Skip to main content
Top
Published in: Child's Nervous System 8/2018

01-08-2018 | Original Paper

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

Authors: Xu-Gui Chen, Li-Hua Chen, Ru-Xiang Xu, Hong-Tian Zhang

Published in: Child's Nervous System | Issue 8/2018

Login to get access

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.
Literature
1.
go back to reference 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 319:129–132CrossRefPubMed 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 319:129–132CrossRefPubMed
2.
go back to reference Hausmann ON (2003) Post-traumatic inflammation following spinal cord injury. Spinal Cord 41:369–378CrossRefPubMed Hausmann ON (2003) Post-traumatic inflammation following spinal cord injury. Spinal Cord 41:369–378CrossRefPubMed
3.
go back to reference Beattie MS, Hermann GE, Rogers RC, Bresnahan JC (2002) Cell death in models of spinal cord injury. Prog Brain Res 137:37–47CrossRefPubMed Beattie MS, Hermann GE, Rogers RC, Bresnahan JC (2002) Cell death in models of spinal cord injury. Prog Brain Res 137:37–47CrossRefPubMed
4.
go back to reference 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 11:1816–1823CrossRefPubMedPubMedCentral 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 11:1816–1823CrossRefPubMedPubMedCentral
5.
go back to reference 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 33:468–481CrossRefPubMedPubMedCentral 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 33:468–481CrossRefPubMedPubMedCentral
6.
go back to reference Rouanet C, Reges D, Rocha E, Gagliardi V, Silva GS (2017) Traumatic spinal cord injury: current concepts and treatment update. Arq Neuropsiquiatr 75:387–393CrossRefPubMed Rouanet C, Reges D, Rocha E, Gagliardi V, Silva GS (2017) Traumatic spinal cord injury: current concepts and treatment update. Arq Neuropsiquiatr 75:387–393CrossRefPubMed
7.
go back to reference 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 183:286–297CrossRefPubMed 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 183:286–297CrossRefPubMed
8.
go back to reference 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 101:1552–1566CrossRefPubMed 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 101:1552–1566CrossRefPubMed
9.
go back to reference 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 14:193–204CrossRefPubMedPubMedCentral 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 14:193–204CrossRefPubMedPubMedCentral
11.
go back to reference Cox A, Varma A, Banik N (2015) Recent advances in the pharmacologic treatment of spinal cord injury. Metab Brain Dis 30:473–482CrossRefPubMed Cox A, Varma A, Banik N (2015) Recent advances in the pharmacologic treatment of spinal cord injury. Metab Brain Dis 30:473–482CrossRefPubMed
12.
go back to reference 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 11:1678–1684CrossRefPubMedPubMedCentral 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 11:1678–1684CrossRefPubMedPubMedCentral
13.
go back to reference 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 19:9355–9363CrossRefPubMed 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 19:9355–9363CrossRefPubMed
14.
go back to reference 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 40:1379–1392CrossRefPubMed 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 40:1379–1392CrossRefPubMed
15.
go back to reference 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 1527:40–46CrossRef 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 1527:40–46CrossRef
16.
go back to reference 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 18:556–565CrossRefPubMed 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 18:556–565CrossRefPubMed
17.
go back to reference 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 65:59–70CrossRefPubMed 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 65:59–70CrossRefPubMed
18.
go back to reference 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 12:1229–1241CrossRefPubMed 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 12:1229–1241CrossRefPubMed
19.
go back to reference 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 16:145–161CrossRefPubMed 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 16:145–161CrossRefPubMed
20.
go back to reference Hall ED (1991) Inhibition of lipid peroxidation in CNS trauma. J Neurotrauma 8(Suppl 1):S31–S40PubMed Hall ED (1991) Inhibition of lipid peroxidation in CNS trauma. J Neurotrauma 8(Suppl 1):S31–S40PubMed
21.
go back to reference Harrop JS (2014) Spinal cord injury: debating the efficacy of methylprednisolone. Neurosurgery 61(Suppl 1):30–31CrossRefPubMed Harrop JS (2014) Spinal cord injury: debating the efficacy of methylprednisolone. Neurosurgery 61(Suppl 1):30–31CrossRefPubMed
22.
go back to reference 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 8:3077–3086PubMedPubMedCentral 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 8:3077–3086PubMedPubMedCentral
23.
go back to reference 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–S83CrossRefPubMed 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–S83CrossRefPubMed
24.
go back to reference 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 31:201–206CrossRefPubMed 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 31:201–206CrossRefPubMed
25.
go back to reference 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) 26:426–430CrossRef 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) 26:426–430CrossRef
26.
go back to reference 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 277:1597–1604CrossRefPubMed 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 277:1597–1604CrossRefPubMed
27.
go back to reference Hurlbert RJ (2001) The role of steroids in acute spinal cord injury: an evidence-based analysis. Spine (Phila Pa 1976) 26:S39–S46CrossRef Hurlbert RJ (2001) The role of steroids in acute spinal cord injury: an evidence-based analysis. Spine (Phila Pa 1976) 26:S39–S46CrossRef
28.
go back to reference Lu J, Ashwell KW, Waite P (2000) Advances in secondary spinal cord injury: role of apoptosis. Spine (Phila Pa 1976) 25:1859–1866CrossRef Lu J, Ashwell KW, Waite P (2000) Advances in secondary spinal cord injury: role of apoptosis. Spine (Phila Pa 1976) 25:1859–1866CrossRef
29.
go back to reference Burté F, Carelli V, Chinnery PF, Yu-Wai-Man P (2015) Disturbed mitochondrial dynamics and neurodegenerative disorders. Nat Rev Neurol 11:11–24CrossRefPubMed Burté F, Carelli V, Chinnery PF, Yu-Wai-Man P (2015) Disturbed mitochondrial dynamics and neurodegenerative disorders. Nat Rev Neurol 11:11–24CrossRefPubMed
31.
go back to reference Knott AB, Bossy-Wetzel E (2008) Impairing the mitochondrial fission and fusion balance: a new mechanism of neurodegeneration. Ann N Y Acad Sci 1147:283–292CrossRefPubMedPubMedCentral Knott AB, Bossy-Wetzel E (2008) Impairing the mitochondrial fission and fusion balance: a new mechanism of neurodegeneration. Ann N Y Acad Sci 1147:283–292CrossRefPubMedPubMedCentral
32.
go back to reference 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 1:515–525CrossRefPubMed 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 1:515–525CrossRefPubMed
33.
go back to reference 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 1619:155–165CrossRefPubMed 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 1619:155–165CrossRefPubMed
34.
go back to reference 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 10:241PubMedPubMedCentral 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 10:241PubMedPubMedCentral
35.
go back to reference 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 8:8976–8982PubMedPubMedCentral 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 8:8976–8982PubMedPubMedCentral
Metadata
Title
Effect evaluation of methylprednisolone plus mitochondrial division inhibitor-1 on spinal cord injury rats
Authors
Xu-Gui Chen
Li-Hua Chen
Ru-Xiang Xu
Hong-Tian Zhang
Publication date
01-08-2018
Publisher
Springer Berlin Heidelberg
Published in
Child's Nervous System / Issue 8/2018
Print ISSN: 0256-7040
Electronic ISSN: 1433-0350
DOI
https://doi.org/10.1007/s00381-018-3792-z

Other articles of this Issue 8/2018

Child's Nervous System 8/2018 Go to the issue