Skip to main content
SpringerLink
Log in

Mdivi-1 Alleviates Early Brain Injury After Experimental Subarachnoid Hemorrhage in Rats, Possibly via Inhibition of Drp1-Activated Mitochondrial Fission and Oxidative Stress

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Mdivi-1 is a selective inhibitor of mitochondrial fission protein, Drp1, and can penetrate the blood–brain barrier. Previous studies have shown that Mdivi-1 improves neurological outcomes after ischemia, seizures and trauma but it remains unclear whether Mdivi-1 can attenuate early brain injury after subarachnoid hemorrhage (SAH). We thus investigated the therapeutic effect of Mdivi-1 on early brain injury following SAH. Rats were randomly divided into four groups: sham; SAH; SAH + vehicle; and SAH + Mdivi-1. The SAH model was induced by standard intravascular perforation and all of the rats were subsequently sacrificed 24 h after SAH. Mdivi-1 (1.2 mg/kg) was administered to rats 30 min after SAH. We found that Mdivi-1 markedly improved neurologic deficits, alleviated brain edema and BBB permeability, and attenuated apoptotic cell death. Mdivi-1 also significantly reduced the expression of cleaved caspase-3, Drp1 and p-Drp1(Ser616), attenuated the release of Cytochrome C from mitochondria, inhibited excessive mitochondrial fission, and restored the ultra-structure of mitochondria. Furthermore, Mdivi-1 reduced levels of MDA, 3-NT, and 8-OHdG, and improved SOD activity. Taken together, our data suggest that Mdivi-1 exerts neuroprotective effects against cell death induced by SAH and the underlying mechanism may be inhibition of Drp1-activated mitochondrial fission and oxidative stress.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

SAH:

Subarachnoid hemorrhage

Drp1:

Dynamin-like protein 1

EBI:

Early brain injury

ECA:

External carotid artery

ICA:

Internal carotid artery

References

  1. Fujii M, Yan J, Rolland WB, Soejima Y, Caner B, Zhang JH (2013) Early brain injury, an evolving frontier in subarachnoid hemorrhage research. Transl Stroke Res 4(4):432–446. doi:10.1007/s12975-013-0257-2

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sehba FA, Hou J, Pluta RM, Zhang JH (2012) The importance of early brain injury after subarachnoid hemorrhage. Prog Neurobiol 97(1):14–37. doi:10.1016/j.pneurobio.2012.02.003

    Article  PubMed  PubMed Central  Google Scholar 

  3. Serrone JC, Maekawa H, Tjahjadi M, Hernesniemi J (2015) Aneurysmal subarachnoid hemorrhage: pathobiology, current treatment and future directions. Expert Rev Neurother 15(4):367–380. doi:10.1586/14737175.2015.1018892

    Article  CAS  PubMed  Google Scholar 

  4. Conzen C, Schubert GA (2016) About the importance of the acute phase of subarachnoid hemorrhage and the chances for successful translation. J Neurol Sci. doi:10.1016/j.jns.2016.09.031

    PubMed  Google Scholar 

  5. Yuksel S, Tosun YB, Cahill J, Solaroglu I (2012) Early brain injury following aneurysmal subarachnoid hemorrhage: emphasis on cellular apoptosis. Turk Neurosurg 22(5):529–533. doi:10.5137/1019-5149.JTN.5731-12.1

    PubMed  Google Scholar 

  6. Cai J, Cao S, Chen J, Yan F, Chen G, Dai Y (2015) Progesterone alleviates acute brain injury via reducing apoptosis and oxidative stress in a rat experimental subarachnoid hemorrhage model. Neurosci Lett 600:238–243. doi:10.1016/j.neulet.2015.06.023

    Article  CAS  PubMed  Google Scholar 

  7. Zhang ZY, Sun BL, Liu JK, Yang MF, Li DW, Fang J, Zhang S, Yuan QL, Huang SL (2015) Activation of mGluR5 attenuates microglial activation and neuronal apoptosis in early brain injury after experimental subarachnoid hemorrhage in rats. Neurochem Res 40(6):1121–1132. doi:10.1007/s11064-015-1572-7

    Article  CAS  PubMed  Google Scholar 

  8. Jacobsen A, Nielsen TH, Nilsson O, Schalen W, Nordstrom CH (2014) Bedside diagnosis of mitochondrial dysfunction in aneurysmal subarachnoid hemorrhage. Acta Neurol Scand 130(3):156–163. doi:10.1111/ane.12258

    Article  CAS  PubMed  Google Scholar 

  9. Otera H, Ishihara N, Mihara K (2013) New insights into the function and regulation of mitochondrial fission. Biochim Biophys Acta 1833(5):1256–1268. doi:10.1016/j.bbamcr.2013.02.002

    Article  CAS  PubMed  Google Scholar 

  10. Zaja I, Bai X, Liu Y, Kikuchi C, Dosenovic S, Yan Y, Canfield SG, Bosnjak ZJ (2014) Cdk1, PKCdelta and calcineurin-mediated Drp1 pathway contributes to mitochondrial fission-induced cardiomyocyte death. Biochem Biophys Res Commun 453(4):710–721. doi:10.1016/j.bbrc.2014.09.144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang N, Wang S, Li Y, Che L, Zhao Q (2013) A selective inhibitor of Drp1, mdivi-1, acts against cerebral ischemia/reperfusion injury via an anti-apoptotic pathway in rats. Neurosci Lett 535:104–109. doi:10.1016/j.neulet.2012.12.049

    Article  CAS  PubMed  Google Scholar 

  12. Cherubini M, Gines S (2016) Mitochondrial fragmentation in neuronal degeneration: Toward an understanding of HD striatal susceptibility. Biochem Biophys Res Commun. doi:10.1016/j.bbrc.2016.08.042

    PubMed  Google Scholar 

  13. Xie N, Wang C, Lian Y, Zhang H, Wu C, Zhang Q (2013) A selective inhibitor of Drp1, mdivi-1, protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats. Neurosci Lett 545:64–68. doi:10.1016/j.neulet.2013.04.026

    Article  CAS  PubMed  Google Scholar 

  14. Pletjushkina OY, Lyamzaev KG, Popova EN, Nepryakhina OK, Ivanova OY, Domnina LV, Chernyak BV, Skulachev VP (2006) Effect of oxidative stress on dynamics of mitochondrial reticulum. Biochim Biophys Acta 1757(5–6):518–524. doi:10.1016/j.bbabio.2006.03.018

    Article  CAS  PubMed  Google Scholar 

  15. Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, Smith CL, Youle RJ (2001) The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 1(4):515–525

    Article  CAS  PubMed  Google Scholar 

  16. Rosdah AA, J KH, Delbridge LM, Dusting GJ, Lim SY (2016) Mitochondrial fission - a drug target for cytoprotection or cytodestruction? Pharmacol Res Perspect 4 (3):e00235. doi:10.1002/prp2.235

    Article  PubMed  PubMed Central  Google Scholar 

  17. Xie N, Wang C, Wu C, Cheng X, Gao Y, Zhang H, Zhang Y, Lian Y (2016) Mdivi-1 protects epileptic hippocampal neurons from apoptosis via inhibiting oxidative stress and endoplasmic reticulum stress in vitro. Neurochem Res 41(6):1335–1342. doi:10.1007/s11064-016-1835-y

    Article  CAS  PubMed  Google Scholar 

  18. Wu Q, Xia SX, Li QQ, Gao Y, Shen X, Ma L, Zhang MY, Wang T, Li YS, Wang ZF, Luo CL, Tao LY (2016) Mitochondrial division inhibitor 1 (Mdivi-1) offers neuroprotection through diminishing cell death and improving functional outcome in a mouse model of traumatic brain injury. Brain Res 1630:134–143. doi:10.1016/j.brainres.2015.11.016

    Article  CAS  PubMed  Google Scholar 

  19. Sugawara T, Ayer R, Jadhav V, Zhang JH (2008) A new grading system evaluating bleeding scale in filament perforation subarachnoid hemorrhage rat model. J Neurosci Methods 167(2):327–334. doi:10.1016/j.jneumeth.2007.08.004

    Article  PubMed  Google Scholar 

  20. Garcia JH, Wagner S, Liu KF, Hu XJ (1995) Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation. Stroke 26 (4):627–634; discussion 635

    Article  CAS  PubMed  Google Scholar 

  21. Zhao H, Ji Z, Tang D, Yan C, Zhao W, Gao C (2013) Role of autophagy in early brain injury after subarachnoid hemorrhage in rats. Mol Biol Rep 40(2):819–827. doi:10.1007/s11033-012-2120-z

    Article  CAS  PubMed  Google Scholar 

  22. Zheng B, Zheng T, Wang L, Chen X, Shi C, Zhao S (2010) Aminoguanidine inhibition of iNOS activity ameliorates cerebral vasospasm after subarachnoid hemorrhage in rabbits via restoration of dysfunctional endothelial cells. J Neurol Sci 295(1–2):97–103. doi:10.1016/j.jns.2010.04.012

    Article  CAS  PubMed  Google Scholar 

  23. Cheng G, Chunlei W, Pei W, Zhen L, Xiangzhen L (2010) Simvastatin activates Akt/glycogen synthase kinase-3beta signal and inhibits caspase-3 activation after experimental subarachnoid hemorrhage. Vasc Pharmacol 52(1–2):77–83. doi:10.1016/j.vph.2009.12.001

    Article  Google Scholar 

  24. Fischer TD, Hylin MJ, Zhao J, Moore AN, Waxham MN, Dash PK (2016) Altered mitochondrial dynamics and TBI pathophysiology. Front Syst Neurosci 10:29. doi:10.3389/fnsys.2016.00029

    Article  PubMed  PubMed Central  Google Scholar 

  25. Qiu X, Cao L, Yang X, Zhao X, Liu X, Han Y, Xue Y, Jiang H, Chi Z (2013) Role of mitochondrial fission in neuronal injury in pilocarpine-induced epileptic rats. Neuroscience 245:157–165. doi:10.1016/j.neuroscience.2013.04.019

    Article  CAS  PubMed  Google Scholar 

  26. Li G, Jia Z, Cao Y, Wang Y, Li H, Zhang Z, Bi J, Lv G, Fan Z (2015) Mitochondrial division inhibitor 1 ameliorates mitochondrial injury, apoptosis, and motor dysfunction after acute spinal cord injury in rats. Neurochem Res 40(7):1379–1392. doi:10.1007/s11064-015-1604-3

    Article  CAS  PubMed  Google Scholar 

  27. Kim H, Lee JY, Park KJ, Kim WH, Roh GS (2016) A mitochondrial division inhibitor, Mdivi-1, inhibits mitochondrial fragmentation and attenuates kainic acid-induced hippocampal cell death. BMC Neurosci 17(1):33. doi:10.1186/s12868-016-0270-y

    Article  PubMed  PubMed Central  Google Scholar 

  28. Liang N, Wang P, Wang S, Li S, Li Y, Wang J, Wang M (2014) Role of mitochondrial calcium uniporter in regulating mitochondrial fission in the cerebral cortexes of living rats. J Neural Transm 121(6):593–600. doi:10.1007/s00702-014-1166-6

    Article  CAS  PubMed  Google Scholar 

  29. Grohm J, Kim SW, Mamrak U, Tobaben S, Cassidy-Stone A, Nunnari J, Plesnila N, Culmsee C (2012) Inhibition of Drp1 provides neuroprotection in vitro and in vivo. Cell Death Differ 19(9):1446–1458. doi:10.1038/cdd.2012.18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Taguchi N, Ishihara N, Jofuku A, Oka T, Mihara K (2007) Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J Biol Chem 282(15):11521–11529. doi:10.1074/jbc.M607279200

    Article  CAS  PubMed  Google Scholar 

  31. Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, Kuwana T, Kurth MJ, Shaw JT, Hinshaw JE, Green DR, Nunnari J (2008) Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 14(2):193–204. doi:10.1016/j.devcel.2007.11.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Puttachary S, Sharma S, Stark S, Thippeswamy T (2015) Seizure-induced oxidative stress in temporal lobe epilepsy. BioMed Res Int 2015:745613. doi:10.1155/2015/745613

    Article  PubMed  PubMed Central  Google Scholar 

  33. Yu T, Jhun BS, Yoon Y (2011) High-glucose stimulation increases reactive oxygen species production through the calcium and mitogen-activated protein kinase-mediated activation of mitochondrial fission. Antioxid Redox Signal 14(3):425–437. doi:10.1089/ars.2010.3284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research was supported in part by the Innovative Science Research Foundation of Harbin Medical University [Grant Number 2016LCZX59], the National Natural Science Foundation of China [Grant Number 81401009], and the Natural Science Foundation of Heilongjiang Province [grant number QC2013C088]. We thank Professor Zhang for help in designing experiments and advice about the manuscript.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang, China

    Pei Wu, Yuchen Li, Shiyi Zhu, Chunlei Wang, Jiaxing Dai, Guang Zhang, Bingjie Zheng, Shancai Xu, Ligang Wang, Tongyu Zhang, PeiQuan Zhou & Huaizhang Shi

  2. Department of Neurosurgery and Anesthesiology, Loma Linda University, Loma Linda, CA, 92350, USA

    John H. Zhang

Authors
  1. Pei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuchen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shiyi Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chunlei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiaxing Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bingjie Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shancai Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ligang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tongyu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. PeiQuan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. John H. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Huaizhang Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Huaizhang Shi.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, P., Li, Y., Zhu, S. et al. Mdivi-1 Alleviates Early Brain Injury After Experimental Subarachnoid Hemorrhage in Rats, Possibly via Inhibition of Drp1-Activated Mitochondrial Fission and Oxidative Stress. Neurochem Res 42, 1449–1458 (2017). https://doi.org/10.1007/s11064-017-2201-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-017-2201-4

Keywords

Search

Navigation