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Caspase inhibition augments Dichlorvos-induced dopaminergic neuronal cell death by increasing ROS production and PARP1 activation.
Neuroscience. 2014 Jan 31; 258:1-15.N

Abstract

Numerous epidemiological studies have shown an association between pesticide exposure and the increased risk of developing Parkinson's disease. Previously we have reported that Dichlorvos exposure can induce oxidative stress, resulting in over-expression of pro-apoptotic genes and finally caspase-dependent nigrostriatal dopaminergic neuronal cell death in rat brain. Here, we examined the effect of caspase inhibition on PC12 cell death induced by Dichlorvos (30 μM). Reactive oxygen species (ROS) generation followed by protein carbonylation, lipid peroxidation, decreased antioxidant defenses (decreased Mn-superoxide dismutase (MnSOD) activity and decreased glutathione levels) and subsequent caspase activation mediated the apoptosis. Inhibition of caspase cascade with Boc-aspartyl(OMe)-fluoromethylketone (BAF) enhanced the Dichlorvos-induced PC12 cell death, as assessed by the increased cellular efflux of lactate dehydrogenase (LDH). This increase in cell death was accompanied by a marked increase in poly(ADP-ribose) polymerase-1 (PARP1) activity, increased oxidative stress, a reduction in the mitochondrial membrane potential and reduced cellular NAD and ATP levels. Pretreatment of cells with PJ34, a PARP1 inhibitor prevented the cells from undergoing cell death and preserved intracellular NAD and ATP levels. Subsequent release of the apoptosis-inducing factor (AIF) from mitochondria and its translocation into the nucleus was also prevented by PJ34 pretreatment. In conclusion, the results of the present study show that caspase inhibition without concurrent inhibition of PARP1 is unlikely to be effective in preventing cell death because in the presence of the caspase inhibitor, caspase-independent cell death predominates due to PARP activation. These results suggest that combined therapeutic strategies directed at multiple cell death pathways may provide superior neuroprotection than those directed at a single mechanism.

Authors+Show Affiliations

Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India. Electronic address: kdgill2002@yahoo.co.in.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24231740

Citation

Wani, W Y., et al. "Caspase Inhibition Augments Dichlorvos-induced Dopaminergic Neuronal Cell Death By Increasing ROS Production and PARP1 Activation." Neuroscience, vol. 258, 2014, pp. 1-15.
Wani WY, Sunkaria A, Sharma DR, et al. Caspase inhibition augments Dichlorvos-induced dopaminergic neuronal cell death by increasing ROS production and PARP1 activation. Neuroscience. 2014;258:1-15.
Wani, W. Y., Sunkaria, A., Sharma, D. R., Kandimalla, R. J., Kaushal, A., Gerace, E., Chiarugi, A., & Gill, K. D. (2014). Caspase inhibition augments Dichlorvos-induced dopaminergic neuronal cell death by increasing ROS production and PARP1 activation. Neuroscience, 258, 1-15. https://doi.org/10.1016/j.neuroscience.2013.11.004
Wani WY, et al. Caspase Inhibition Augments Dichlorvos-induced Dopaminergic Neuronal Cell Death By Increasing ROS Production and PARP1 Activation. Neuroscience. 2014 Jan 31;258:1-15. PubMed PMID: 24231740.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Caspase inhibition augments Dichlorvos-induced dopaminergic neuronal cell death by increasing ROS production and PARP1 activation. AU - Wani,W Y, AU - Sunkaria,A, AU - Sharma,D R, AU - Kandimalla,R J L, AU - Kaushal,A, AU - Gerace,E, AU - Chiarugi,A, AU - Gill,K D, Y1 - 2013/11/11/ PY - 2013/09/10/received PY - 2013/10/30/revised PY - 2013/11/03/accepted PY - 2013/11/16/entrez PY - 2013/11/16/pubmed PY - 2014/9/30/medline KW - 2,4-dinitrophenyl hydrazine KW - 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide KW - 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid KW - 4′,6-diamidino-2-phenylindole KW - AChE KW - AIF KW - BAF KW - Boc-aspartyl(OMe)-fluoromethylketone KW - DAPI KW - DCFH-DA KW - DNPH KW - Dichlorvos KW - EDTA KW - EGTA KW - ELISA KW - H2DCF-DA KW - HEPES KW - IC50 KW - LDH KW - MDA KW - MMP KW - MPT KW - MTT KW - Mn-superoxide dismutase KW - MnSOD KW - OP KW - PARP1 KW - PARP1 activation KW - PBS KW - ROS KW - RT KW - acetylcholinesterase KW - apoptosis-inducing factor KW - caspase inhibition KW - dichloro-dihydro-fluorescein diacetate KW - dihydrodichlorofluorescein diacetate KW - enzyme-linked immunosorbent assay KW - ethylene glycol tetraacetic acid KW - ethylenediaminetetraacetic acid KW - inhibitory concentration 50 KW - lactate dehydrogenase KW - malondialdehyde KW - mitochondrial membrane potential KW - mitochondrial permeability transition KW - organophosphate KW - oxidative stress KW - phosphate-buffered saline KW - poly(ADP-ribose) polymerase-1 KW - reactive oxygen species KW - room temperature SP - 1 EP - 15 JF - Neuroscience JO - Neuroscience VL - 258 N2 - Numerous epidemiological studies have shown an association between pesticide exposure and the increased risk of developing Parkinson's disease. Previously we have reported that Dichlorvos exposure can induce oxidative stress, resulting in over-expression of pro-apoptotic genes and finally caspase-dependent nigrostriatal dopaminergic neuronal cell death in rat brain. Here, we examined the effect of caspase inhibition on PC12 cell death induced by Dichlorvos (30 μM). Reactive oxygen species (ROS) generation followed by protein carbonylation, lipid peroxidation, decreased antioxidant defenses (decreased Mn-superoxide dismutase (MnSOD) activity and decreased glutathione levels) and subsequent caspase activation mediated the apoptosis. Inhibition of caspase cascade with Boc-aspartyl(OMe)-fluoromethylketone (BAF) enhanced the Dichlorvos-induced PC12 cell death, as assessed by the increased cellular efflux of lactate dehydrogenase (LDH). This increase in cell death was accompanied by a marked increase in poly(ADP-ribose) polymerase-1 (PARP1) activity, increased oxidative stress, a reduction in the mitochondrial membrane potential and reduced cellular NAD and ATP levels. Pretreatment of cells with PJ34, a PARP1 inhibitor prevented the cells from undergoing cell death and preserved intracellular NAD and ATP levels. Subsequent release of the apoptosis-inducing factor (AIF) from mitochondria and its translocation into the nucleus was also prevented by PJ34 pretreatment. In conclusion, the results of the present study show that caspase inhibition without concurrent inhibition of PARP1 is unlikely to be effective in preventing cell death because in the presence of the caspase inhibitor, caspase-independent cell death predominates due to PARP activation. These results suggest that combined therapeutic strategies directed at multiple cell death pathways may provide superior neuroprotection than those directed at a single mechanism. SN - 1873-7544 UR - https://www.unboundmedicine.com/medline/citation/24231740/Caspase_inhibition_augments_Dichlorvos_induced_dopaminergic_neuronal_cell_death_by_increasing_ROS_production_and_PARP1_activation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(13)00944-5 DB - PRIME DP - Unbound Medicine ER -