Advertisement

Child's Nervous System

, Volume 34, Issue 8, pp 1479–1487 | Cite as

Effect evaluation of methylprednisolone plus mitochondrial division inhibitor-1 on spinal cord injury rats

  • Xu-Gui Chen
  • Li-Hua Chen
  • Ru-Xiang Xu
  • Hong-Tian Zhang
Original Paper

Abstract

Purpose

To investigate the combination effect of methylprednisolone (MP) and mitochondrial division inhibitor-1 (Mdivi-1) on the neurological function recovery of rat spinal cord injury (SCI) model.

Methods

The weight-drop method was used to establish the rat SCI model; then, rats were randomized into sham group, SCI group, MP group, Mdivi-1 group and MP+Mdivi-1 group. Motor function scores were quantified to evaluate locomotor ability; HE staining was used to assess spinal cord histopathology; tissue water content, oxidative stress, tissue mitochondrial function, neurons apoptosis, and apoptosis-related protein expression were detected.

Results

From the third day after SCI, BBB score of the MP+Mdivi-1 group was obviously higher than the other experimental groups (p < 0.05). Compared with the SCI group, tissue water content of the Mdivi-1 group and MP+Mdivi-1 group reduced obviously (p < 0.05), mitochondrial membrane potential (MMP) level and ATP content in the Mdivi-1 group and MP+Mdivi-1 group were both higher (p < 0.05). Meanwhile, three kinds of treatment all reduced apoptosis significantly, while MP plus Mdivi-1 exhibited the best inhibition effect on apoptosis (p < 0.05). The expression levels of Drp1, cytochrome c, and caspase-3 were all upregulated obviously; Mdivi-1 could inhibit Drp1 upregulation induced by SCI; for the upregulation of cytochrome c and caspase-3, the inhibition effect of Mdivi-1 approached MP. When MP combined with Mdivi-1, there was the best inhibition effect.

Conclusions

MP combined with Mdivi-1 may produce better neurological function recovery, through improving functional status of mitochondria and inhibiting lipid peroxidation in damaged tissue of SCI rats, and thus alleviating apoptosis.

Keywords

Mitochondrial division inhibitor-1 Methylprednisolone Neurological function Spinal cord injury 

Notes

Funding information

This research was supported by the National Natural Science Fund of China (81371345).

Compliance with ethical standards

Conflict of interest

On behalf of all authors, we state that there is no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

References

  1. 1.
    Díaz-Ruiz A, Ibarra A, Pérez-Severiano F, Guízar-Sahagún G, Grijalva I, Ríos C (2002) Constitutive and inducible nitric oxide synthase activities after spinal cord contusion in rats. Neurosci Lett 319:129–132CrossRefPubMedGoogle Scholar
  2. 2.
    Hausmann ON (2003) Post-traumatic inflammation following spinal cord injury. Spinal Cord 41:369–378CrossRefPubMedGoogle Scholar
  3. 3.
    Beattie MS, Hermann GE, Rogers RC, Bresnahan JC (2002) Cell death in models of spinal cord injury. Prog Brain Res 137:37–47CrossRefPubMedGoogle Scholar
  4. 4.
    Lu GB, Niu FW, Zhang YC, Du L, Liang ZY, Gao Y, Yan TZ, Nie ZK, Gao K (2016) Methylprednisolone promotes recovery of neurological function after spinal cord injury: association with Wnt/β-catenin signaling pathway activation. Neural Regen Res 11:1816–1823CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Evaniew N, Belley-Côté EP, Fallah N, Noonan VK, Rivers CS, Dvorak MF (2016) Mehtylprednisolone for the treatment of patients with acute spinal cord injuries: a systematic review and meta-analysis. J Neurotrauma 33:468–481CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Rouanet C, Reges D, Rocha E, Gagliardi V, Silva GS (2017) Traumatic spinal cord injury: current concepts and treatment update. Arq Neuropsiquiatr 75:387–393CrossRefPubMedGoogle Scholar
  7. 7.
    Yan P, Liu N, Kim GM, Xu J, Xu J, Li Q, Hsu CY, Xu XM (2003) Expression of the type 1 and type 2 receptors for tumor necrosis factor after traumatic spinal cord injury in adult rats. Exp Neurol 183:286–297CrossRefPubMedGoogle Scholar
  8. 8.
    Wu KL, Hsu C, Chan JY (2007) Impairment of the mitochondrial respiratory enzyme activity triggers sequential activation of apoptosis-inducing factor-dependent and caspase-dependent signaling pathways to induce apoptosis after spinal cord injury. J Neurochem 101:1552–1566CrossRefPubMedGoogle Scholar
  9. 9.
    Cassidy-Stone A, Chipuk JE, Ingerman E, Song 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 mitochondrila outer membrane permeabilization. Dev Cell 14:193–204CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ruiz A, Alberdi E, Matute C (2018) Mitochondrial division inhibitor 1 (mdivi-1) protects neurons against excitotoxicity through the modulation of mitochondrial function and intracellular Ca2+ signaling. Front Mol Neurosci 11:3.  https://doi.org/10.3389/fnmol.2018.00003 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Cox A, Varma A, Banik N (2015) Recent advances in the pharmacologic treatment of spinal cord injury. Metab Brain Dis 30:473–482CrossRefPubMedGoogle Scholar
  12. 12.
    Li XG, Lin XJ, Du JH, Xu SZ, Lou XF, Chen Z (2016) Combination of methylprenisolone and rosiglitazone promotes recovery of neurological function after spinal cord injury. Neural Regen Res 11:1678–1684CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Yan P, Xu J, Li Q, Chen S, Kim GM, Hsu CY, Xu XM (1999) Glucocorticoid receptor expression in the spinal cord after traumatic injury in adult rats. J Neurosci 19:9355–9363CrossRefPubMedGoogle Scholar
  14. 14.
    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 40:1379–1392CrossRefPubMedGoogle Scholar
  15. 15.
    Rui G, Yue Z, Yao D, Lin T, Wei Y, Xiong XC (2013) Anti-edema effect of epigallocatechin gallate on spinal cord injury in rats. Brain Res 1527:40–46CrossRefGoogle Scholar
  16. 16.
    Jiang L, Liu Y, Ma MM, Tang YB, Zhou JG, Guan YY (2013) Mitochondria dependent pathway is involved in the protective effect of bestropin-3 on hydrogen peroxide-induced apoptosis in basilar artery smooth muscle cells. Apoptosis 18:556–565CrossRefPubMedGoogle Scholar
  17. 17.
    Suzuki Y, Hasegawa H, Tsuji T, Tsuruda K, Sasaki D, Ishihara K, Nagai K, Yanagihara K, Yamada Y, Kamihira S (2013) Relationships of diverse apoptotic death process patterns to mitochondrial membrane potential (Δψ(m)) evaluated by three-parameter flow cytometric analysis. Cytotechnology 65:59–70CrossRefPubMedGoogle Scholar
  18. 18.
    Choi JS, Shin S, Jin YH, Yim H, Koo KT, Chun KH, Oh YT, Lee WH, Lee SK (2007) Cyclin-dependent protein kinase 2 activity is required for mitochondrial translocation of Bax and disruption of mitochondrial transmembrane potential during etoposide-induced apoptosis. Apoptosis 12:1229–1241CrossRefPubMedGoogle Scholar
  19. 19.
    Ravindran J, Gupta N, Agrawal M, Bala Bhaskar AS, Lakshmana Rao PV (2011) Modulation of ROS/MAPK signaling pathways by okadaic acid leads to cell death via, mitochondrial mediated caspase-dependent mechanism. Apoptosis 16:145–161CrossRefPubMedGoogle Scholar
  20. 20.
    Hall ED (1991) Inhibition of lipid peroxidation in CNS trauma. J Neurotrauma 8(Suppl 1):S31–S40PubMedGoogle Scholar
  21. 21.
    Harrop JS (2014) Spinal cord injury: debating the efficacy of methylprednisolone. Neurosurgery 61(Suppl 1):30–31CrossRefPubMedGoogle Scholar
  22. 22.
    Zhang ZC, Li F, Sun TS (2013) An expert consensus on the evaluation and treatment of acute thoracolumbar spine and spinal cord injury in China. Neural Regen Res 8:3077–3086PubMedPubMedCentralGoogle Scholar
  23. 23.
    Hurlbert RJ, Hadley MN, Walters BC, Aarabi B, Dhall SS, Gelb DE, Rozzelle CJ, Ryken TC, Theodore N (2015) Pharmacological therapy for acute spinal cord injury. Neurosurgery 76(Suppl 1):S71–S83CrossRefPubMedGoogle Scholar
  24. 24.
    Chikuda H, Yasunaga H, Takeshita K, Horiguichi H, Kawaguichi H, Ohe K, Fushimi K, Tanaka S (2014) Mortality and morbidity after high-dose methylprednisolone treatment in patients with acute cervical spinal cord injury: a propensity-matched analysis using a nationwide administrative database. Emerg Med J 31:201–206CrossRefPubMedGoogle Scholar
  25. 25.
    Matsumoto T, Tamaki T, Kawakami M, Yoshida M, Ando M, Yamada H (2001) Early complications of high-dose methylprednisolone sodium succinate treatment in the follow-up of acute cervical spinal cord injury. Spine (Phila Pa 1976) 26:426–430CrossRefGoogle Scholar
  26. 26.
    Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, Fehlings M, Herr DL, Hitchon PW, Marshall LF, Nockels RP, Pascale V, Perot PL Jr, Piepmeier J, Sonntag VK, Wagner F, Wilberger JE, Winn HR, Young W (1997) Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA 277:1597–1604CrossRefPubMedGoogle Scholar
  27. 27.
    Hurlbert RJ (2001) The role of steroids in acute spinal cord injury: an evidence-based analysis. Spine (Phila Pa 1976) 26:S39–S46CrossRefGoogle Scholar
  28. 28.
    Lu J, Ashwell KW, Waite P (2000) Advances in secondary spinal cord injury: role of apoptosis. Spine (Phila Pa 1976) 25:1859–1866CrossRefGoogle Scholar
  29. 29.
    Burté F, Carelli V, Chinnery PF, Yu-Wai-Man P (2015) Disturbed mitochondrial dynamics and neurodegenerative disorders. Nat Rev Neurol 11:11–24CrossRefPubMedGoogle Scholar
  30. 30.
    Fischer TD, Hylin MJ, Zhao J, Moore AN, Waxham MN, Dash PK (2016) Altered mitochondrial dynamics and TBI pathophysiology. Front Syst Neurosci 10:29.  https://doi.org/10.3389/fnsys.2016.00029 eCollection 2016CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Knott AB, Bossy-Wetzel E (2008) Impairing the mitochondrial fission and fusion balance: a new mechanism of neurodegeneration. Ann N Y Acad Sci 1147:283–292CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Frank S, Gaume B, Bergmann-Lertner 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 1:515–525CrossRefPubMedGoogle Scholar
  33. 33.
    Liu JM, Yi Z, Liu SZ, Chang JH, Dang XB, Li QY, Zhang YL (2015) The mitochondrial division inhibitor mdivi-1 attenuates spinal cord ischemia-reperfusion injury both in vitro and in vivo: involvement of BK channels. Brain Res 1619:155–165CrossRefPubMedGoogle Scholar
  34. 34.
    Li G, Cao Y, Shen F, Wang Y, Bai L, Guo W, Bi Y, Lv G, Fan Z (2016) Mdivi-1 inhibits astrocyte activation and astroglial scar formation and enhances axonal regeneration after spinal cord injury in rats. Front Cell Neurosci 10:241PubMedPubMedCentralGoogle Scholar
  35. 35.
    Tan JW, Wang KY, Liao GJ, Chen FM, Mu MZ (2015) Neuroprotective effect of methylprednisolone combined with placenta-derived mesenchymal stem cell in rabbit model of spinal cord injury. Int J Clin Exp Pathol 8:8976–8982PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Xu-Gui Chen
    • 1
  • Li-Hua Chen
    • 1
  • Ru-Xiang Xu
    • 1
  • Hong-Tian Zhang
    • 1
  1. 1.The Affiliated Bayi Brain Hospitalthe Army General Hospital PLABeijingChina

Personalised recommendations