocked MPP + -induced ROS production. In Sytox cell death assays, co-treatment with AEBSF, apocynin, or DPI for 24 hr significantly suppressed MPP + -induced cytotoxic cell death. Similarly, co-treatment with these inhibitors also significantly attenuated MPP + -induced increases in caspase-3 enzymatic activity. Furthermore, quantitative DNA fragmentation ELISA assays revealed that AEBSF, DPI, and apocynin rescue N27 cells from MPP + -induced apoptotic cell death. Together, these results indicate for the first time that intracellular ROS generated by NAPDH oxidase are present within the mesencephalic neuronal cells, and are a key determinant of MPP + -mediated dopaminergic degeneration in in vitro models of dopaminergic degeneration. This study supports a critical role of NADPH oxidase in the oxidative damage in PD; targeting this enzyme may lead to novel therapies for PD.

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“…21,124 In cortical neurons of the central nervous system, Jessica et al 125 analyzed the expression of different AQPs while cells undergo apoptosis induced by treatment with lactacystin, a specific proteasome inhibitor. [126][127][128] These authors found that AQP4 was highly downregulated, suggesting that this aquaporin, considered to be the main water channel in the brain, 129 does not play an important role in the loss of water during AVD. In contrast, overexpression of AQP1, AQP8 and AQP9 was observed after lactacystin treatment.…”

Section: Apoptosis and Aqpsmentioning

confidence: 99%

“…In contrast, overexpression of AQP1, AQP8 and AQP9 was observed after lactacystin treatment. [126][127][128] However, favoring a role for AQP4 in apoptosis, Kong et al 87 observed increased basal apoptosis in adult neural stem cells obtained from KO AQP4 ¡/¡ mice.…”

Section: Apoptosis and Aqpsmentioning

confidence: 99%

Role of aquaporins in cell proliferation: What else beyond water permeability?

2016

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In addition to the extensive data demonstrating the importance of mammalian AQPs for the movement of water and some small solutes across the cell membrane, there is now a growing body of evidence indicating the involvement of these proteins in numerous cellular processes seemingly unrelated, at least some of them in a direct way, to their canonical function of water permeation. Here, we have presented a broad range of evidence demonstrating that these proteins have a role in cell proliferation by various different mechanisms, namely, by allowing fast cell volume regulation during cell division; by affecting progression of cell cycle and helping maintain the balance between proliferation and apoptosis, and by crosstalk with other cell membrane proteins or transcription factors that, in turn, modulate progression of the cell cycle or regulate biosynthesis pathways of cell structural components. In the end, however, after discussing all these data that strongly support a role for AQPs in the cell proliferation process, it remains impossible to conclude that all these other functions attributed to AQPs occur completely independently of their water permeability, and there is a need for new experiments designed specifically to address this interesting issue.

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Proteasome inhibitor MG-132 induces dopaminergic degeneration in cell culture and animal models

Cited by 97 publications

References 37 publications

Original article Nigrostriatal pathway degeneration in rats after intraperitoneal administration of proteasome inhibitor MG-132

Original article Nigrostriatal pathway degeneration in rats after intraperitoneal administration of proteasome inhibitor MG-132

Pharmacological inhibition of neuronal NADPH oxidase protects against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in mesencephalic dopaminergic neuronal cells

Role of aquaporins in cell proliferation: What else beyond water permeability?

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