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Intervention timing and effect of PJ34 on astrocytes during oxygen-glucose deprivation/reperfusion and cell death pathways

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Summary

Poly (ADP-ribose) polymerase-1 (PARP-1) plays as a double edged sword in cerebral ischemia-reperfusion, hinging on its effect on the intracellular energy storage and injury severity, and the prognosis has relationship with intervention timing. During ischemia injury, apoptosis and oncosis are the two main cell death pathway sin the ischemic core. The participation of astrocytes in ischemia-reperfusion induced cell death has triggered more and more attention. Here, we examined the protective effects and intervention timing of the PARP-1 inhibitor PJ34, by using a mixed oxygen-glucose deprivation/reperfusion (OGDR) model of primary rat astrocytes in vitro, which could mimic the ischemia-reperfusion damage in the “ischemic core”. Meanwhile, cell death pathways of various PJ34 treated astrocytes were also investigated. Our results showed that PJ34 incubation (10 μmol/L) did not affect release of lactate dehydrogenase (LDH) from astrocytes and cell viability or survival 1 h after OGDR. Interestingly, after 3 or 5 h OGDR, PJ34 significantly reduced LDH release and percentage of PI-positive cells and increased cell viability, and simultaneously increased the caspase-dependent apoptotic rate. The intervention timing study demonstrated that an earlier and longer PJ34 intervention during reperfusion was associated with more apparent protective effects. In conclusion, earlier and longer PJ34 intervention provides remarkable protective effects for astrocytes in the “ischaemic core” mainly by reducing oncosis of the astrocytes, especially following serious OGDR damage.

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References

  1. Eliasson MJ, Sampei K, Mandir AS, et al. Poly (ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med, 1997,3(10):1089–1095

    Article  CAS  PubMed  Google Scholar 

  2. Jagtap P, Szabó C. Poly (ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat Rev Drug Discov, 2005,4(5):421–440

    Article  CAS  PubMed  Google Scholar 

  3. Juurlink BH, Hertz L, Yager JY. Astrocyte maturation and susceptibility to ischaemia or substrate deprivation. Neuroreport, 1992,3(12):1135–1137

    Article  CAS  PubMed  Google Scholar 

  4. Salvesen GS. Caspases: opening the boxes and interpreting the arrows. Cell Death Differ, 2002,9(1):3

    Article  PubMed  Google Scholar 

  5. Ghavami S, Hashemi M, Ande SR, et al. Apoptosis and cancer: mutations within caspase genes. J Med Genet, 2009,46(8):497–510

    Article  CAS  PubMed  Google Scholar 

  6. Huang Q, Zhang R, Zou L, et al. Cell death pathways in astrocytes with a modified model of oxygen-glucose deprivation. PLoS ONE, 2013,8(4):e61345

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Montgomery DL. Astrocytes: form, functions, and roles in disease. Vet Pathol, 1994,31(2):145–167

    Article  CAS  PubMed  Google Scholar 

  8. Benjelloun N, Joly LM, Palmier B, et al. Apoptotic mitochondrial pathway in neurones and astrocytes after neonatal hypoxia-ischaemia in the ratbrain. Neuropath Appl Neuro, 2003,29(4):350–360

    Article  CAS  Google Scholar 

  9. Giffard RG, Swanson RA. Ischemia-induced programmed cell death in astrocytes. Glia, 2005,50(4):299–306

    Article  PubMed  Google Scholar 

  10. Giffard RG, Xu L, Zhao H, et al. Chaperones, protein aggregation, and brain protection from hypoxic/ischemic injury. J Exp Biol, 2004,207(18):3213–3220

    Article  CAS  PubMed  Google Scholar 

  11. Takuma K, Baba A, Matsuda T. Astrocyte apoptosis: implications for neuroprotection. Prog Neurobiol, 2004,72(2):111–127

    Article  CAS  PubMed  Google Scholar 

  12. Chu X, Fu X, Zou L, et al. Oncosis, the possible cell death pathway in astrocytes after focal cerebral ischemia. Brain Res, 2007,1149:157–164

    Article  CAS  PubMed  Google Scholar 

  13. Cao X, Zhang Y, Zou L, et al. Persistent oxygen-glucose deprivation induces astrocytic death through two different pathways and calpain-mediated proteolysis of cytoskeletal proteins during astrocytic oncosis. Neurosci Lett, 2010,479(2):118–122

    Article  CAS  PubMed  Google Scholar 

  14. Zhang R, Huang Q, Zou L, et al. Beneficial effects of deferoxamine against astrocyte death induced by modified oxygen glucose deprivation. Brain Res, 2014,1583:23–33

    Article  CAS  PubMed  Google Scholar 

  15. Kern JC, Kehrer JP. Acrolein-induced cell death: a caspase-influenced decision between apoptosis and oncosis/necrosis. Chem Biol Interact, 2002,139(1):79–95

    Article  CAS  PubMed  Google Scholar 

  16. Del Nagro C, Xiao Y, Rangell L, et al. Depletion of the central metabolite NAD leads to oncosis-mediated cell death. J Biol Chem, 2014,289(51):35182–35192

    Article  CAS  PubMed  Google Scholar 

  17. Abdelkarim GE, Gertz K, Harms C, et al. Protective effects of P34, a novel, potent inhibitor of poly (ADP-ribose) polymerase (PARP) in in vitro and in vivo models of stroke. Int J Mol Med, 2001,7:255–260

    CAS  PubMed  Google Scholar 

  18. Nagayama T, Simon RP, Chen D, et al. Activation of poly (ADP-ribose) polymerase in the rat hippocampus may contribute to cellular recovery following sublethal transient global ischemia. J Neurochem, 2000,74(4):1636–1645

    Article  CAS  PubMed  Google Scholar 

  19. Zakeri Z, Bursch W, Tenniswood M, et al. Cell death: programmed, apoptosis, necrosis, or other? Cell Death Differ, 1995,2(2):87–96

    CAS  PubMed  Google Scholar 

  20. Sayk F, Bartels C. Oncosis rather than apoptosis? Ann Thorac Surg, 2004,77(1):382; author reply 382–383

    Article  PubMed  Google Scholar 

  21. Jugdutt BI, Idikio HA. Apoptosis and oncosis in acute coronary syndromes: assessment and implications. Mol Cell Biochem, 2005,270(1–2):177–200

    Article  CAS  PubMed  Google Scholar 

  22. Weerasinghe P, Buja LM. Oncosis: an important non-apoptotic mode of cell death. Exp Mol Pathol, 2012,93(3):302–308

    Article  CAS  PubMed  Google Scholar 

  23. Walisser JA, Thies RL. Poly (ADP-ribose) polymerase inhibition in oxidant-stressed endothelial cells prevents oncosis and permits caspase activation and apoptosis. Exp Cell Res, 1999,251(2):401–413

    Article  CAS  PubMed  Google Scholar 

  24. Lieberthal W, Menza SA, Levine JS. Graded ATP depletion can cause necrosis or apoptosis of cultured mouse proximal tubular cells. Am J Physiol-renal, 1998,274(2):F315–F327

    CAS  Google Scholar 

  25. Schreiber V, Dantzer F, Ame J-C, et al. Poly (ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Bio, 2006,7(7):517–528

    Article  CAS  Google Scholar 

  26. Ma LS, Jiang CY, Cui M, et al. Fluopsin C induces oncosis of human breast adenocarcinoma cells. Acta Pharmacol Sin, 2013,34(8):1093–1100

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Sun L, Zhao Y, Yuan H, et al. Solamargine, a steroidal alkaloid glycoside, induces oncosis in human K562 leukemia and squamous cell carcinoma KB cells. Cancer Chemother Pharmacol, 2011,67(4):813–821

    Article  CAS  PubMed  Google Scholar 

  28. Virág L, Robaszkiewicz A, Rodriguez-Vargas JM, et al. Poly (ADP-ribose) signaling in cell death. Mol Aspects Med, 2013,34(6):1153–1167

    Article  PubMed  Google Scholar 

  29. Stoica BA, Loane DJ, Zhao Z, et al. PARP-1 inhibition attenuates neuronal loss, microglia activation and neurological deficits after traumatic brain injury. J Neurotrauma, 2014,31(8):758–772

    Article  PubMed Central  PubMed  Google Scholar 

  30. Hensley P, Mishra M, Kyprianou N. Targeting caspases in cancer therapeutics. Biol Chem, 2013,394(7):831–843

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. 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

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Second Clinical College, Jinan University, Shenzhen, 518020, China

    Chuan Cai  (蔡川), Rui Zhang  (张睿), Qiao-ying Huang  (黄巧英), Xu Cao  (曹旭), Liang-yu Zou  (邹良玉) & Xiao-fan Chu  (褚晓凡)

  2. Research Centre for Neural Engineering, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China

    Chuan Cai  (蔡川), Rui Zhang  (张睿) & Qiao-ying Huang  (黄巧英)

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  1. Chuan Cai  (蔡川)
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  2. Rui Zhang  (张睿)
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  3. Qiao-ying Huang  (黄巧英)
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  4. Xu Cao  (曹旭)
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  5. Liang-yu Zou  (邹良玉)
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  6. Xiao-fan Chu  (褚晓凡)
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Corresponding author

Correspondence to Xiao-fan Chu  (褚晓凡).

Additional information

The two authors contributed equally to this work.

This work was supported by the National Natural Science Foundation of China (No. 30971024).

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Cai, C., Zhang, R., Huang, Qy. et al. Intervention timing and effect of PJ34 on astrocytes during oxygen-glucose deprivation/reperfusion and cell death pathways. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 35, 397–404 (2015). https://doi.org/10.1007/s11596-015-1444-z

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  • DOI: https://doi.org/10.1007/s11596-015-1444-z

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