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Neuroscience Bulletin logoLink to Neuroscience Bulletin
. 2013 Jul 13;29(4):484–492. doi: 10.1007/s12264-013-1355-6

Valproic acid reduces autophagy and promotes functional recovery after spinal cord injury in rats

Hai-Hu Hao 11355, Li Wang 21355, Zhi-Jian Guo 31355, Lang Bai 31355, Rui-Ping Zhang 41355, Wei-Bing Shuang 51355, Yi-Jia Jia 11355, Jie Wang 21355, Xiao-Yu Li 21355, Qiang Liu 61355,
PMCID: PMC5561937  PMID: 23852559

Abstract

Secondary damage is a critical determinant of the functional outcome in patients with spinal cord injury (SCI), and involves multiple mechanisms of which the most important is the loss of nerve cells mediated by multiple factors. Autophagy can result in cell death, and plays a key role in the development of SCI. It has been recognized that valproic acid (VPA) is neuroprotective in certain experimental animal models, however, the levels of autophagic changes in the process of neuroprotection by VPA treatment following SCI are still unknown. In the present study, we determined the extent of autophagy after VPA treatment in a rat model of SCI. We found that both the mRNA and protein levels of Beclin-1 and LC3 were significantly increased at 1, 2, and 6 h after SCI and peaked at 2 h; however, Western blot showed that autophagy was markedly decreased by VPA treatment at 2 h post-injury. Besides, post-SCI treatment with VPA improved the Basso-Beattie-Bresnahan scale, increased the number of ventral horn motoneurons, and reduced myelin sheath damage compared with vehicle-treated animals at 42 days after SCI. Together, our results demonstrated the characteristics of autophagy expression following SCI, and found that VPA reduced autophagy and enhanced motor function.

Keywords: spinal cord injury, autophagy, valproic acid, LC3, Beclin-1

References

  • [1].He J, Gu D, Wu X, Reynolds K, Duan X, Yao C, et al. Major causes of death among men and women in China. N Engl J Med. 2005;353:1124–1134. doi: 10.1056/NEJMsa050467. [DOI] [PubMed] [Google Scholar]
  • [2].McKenna MT, Michaud CM, Murray CJ, Marks JS. Assessing the burden of disease in the United States using disabilityadjusted life years. Am J Prev Med. 2005;28:415–423. doi: 10.1016/j.amepre.2005.02.009. [DOI] [PubMed] [Google Scholar]
  • [3].WHO Scientific Group on the Burden of Musculoskeletal Conditions at the start of the New Millennium. The burden of musculoskeletal conditions at the start of the new millennium. World Health Organ Tech Rep Ser. 2003;919(i–x):1–218. [PubMed] [Google Scholar]
  • [4].Cao HQ, Dong ED. An update on spinal cord injury research. Neurosci Bull. 2013;29:94–102. doi: 10.1007/s12264-012-1277-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [5].Oyinbo CA. Secondary injury mechanisms in traumatic spinal cord injury: a nugget of this multiply cascade. Acta Neurobiol Exp (Wars) 2011;71:281–299. doi: 10.55782/ane-2011-1848. [DOI] [PubMed] [Google Scholar]
  • [6].Baranov D, Neligan P. Trauma and aggressive homeostasis management. Anesthesiol Clin. 2007;25:49–63. doi: 10.1016/j.atc.2006.11.003. [DOI] [PubMed] [Google Scholar]
  • [7].Kroemer G, Marino G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010;40:280–293. doi: 10.1016/j.molcel.2010.09.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [8].Luo CL, Li BX, Li QQ, Chen XP, Sun YX, Bao HJ, et al. Autophagy is involved in traumatic brain injury-induced cell death and contributes to functional outcome deficits in mice. Neuroscience. 2011;184:54–63. doi: 10.1016/j.neuroscience.2011.03.021. [DOI] [PubMed] [Google Scholar]
  • [9].Kanno H, Ozawa H, Sekiguchi A, Itoi E. Spinal cord injury induces upregulation of Beclin 1 and promotes autophagic cell death. Neurobiol Dis. 2009;33:143–148. doi: 10.1016/j.nbd.2008.09.009. [DOI] [PubMed] [Google Scholar]
  • [10].Kanno H, Ozawa H, Sekiguchi A, Itoi E. The role of autophagy in spinal cord injury. Autophagy. 2009;5:390–392. doi: 10.4161/auto.5.3.7724. [DOI] [PubMed] [Google Scholar]
  • [11].Mizushima N. Autophagy: process and function. Genes Dev. 2007;21:2861–2873. doi: 10.1101/gad.1599207. [DOI] [PubMed] [Google Scholar]
  • [12].Huang J, Klionsky DJ. Autophagy and human disease. Cell Cycle. 2007;6:1837–1849. doi: 10.4161/cc.6.15.4511. [DOI] [PubMed] [Google Scholar]
  • [13].Xu F, Gu JH, Qin ZH. Neuronal autophagy in cerebral ischemia. Neurosci Bull. 2012;28:658–666. doi: 10.1007/s12264-012-1268-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [14].Mazure NM, Pouyssegur J. Hypoxia-induced autophagy: cell death or cell survival? Curr Opin Cell Biol. 2010;22:177–180. doi: 10.1016/j.ceb.2009.11.015. [DOI] [PubMed] [Google Scholar]
  • [15].Kanno H, Ozawa H, Sekiguchi A, Yamaya S, Itoi E. Induction of autophagy and autophagic cell death in damaged neural tissue after acute spinal cord injury in mice. Spine (Phila Pa 1976) 2011;36:E1427–1434. doi: 10.1097/BRS.0b013e3182028c3a. [DOI] [PubMed] [Google Scholar]
  • [16].Chen HC, Fong TH, Lee AW, Chiu WT. Autophagy is activated in injured neurons and inhibited by methylprednisolone after experimental spinal cord injury. Spine (Phila Pa 1976) 2012;37:470–475. doi: 10.1097/BRS.0b013e318221e859. [DOI] [PubMed] [Google Scholar]
  • [17].Walker CL, Walker MJ, Liu NK, Risberg EC, Gao X, Chen J, et al. Systemic bisperoxovanadium activates Akt/mTOR, reduces autophagy, and enhances recovery following cervical spinal cord injury. PLoS One. 2012;7:e30012. doi: 10.1371/journal.pone.0030012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [18].Cui SS, Yang CP, Bowen RC, Bai O, Li XM, Jiang W, et al. Valproic acid enhances axonal regeneration and recovery of motor function after sciatic nerve axotomy in adult rats. Brain Res. 2003;975:229–236. doi: 10.1016/S0006-8993(03)02699-4. [DOI] [PubMed] [Google Scholar]
  • [19].Dash PK, Orsi SA, Zhang M, Grill RJ, Pati S, Zhao J, et al. Valproate administered after traumatic brain injury provides neuroprotection and improves cognitive function in rats. PLoS One. 2010;5:e11383. doi: 10.1371/journal.pone.0011383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [20].Sinn DI, Kim SJ, Chu K, Jung KH, Lee ST, Song EC, et al. Valproic acid-mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation. Neurobiol Dis. 2007;26:464–472. doi: 10.1016/j.nbd.2007.02.006. [DOI] [PubMed] [Google Scholar]
  • [21].Lv L, Sun Y, Han X, Xu CC, Tang YP, Dong Q. Valproic acid improves outcome after rodent spinal cord injury: potential roles of histone deacetylase inhibition. Brain Res. 2011;1396:60–68. doi: 10.1016/j.brainres.2011.03.040. [DOI] [PubMed] [Google Scholar]
  • [22].Fu J, Shao CJ, Chen FR, Ng HK, Chen ZP. Autophagy induced by valproic acid is associated with oxidative stress in glioma cell lines. Neuro Oncol. 2010;12:328–340. doi: 10.1093/neuonc/nop005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Sekiguchi A, Kanno H, Ozawa H, Yamaya S, Itoi E. Rapamycin promotes autophagy and reduces neural tissue damage and locomotor impairment after spinal cord injury in mice. J Neurotrauma. 2012;29:946–956. doi: 10.1089/neu.2011.1919. [DOI] [PubMed] [Google Scholar]
  • [24].Gruner JA. A monitored contusion model of spinal cord injury in the rat. J Neurotrauma. 1992;9:123–126. doi: 10.1089/neu.1992.9.123. [DOI] [PubMed] [Google Scholar]
  • [25].Kim HJ, Rowe M, Ren M, Hong JS, Chen PS, Chuang DM. Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J Pharmacol Exp Ther. 2007;321:892–901. doi: 10.1124/jpet.107.120188. [DOI] [PubMed] [Google Scholar]
  • [26].Jensen EC. Quantitative analysis of histological staining and fluorescence using imageJ. Anat Rec (Hoboken) 2013;296:378–381. doi: 10.1002/ar.22554. [DOI] [PubMed] [Google Scholar]
  • [27].Basso DM, Beattie MS, Bresnahan JC. Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp Neurol. 1996;139:244–256. doi: 10.1006/exnr.1996.0098. [DOI] [PubMed] [Google Scholar]
  • [28].Scheff SW, Saucier DA, Cain ME. A statistical method for analyzing rating scale data: the BBB locomotor score. J Neurotrauma. 2002;19:1251–1260. doi: 10.1089/08977150260338038. [DOI] [PubMed] [Google Scholar]
  • [29].Tsujimoto Y, Shimizu S. Another way to die: autophagic programmed cell death. Cell Death Differ. 2005;12(Suppl2):1528–1534. doi: 10.1038/sj.cdd.4401777. [DOI] [PubMed] [Google Scholar]
  • [30].Viscomi MT, D’Amelio M, Cavallucci V, Latini L, Bisicchia E, Nazio F, et al. Stimulation of autophagy by rapamycin protects neurons from remote degeneration after acute focal brain damage. Autophagy. 2012;8:222–235. doi: 10.4161/auto.8.2.18599. [DOI] [PubMed] [Google Scholar]
  • [31].Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132:27–42. doi: 10.1016/j.cell.2007.12.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [32].Maiuri MC, Criollo A, Tasdemir E, Vicencio JM, Tajeddine N, Hickman JA, et al. BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L) Autophagy. 2007;3:374–376. doi: 10.4161/auto.4237. [DOI] [PubMed] [Google Scholar]
  • [33].Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, Benz CC. Clinical development of histone deacetylase inhibitors as anticancer agents. Annu Rev Pharmacol Toxicol. 2005;45:495–528. doi: 10.1146/annurev.pharmtox.45.120403.095825. [DOI] [PubMed] [Google Scholar]

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