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The Neuroprotective Effect of Treatment of Valproic Acid in Acute Spinal Cord Injury

  • Yu, Song-Hee (Department of Neurosurgery, School of Medicine, Kyungpook National University) ;
  • Cho, Dae-Chul (Department of Neurosurgery, School of Medicine, Kyungpook National University) ;
  • Kim, Kyoung-Tae (Department of Neurosurgery, School of Medicine, Kyungpook National University) ;
  • Nam, Kyung-Hun (Department of Neurosurgery, School of Medicine, Kyungpook National University) ;
  • Cho, Hee-Jung (Department of Anatomy, School of Medicine, Kyungpook National University) ;
  • Sung, Joo-Kyung (Department of Neurosurgery, School of Medicine, Kyungpook National University)
  • 투고 : 2012.01.05
  • 심사 : 2012.04.15
  • 발행 : 2012.04.28

초록

Objective: Valproic acid (VPA), as known as histone deacetylase inhibitor, has neuroprotective effects. This study investigated the histological changes and functional recovery from spinal cord injury (SCI) associated with VPA treatment in a rat model. Methods: Locomotor function was assessed according to the Basso-Beatlie-Bresnahan scale for 2 weeks in rats after receiving twice daily intraperitoneal injections of 200 mg/kg VPA or the equivalent volume of normal saline for 7 days following SCI. The injured spinal cord was then examined histologically, including quantification of cavitation. Results: Basso-Beatlie-Bresnahan scale scores in rats receiving VPA were significantly higher than in the saline group (p<0.05). The cavity volume in the VPA group was Significantly reduced compared with the control (saline-injected) group (p<0.05). The level of histone acetylation recovered in the VPA group, while it was significantly decreased in the control rats (p<0.05). The macrophage level was significantly decreased in the VPA group (p<0.05). Conclusion: VPA influences the restoration of hyperacetylation and reduction of the inflammatory reaction resulting from SCI, and is effective for histology and motor function recovery.

키워드

참고문헌

  1. Balentine JD : Pathology of experimental spinal cord trauma. I. The necrotic lesion as a function of vascular injury. Lab Invest 39 : 236-253, 1978
  2. Balentine JD : Pathology of experimental spinal cord trauma. II. Ultrastructure of axons and myelin. Lab Invest 39 : 254-266, 1978
  3. 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 139 : 244-256, 1996 https://doi.org/10.1006/exnr.1996.0098
  4. Beattie MS : Inflammation and apoptosis : linked therapeutic targets in spinal cord injury. Trends Mol Med 10 : 580-583, 2004 https://doi.org/10.1016/j.molmed.2004.10.006
  5. Blaheta RA, Nau H, Michaelis M, Cinatl J Jr : Valproate and valproate-analogues : potent tools to fight against cancer. Curr Med Chem 9 : 1417-1433, 2002 https://doi.org/10.2174/0929867023369763
  6. Blight AR, Young W : Central axons in injured cat spinal cord recover electrophysiological function following remyelination by Schwann cells. J Neurol Sci 91 : 15-34, 1989 https://doi.org/10.1016/0022-510X(89)90073-7
  7. Bolden JE, Peart MJ, Johnstone RW : Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5 : 769-784, 2006 https://doi.org/10.1038/nrd2133
  8. Bracken MB, Collins WF, Freeman DF, Shepard MJ, Wagner FW, Silten RM, et al. : Efficacy of methylprednisolone in acute spinal cord injury. JAMA 251 : 45-52, 1984 https://doi.org/10.1001/jama.1984.03340250025015
  9. Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, et al. : 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 : 1597-1604, 1997 https://doi.org/10.1001/jama.1997.03540440031029
  10. Brichta L, Holker I, Haug K, Klockgether T, Wirth B : In vivo activation of SMN in spinal muscular atrophy carriers and patients treated with valproate. Ann Neurol 59 : 970-975, 2006 https://doi.org/10.1002/ana.20836
  11. Celik M, Gokmen N, Erbayraktar S, Akhisaroglu M, Konakc S, Ulukus C, et al. : Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury. Proc Natl Acad Sci USA 99 : 2258-2263, 2002 https://doi.org/10.1073/pnas.042693799
  12. Chen PS, Wang CC, Bortner CD, Peng GS, Wu X, Pang H, et al. : Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity. Neuroscience 149 : 203-212, 2007 https://doi.org/10.1016/j.neuroscience.2007.06.053
  13. Cho DC, Cheong JH, Yang MS, Hwang SJ, Kim JM, Kim CH : The effect of minocycline on motor neuron recovery and neuropathic pain in a rat model of spinal cord injury. J Korean Neurosurg Soc 49 : 83-91, 2011 https://doi.org/10.3340/jkns.2011.49.2.83
  14. Cui SS, Yang CP, Bowen RC, Bai O, Li XM, Jiang W, Zhang X : Valproic acid enhances axonal regeneration and recovery of motor function after sciatic nerve axotomy in adult rats. Brain Res 975 : 229-236, 2003 https://doi.org/10.1016/S0006-8993(03)02699-4
  15. 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 5 : e11383, 2010 https://doi.org/10.1371/journal.pone.0011383
  16. Faraco G, Pancani T, Formentini L, Mascagni P, Fossati G, Leoni F, et al. : Pharmacological inhibition of histone deacetylases by suberoylanilide hydroxamic acid specifically alters gene expression and reduces ischemic injury in the mouse brain. Mol Pharmacol 70 : 1876-1884, 2006 https://doi.org/10.1124/mol.106.027912
  17. Feng HL, Leng Y, Ma CH, Zhang J, Ren M, Chuang DM : Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model. Neuroscience 155 : 567-572, 2008 https://doi.org/10.1016/j.neuroscience.2008.06.040
  18. Fournier AE, Strittmatter SM : Repulsive factors and axon regeneration in the CNS. Curr Opin Neurobiol 11 : 89-94, 2001 https://doi.org/10.1016/S0959-4388(00)00178-1
  19. Fukuchi M, Nii T, Ishimaru N, Minamino A, Hara D, Takasaki I, et al. : Valproic acid induces up- or down-regulation of gene expression responsible for the neuronal excitation and inhibition in rat cortical neurons through its epigenetic actions. Neurosci Res 65 : 35-43, 2009 https://doi.org/10.1016/j.neures.2009.05.002
  20. Giffard RG, Yenari MA : Many mechanisms for hsp70 protection from cerebral ischemia. J Neurosurg Anesthesiol 16 : 53-61, 2004 https://doi.org/10.1097/00008506-200401000-00010
  21. Gorio A, Gokmen N, Erbayraktar S, Yilmaz O, Madaschi L, Cichetti C, et al. : Recombinant human erythropoietin counteracts secondary injury and markedly enhances neurological recovery from experimental spinal cord trauma. Proc Natl Acad Sci U S A 99 : 9450-9455, 2002 https://doi.org/10.1073/pnas.142287899
  22. Gottlicher M, Minucci S, Zhu P, Kramer OH, Schimpf A, Giavara S, et al. : Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20 : 6969-6978, 2001 https://doi.org/10.1093/emboj/20.24.6969
  23. Hall ED, Springer JE : Neuroprotection and acute spinal cord injury : a reappraisal. NeuroRx 1 : 80-100, 2004 https://doi.org/10.1602/neurorx.1.1.80
  24. Hashimoto R, Hough C, Nakazawa T, Yamamoto T, Chuang DM : Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons : involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation. J Neurochem 80 : 589-597, 2002 https://doi.org/10.1046/j.0022-3042.2001.00728.x
  25. Heneka MT, Gavrilyuk V, Landreth GE, O'Banion MK, Weinberg G, Feinstein DL : Noradrenergic depletion increases inflammatory responses in brain : effects on IkappaB and HSP70 expression. J Neurochem 85 : 387-398, 2003 https://doi.org/10.1046/j.1471-4159.2003.01694.x
  26. Hsieh J, Gage FH : Chromatin remodeling in neural development and plasticity. Curr Opin Cell Biol 17 : 664-671, 2005 https://doi.org/10.1016/j.ceb.2005.09.002
  27. Jeong MR, Hashimoto R, Senatorov VV, Fujimaki K, Ren M, Lee MS, et al. : Valproic acid, a mood stabilizer and anticonvulsant, protects rat cerebral cortical neurons from spontaneous cell death : a role of histone deacetylase inhibition. FEBS Lett 542 : 74-78, 2003 https://doi.org/10.1016/S0014-5793(03)00350-8
  28. Kanai H, Sawa A, Chen RW, Leeds P, Chuang DM : Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons. Pharmacogenomics J 4 : 336-344, 2004 https://doi.org/10.1038/sj.tpj.6500269
  29. Kazantsev AG, Thompson LM : Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nat Rev Drug Discov 7 : 854-868, 2008 https://doi.org/10.1038/nrd2681
  30. Khalatbary AR, Tiraihi T, Boroujeni MB, Ahmadvand H, Tavafi M, Tamjidipoor A : Effects of epigallocatechin gallate on tissue protection and functional recovery after contusive spinal cord injury in rats. Brain Res 1306 : 168-175, 2010 https://doi.org/10.1016/j.brainres.2009.09.109
  31. Langley B, Gensert JM, Beal MF, Ratan RR : Remodeling chromatin and stress resistance in the central nervous system : histone deacetylase inhibitors as novel and broadly effective neuroprotective agents. Curr Drug Targets CNS Neurol Disord 4 : 41-50, 2005 https://doi.org/10.2174/1568007053005091
  32. Lee SM, Yune TY, Kim SJ, Park DW, Lee YK, Kim YC, et al. : Minocycline reduces cell death and improves functional recovery after traumatic spinal cord injury in the rat. J Neurotrauma 20 : 1017-1027, 2003 https://doi.org/10.1089/089771503770195867
  33. Li S, Strittmatter SM : Delayed systemic Nogo-66 receptor antagonist promotes recovery from spinal cord injury. J Neurosci 23 : 4219-4227, 2003
  34. Li WW, Setzu A, Zhao C, Franklin RJ : Minocycline-mediated inhibition of microglia activation impairs oligodendrocyte progenitor cell responses and remyelination in a non-immune model of demyelination. J Neuroimmunol 158 : 58-66, 2005 https://doi.org/10.1016/j.jneuroim.2004.08.011
  35. Lin MS, Lee YH, Chiu WT, Hung KS : Curcumin provides neuroprotection after spinal cord injury. J Surg Res 166 : 280-289, 2011 https://doi.org/10.1016/j.jss.2009.07.001
  36. Nalivaeva NN, Belyaev ND, Turner AJ : Sodium valproate : an old drug with new roles. Trends Pharmacol Sci 30 : 509-514, 2009 https://doi.org/10.1016/j.tips.2009.07.002
  37. Ouyang YB, Giffard RG : Cellular neuroprotective mechanisms in cerebral ischemia : Bcl-2 family proteins and protection of mitochondrial function. Cell Calcium 36 : 303-311, 2004 https://doi.org/10.1016/j.ceca.2004.02.015
  38. Pandey P, Saleh A, Nakazawa A, Kumar S, Srinivasula SM, Kumar V, et al. : Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90. EMBO J 19 : 4310-4322, 2000 https://doi.org/10.1093/emboj/19.16.4310
  39. Pannu R, Barbosa E, Singh AK, Singh I : Attenuation of acute inflammatory response by atorvastatin after spinal cord injury in rats. J Neurosci Res 79 : 340-350, 2005 https://doi.org/10.1002/jnr.20345
  40. Penas C, Verdu E, Asensio-Pinilla E, Guzman-Lenis MS, Herrando-Grabulosa M, Navarro X, et al. : Valproate reduces CHOP levels and preserves oligodendrocytes and axons after spinal cord injury. Neuroscience 178 : 33-44, 2011 https://doi.org/10.1016/j.neuroscience.2011.01.012
  41. Peng W, Cotrina ML, Han X, Yu H, Bekar L, Blum L, et al. : Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury. Proc Natl Acad Sci U S A 106 : 12489-12493, 2009 https://doi.org/10.1073/pnas.0902531106
  42. Perez M, Rojo AI, Wandosell F, Diaz-Nido J, Avila J : Prion peptide induces neuronal cell death through a pathway involving glycogen synthase kinase 3. Biochem J 372 : 129-136, 2003 https://doi.org/10.1042/BJ20021596
  43. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS : Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276 : 36734-36741, 2001 https://doi.org/10.1074/jbc.M101287200
  44. Reckling JC : Neuroprotective effects of anticonvulsants in rat hippocampal slice cultures exposed to oxygen/glucose deprivation. Neurosci Lett 335 : 167-170, 2003 https://doi.org/10.1016/S0304-3940(02)01193-X
  45. Ren M, Leng Y, Jeong M, Leeds PR, Chuang DM : Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats : potential roles of histone deacetylase inhibition and heat shock protein induction. J Neurochem 89 : 1358-1367, 2004 https://doi.org/10.1111/j.1471-4159.2004.02406.x
  46. Rogawski MA, Loscher W : The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. Nat Med 10 : 685-692, 2004 https://doi.org/10.1038/nm1074
  47. Rowland JW, Hawryluk GW, Kwon B, Fehlings MG : Current status of acute spinal cord injury pathophysiology and emerging therapies : promise on the horizon. Neurosurg Focus 25 : E2, 2008
  48. Shin YC, Choi KY, Kim WG : Cyclosporin A has a protective effect with induced upregulation of Hsp70 and nNOS on severe spinal cord ischemic injury in rabbits. J Invest Surg 20 : 113-120, 2007 https://doi.org/10.1080/08941930701235833
  49. 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 26 : 464-472, 2007 https://doi.org/10.1016/j.nbd.2007.02.006
  50. Stepien K, Tomaszewski M, Czuczwar SJ : Neuroprotective properties of statins. Pharmacol Rep 57 : 561-569, 2005
  51. von Euler M, Seiger A, Sundstrom E : Clip compression injury in the spinal cord : a correlative study of neurological and morphological alterations. Exp Neurol 145 : 502-510, 1997 https://doi.org/10.1006/exnr.1997.6481
  52. Wang Z, Leng Y, Tsai LK, Leeds P, Chuang DM : Valproic acid attenuates blood-brain barrier disruption in a rat model of transient focal cerebral ischemia : the roles of HDAC and MMP-9 inhibition. J Cereb Blood Flow Metab 31 : 52-57, 2011 https://doi.org/10.1038/jcbfm.2010.195
  53. Wells JE, Hurlbert RJ, Fehlings MG, Yong VW : Neuroprotection by minocycline facilitates significant recovery from spinal cord injury in mice. Brain 126 : 1628-1637, 2003 https://doi.org/10.1093/brain/awg178
  54. Yildirim F, Gertz K, Kronenberg G, Harms C, Fink KB, Meisel A, et al. : Inhibition of histone deacetylation protects wildtype but not gelsolin-deficient mice from ischemic brain injury. Exp Neurol 210 : 531-542, 2008 https://doi.org/10.1016/j.expneurol.2007.11.031
  55. Young W : Secondary injury mechanisms in acute spinal cord injury. J Emerg Med 11 Suppl 1 : 13-22, 1993
  56. Yune TY, Kim SJ, Lee SM, Lee YK, Oh YJ, Kim YC, et al. : Systemic administration of 17beta-estradiol reduces apoptotic cell death and improves functional recovery following traumatic spinal cord injury in rats. J Neurotrauma 21 : 293-306, 2004 https://doi.org/10.1089/089771504322972086
  57. Yune TY, Park HG, Lee JY, Oh TH : Estrogen-induced Bcl-2 expression after spinal cord injury is mediated through phosphoinositide-3-kinase/Akt-dependent CREB activation. J Neurotrauma 25 : 1121-1131, 2008 https://doi.org/10.1089/neu.2008.0544

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