Neurochemical Research

, Volume 39, Issue 9, pp 1621–1633 | Cite as

Valproic Acid: A New Candidate of Therapeutic Application for the Acute Central Nervous System Injuries

  • Sheng Chen
  • Haijian Wu
  • Damon Klebe
  • Yuan Hong
  • Jianmin Zhang


Acute central nervous system (CNS) injuries, including stroke, traumatic brain injury (TBI), and spinal cord injury (SCI), are common causes of human disabilities and deaths, but the pathophysiology of these diseases is not fully elucidated and, thus, effective pharmacotherapies are still lacking. Valproic acid (VPA), an inhibitor of histone deacetylation, is mainly used to treat epilepsy and bipolar disorder with few complications. Recently, the neuroprotective effects of VPA have been demonstrated in several models of acute CNS injuries, such as stroke, TBI, and SCI. VPA protects the brain from injury progression via anti-inflammatory, anti-apoptotic, and neurotrophic effects. In this review, we focus on the emerging neuroprotective properties of VPA and explore the underlying mechanisms. In particular, we discuss several potential related factors in VPA research and present the opportunity to administer VPA as a novel neuropective agent.


Valproic acid Brain injuries Histone deacetylases inhibitor Neuroprotection 



This study was supported by National Natural Science Foundation of China (No.81171096 and No.81371433) to JM Zhang and by National Natural Science Foundation of China (No. 81371369) to Y Hong.

Conflict of interest

The authors report no conflicts of interest.


  1. 1.
    Mukherjee D, Patil CG (2011) Epidemiology and the global burden of stroke. World Neurosurg 76:S85–S90PubMedGoogle Scholar
  2. 2.
    Corrigan JD, Selassie AW, Orman JA (2010) The epidemiology of traumatic brain injury. J Head Trauma Rehabil 25:72–80PubMedGoogle Scholar
  3. 3.
    Ackery A, Tator C, Krassioukov A (2004) A global perspective on spinal cord injury epidemiology. J Neurotrauma 21:1355–1370PubMedGoogle Scholar
  4. 4.
    Kunz A, Dirnagl U, Mergenthaler P (2010) Acute pathophysiological processes after ischaemic and traumatic brain injury. Best Pract Res Clin Anaesthesiol 24:495–509PubMedGoogle Scholar
  5. 5.
    Ambrozaitis KV, Kontautas E, Spakauskas B, Vaitkaitis D (2006) Pathophysiology of acute spinal cord injury. Medicina (Kaunas) 42:255–261Google Scholar
  6. 6.
    McConeghy KW, Hatton J, Hughes L, Cook AM (2012) A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury. CNS Drugs 26:613–636PubMedGoogle Scholar
  7. 7.
    Filli L, Schwab ME (2012) The rocky road to translation in spinal cord repair. Ann Neurol 72:491–501PubMedGoogle Scholar
  8. 8.
    Marsh JD, Keyrouz SG (2010) Stroke prevention and treatment. J Am Coll Cardiol 56:683–691PubMedGoogle Scholar
  9. 9.
    Jaffer H, Morris VB, Stewart D, Labhasetwar V (2011) Advances in stroke therapy. Drug Deliv Transl Res 1:409–419PubMedCentralPubMedGoogle Scholar
  10. 10.
    Rogawski MA, Loscher W (2004) The neurobiology of antiepileptic drugs. Nat Rev Neurosci 5:553–564PubMedGoogle Scholar
  11. 11.
    Rosenberg G (2007) The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? Cell Mol Life Sci 64:2090–2103PubMedGoogle Scholar
  12. 12.
    Davis R, Peters DH, McTavish D (1994) Valproic acid. A reappraisal of its pharmacological properties and clinical efficacy in epilepsy. Drugs 47:332–372PubMedGoogle Scholar
  13. 13.
    Vajda FJ (2002) Valproate and neuroprotection. J Clin Neurosci 9:508–514PubMedGoogle Scholar
  14. 14.
    Monti B, Polazzi E, Contestabile A (2009) Biochemical, molecular and epigenetic mechanisms of valproic acid neuroprotection. Curr Mol Pharmacol 2:95–109PubMedGoogle Scholar
  15. 15.
    Nalivaeva NN, Belyaev ND, Turner AJ (2009) Sodium valproate: an old drug with new roles. Trends Pharmacol Sci 30:509–514PubMedGoogle Scholar
  16. 16.
    Ren M, Leng Y, Jeong M, Leeds PR, Chuang DM (2004) 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 89:1358–1367PubMedGoogle Scholar
  17. 17.
    Sinn DI, Kim SJ, Chu K, Jung KH, Lee ST, Song EC, Kim JM, Park DK, Kun Lee S, Kim M, Roh JK (2007) Valproic acid-mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation. Neurobiol Dis 26:464–472PubMedGoogle Scholar
  18. 18.
    Liu XS, Chopp M, Kassis H, Jia LF, Hozeska-Solgot A, Zhang RL, Chen C, Cui YS, Zhang ZG (2012) Valproic acid increases white matter repair and neurogenesis after stroke. Neuroscience 220:313–321PubMedCentralPubMedGoogle Scholar
  19. 19.
    Shults C, Sailhamer EA, Li Y, Liu B, Tabbara M, Butt MU, Shuja F, Demoya M, Velmahos G, Alam HB (2008) Surviving blood loss without fluid resuscitation. J Trauma 64:629–638; discussion 638–640Google Scholar
  20. 20.
    Saha RN, Pahan K (2006) HATs and HDACs in neurodegeneration: a tale of disconcerted acetylation homeostasis. Cell Death Differ 13:539–550PubMedCentralPubMedGoogle Scholar
  21. 21.
    Shein NA, Shohami E (2011) Histone deacetylase inhibitors as therapeutic agents for acute central nervous system injuries. Mol Med 17:448–456PubMedCentralPubMedGoogle Scholar
  22. 22.
    D’Mello SR (2009) Histone deacetylases as targets for the treatment of human neurodegenerative diseases. Drug News Perspect 22:513–524PubMedCentralPubMedGoogle Scholar
  23. 23.
    Graff J, Tsai LH (2013) Histone acetylation: molecular mnemonics on the chromatin. Nat Rev Neurosci 14:97–111PubMedGoogle Scholar
  24. 24.
    Lahue RS, Frizzell A (2012) Histone deacetylase complexes as caretakers of genome stability. Epigenetics 7:806–810PubMedCentralPubMedGoogle Scholar
  25. 25.
    Rao R, Fiskus W, Ganguly S, Kambhampati S, Bhalla KN (2012) HDAC inhibitors and chaperone function. Adv Cancer Res 116:239–262PubMedGoogle Scholar
  26. 26.
    Sancho-Pelluz J, Alavi MV, Sahaboglu A, Kustermann S, Farinelli P, Azadi S, van Veen T, Romero FJ, Paquet-Durand F, Ekstrom P (2010) Excessive HDAC activation is critical for neurodegeneration in the rd1 mouse. Cell Death Dis 1:e24PubMedCentralPubMedGoogle Scholar
  27. 27.
    Lv L, Sun Y, Han X, Xu CC, Tang YP, Dong Q (2011) Valproic acid improves outcome after rodent spinal cord injury: potential roles of histone deacetylase inhibition. Brain Res 1396:60–68PubMedGoogle Scholar
  28. 28.
    Baltan S, Bachleda A, Morrison RS, Murphy SP (2011) Expression of histone deacetylases in cellular compartments of the mouse brain and the effects of ischemia. Transl Stroke Res 2:411–423PubMedCentralPubMedGoogle Scholar
  29. 29.
    Eyal S, Yagen B, Sobol E, Altschuler Y, Shmuel M, Bialer M (2004) The activity of antiepileptic drugs as histone deacetylase inhibitors. Epilepsia 45:737–744PubMedGoogle Scholar
  30. 30.
    Gottlicher M, Minucci S, Zhu P, Kramer OH, Schimpf A, Giavara S, Sleeman JP, Lo Coco F, Nervi C, Pelicci PG, Heinzel T (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20:6969–6978PubMedCentralPubMedGoogle Scholar
  31. 31.
    Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276:36734–36741PubMedGoogle Scholar
  32. 32.
    Bannister AJ, Kouzarides T (2011) Regulation of chromatin by histone modifications. Cell Res 21:381–395PubMedCentralPubMedGoogle Scholar
  33. 33.
    Marinova Z, Ren M, Wendland JR, Leng Y, Liang MH, Yasuda S, Leeds P, Chuang DM (2009) Valproic acid induces functional heat-shock protein 70 via Class I histone deacetylase inhibition in cortical neurons: a potential role of Sp1 acetylation. J Neurochem 111:976–987PubMedCentralPubMedGoogle Scholar
  34. 34.
    Bolden JE, Peart MJ, Johnstone RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5:769–784PubMedGoogle Scholar
  35. 35.
    Hsieh J, Nakashima K, Kuwabara T, Mejia E, Gage FH (2004) Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proc Natl Acad Sci USA 101:16659–16664PubMedCentralPubMedGoogle Scholar
  36. 36.
    Dash PK, Orsi SA, Zhang M, Grill RJ, Pati S, Zhao J, Moore AN (2010) Valproate administered after traumatic brain injury provides neuroprotection and improves cognitive function in rats. PLoS ONE 5:e11383PubMedCentralPubMedGoogle Scholar
  37. 37.
    Li X, Bijur GN, Jope RS (2002) Glycogen synthase kinase-3beta, mood stabilizers, and neuroprotection. Bipolar Disord 4:137–144PubMedCentralPubMedGoogle Scholar
  38. 38.
    Kao CY, Hsu YC, Liu JW, Lee DC, Chung YF, Chiu IM (2013) The mood stabilizer valproate activates human FGF1 gene promoter through inhibiting HDAC and GSK-3 activities. J Neurochem 126:4–18PubMedGoogle Scholar
  39. 39.
    Hao Y, Creson T, Zhang L, Li P, Du F, Yuan P, Gould TD, Manji HK, Chen G (2004) Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J Neurosci 24:6590–6599PubMedGoogle Scholar
  40. 40.
    Cavallucci V, D’Amelio M (2011) Matter of life and death: the pharmacological approaches targeting apoptosis in brain diseases. Curr Pharm Des 17:215–229PubMedGoogle Scholar
  41. 41.
    Mora A, Gonzalez-Polo RA, Fuentes JM, Soler G, Centeno F (1999) Different mechanisms of protection against apoptosis by valproate and Li+. Eur J Biochem 266:886–891PubMedGoogle Scholar
  42. 42.
    Mora A, Sabio G, Alonso JC, Soler G, Centeno F (2002) Different dependence of lithium and valproate on PI3K/PKB pathway. Bipolar Disord 4:195–200PubMedGoogle Scholar
  43. 43.
    Pan T, Li X, Xie W, Jankovic J, Le W (2005) Valproic acid-mediated Hsp70 induction and anti-apoptotic neuroprotection in SH-SY5Y cells. FEBS Lett 579:6716–6720PubMedGoogle Scholar
  44. 44.
    Yuan PX, Huang LD, Jiang YM, Gutkind JS, Manji HK, Chen G (2001) The mood stabilizer valproic acid activates mitogen-activated protein kinases and promotes neurite growth. J Biol Chem 276:31674–31683PubMedGoogle Scholar
  45. 45.
    Li Y, Yuan Z, Liu B, Sailhamer EA, Shults C, Velmahos GC, Demoya M, Alam HB (2008) Prevention of hypoxia-induced neuronal apoptosis through histone deacetylase inhibition. J Trauma 64:863–870; discussion 870–861Google Scholar
  46. 46.
    Kabakus N, Ay I, Aysun S, Soylemezoglu F, Ozcan A, Celasun B (2005) Protective effects of valproic acid against hypoxic-ischemic brain injury in neonatal rats. J Child Neurol 20:582–587PubMedGoogle Scholar
  47. 47.
    Lucas SM, Rothwell NJ, Gibson RM (2006) The role of inflammation in CNS injury and disease. Br J Pharmacol 147(Suppl 1):S232–S240PubMedCentralPubMedGoogle Scholar
  48. 48.
    Ahmad M, Graham SH (2010) Inflammation after stroke: mechanisms and therapeutic approaches. Transl Stroke Res 1:74–84PubMedCentralPubMedGoogle Scholar
  49. 49.
    Chen PS, Wang CC, Bortner CD, Peng GS, Wu X, Pang H, Lu RB, Gean PW, Chuang DM, Hong JS (2007) Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity. Neuroscience 149:203–212PubMedCentralPubMedGoogle Scholar
  50. 50.
    Gibbons HM, Smith AM, Teoh HH, Bergin PM, Mee EW, Faull RL, Dragunow M (2011) Valproic acid induces microglial dysfunction, not apoptosis, in human glial cultures. Neurobiol Dis 41:96–103PubMedGoogle Scholar
  51. 51.
    Peng GS, Li G, Tzeng NS, Chen PS, Chuang DM, Hsu YD, Yang S, Hong JS (2005) Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia. Brain Res Mol Brain Res 134:162–169PubMedGoogle Scholar
  52. 52.
    Zhang Z, Zhang ZY, Wu Y, Schluesener HJ (2012) Valproic acid ameliorates inflammation in experimental autoimmune encephalomyelitis rats. Neuroscience 221:140–150PubMedGoogle Scholar
  53. 53.
    Strowig T, Henao-Mejia J, Elinav E, Flavell R (2012) Inflammasomes in health and disease. Nature 481:278–286PubMedGoogle Scholar
  54. 54.
    de Rivero Vaccari JP, Lotocki G, Alonso OF, Bramlett HM, Dietrich WD, Keane RW (2009) Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury. J Cereb Blood Flow Metab 29:1251–1261PubMedCentralPubMedGoogle Scholar
  55. 55.
    Yang-Wei Fann D, Lee SY, Manzanero S, Tang SC, Gelderblom M, Chunduri P, Bernreuther C, Glatzel M, Cheng YL, Thundyil J, Widiapradja A, Lok KZ, Foo SL, Wang YC, Li YI, Drummond GR, Basta M, Magnus T, Jo DG, Mattson MP, Sobey CG, Arumugam TV (2013) Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death Dis 4:e790PubMedCentralPubMedGoogle Scholar
  56. 56.
    Liu HD, Li W, Chen ZR, Hu YC, Zhang DD, Shen W, Zhou ML, Zhu L, Hang CH (2013) Expression of the NLRP3 inflammasome in cerebral cortex after traumatic brain injury in a rat model. Neurochem Res 38:2072–2083PubMedGoogle Scholar
  57. 57.
    Dinarello CA, Fossati G, Mascagni P (2011) Histone deacetylase inhibitors for treating a spectrum of diseases not related to cancer. Mol Med 17:333–352PubMedCentralPubMedGoogle Scholar
  58. 58.
    Gross O, Thomas CJ, Guarda G, Tschopp J (2011) The inflammasome: an integrated view. Immunol Rev 243:136–151PubMedGoogle Scholar
  59. 59.
    Bryant C, Fitzgerald KA (2009) Molecular mechanisms involved in inflammasome activation. Trends Cell Biol 19:455–464PubMedGoogle Scholar
  60. 60.
    Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, Hornung V, Latz E (2009) Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 183:787–791PubMedCentralPubMedGoogle Scholar
  61. 61.
    Harder J, Franchi L, Munoz-Planillo R, Park JH, Reimer T, Nunez G (2009) Activation of the Nlrp3 inflammasome by Streptococcus pyogenes requires streptolysin O and NF-kappa B activation but proceeds independently of TLR signaling and P2X7 receptor. J Immunol 183:5823–5829PubMedCentralPubMedGoogle Scholar
  62. 62.
    Segovia J, Sabbah A, Mgbemena V, Tsai SY, Chang TH, Berton MT, Morris IR, Allen IC, Ting JP, Bose S (2012) TLR2/MyD88/NF-kappaB pathway, reactive oxygen species, potassium efflux activates NLRP3/ASC inflammasome during respiratory syncytial virus infection. PLoS ONE 7:e29695PubMedCentralPubMedGoogle Scholar
  63. 63.
    Latz E, Xiao TS, Stutz A (2013) Activation and regulation of the inflammasomes. Nat Rev Immunol 13:397–411PubMedGoogle Scholar
  64. 64.
    Kwon KJ, Kim JN, Kim MK, Kim SY, Cho KS, Jeon SJ, Kim HY, Ryu JH, Han SY, Cheong JH, Ignarro LJ, Han SH, Shin CY (2013) Neuroprotective effects of valproic acid against hemin toxicity: possible involvement of the down-regulation of heme oxygenase-1 by regulating ubiquitin-proteasomal pathway. Neurochem Int 62:240–250PubMedGoogle Scholar
  65. 65.
    Wang Z, Leng Y, Tsai LK, Leeds P, Chuang DM (2011) 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 31:52–57PubMedCentralPubMedGoogle Scholar
  66. 66.
    Park H, Poo MM (2013) Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 14:7–23PubMedGoogle Scholar
  67. 67.
    Allen SJ, Watson JJ, Shoemark DK, Barua NU, Patel NK (2013) GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol Ther 138:155–175PubMedGoogle Scholar
  68. 68.
    Hasan MR, Kim JH, Kim YJ, Kwon KJ, Shin CY, Kim HY, Han SH, Choi DH, Lee J (2013) Effect of HDAC inhibitors on neuroprotection and neurite outgrowth in primary rat cortical neurons following ischemic insult. Neurochem Res 38:1921–1934PubMedGoogle Scholar
  69. 69.
    Fukumoto T, Morinobu S, Okamoto Y, Kagaya A, Yamawaki S (2001) Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain. Psychopharmacology 158:100–106PubMedGoogle Scholar
  70. 70.
    Castro LM, Gallant M, Niles LP (2005) Novel targets for valproic acid: up-regulation of melatonin receptors and neurotrophic factors in C6 glioma cells. J Neurochem 95:1227–1236PubMedGoogle Scholar
  71. 71.
    Chen PS, Peng GS, Li G, Yang S, Wu X, Wang CC, Wilson B, Lu RB, Gean PW, Chuang DM, Hong JS (2006) Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatry 11:1116–1125PubMedGoogle Scholar
  72. 72.
    Wu X, Chen PS, Dallas S, Wilson B, Block ML, Wang CC, Kinyamu H, Lu N, Gao X, Leng Y, Chuang DM, Zhang W, Lu RB, Hong JS (2008) Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons. Int J Neuropsychopharmacol 11:1123–1134PubMedCentralPubMedGoogle Scholar
  73. 73.
    Bredy TW, Wu H, Crego C, Zellhoefer J, Sun YE, Barad M (2007) Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. Learn Mem 14:268–276PubMedCentralPubMedGoogle Scholar
  74. 74.
    Yasuda S, Liang MH, Marinova Z, Yahyavi A, Chuang DM (2009) The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons. Mol Psychiatry 14:51–59PubMedGoogle Scholar
  75. 75.
    Hunsberger JG, Fessler EB, Wang Z, Elkahloun AG, Chuang DM (2012) Post-insult valproic acid-regulated microRNAs: potential targets for cerebral ischemia. Am J Transl Res 4:316–332PubMedCentralPubMedGoogle Scholar
  76. 76.
    Kim HJ, Rowe M, Ren M, Hong JS, Chen PS, Chuang DM (2007) 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 321:892–901PubMedGoogle Scholar
  77. 77.
    Suda S, Katsura K, Kanamaru T, Saito M, Katayama Y (2013) Valproic acid attenuates ischemia-reperfusion injury in the rat brain through inhibition of oxidative stress and inflammation. Eur J Pharmacol 707:26–31PubMedGoogle Scholar
  78. 78.
    Qian YR, Lee MJ, Hwang S, Kook JH, Kim JK, Bae CS (2010) Neuroprotection by valproic Acid in mouse models of permanent and transient focal cerebral ischemia. Korean J Physiol Pharmacol 14:435–440PubMedCentralPubMedGoogle Scholar
  79. 79.
    Xuan A, Long D, Li J, Ji W, Hong L, Zhang M, Zhang W (2012) Neuroprotective effects of valproic acid following transient global ischemia in rats. Life Sci 90:463–468PubMedGoogle Scholar
  80. 80.
    Wang ZF, Tsai LK, Munasinghe J, Leng Y, Fessler EB, Chibane F, Leeds P, Chuang DM (2012) Chronic valproate treatment enhances postischemic angiogenesis and promotes functional recovery in a rat model of ischemic stroke. Stroke 43:2430PubMedCentralPubMedGoogle Scholar
  81. 81.
    Osuka S, Takano S, Watanabe S, Ishikawa E, Yamamoto T, Matsumura A (2012) Valproic acid inhibits angiogenesis in vitro and glioma angiogenesis in vivo in the brain. Neurol Med Chir (Tokyo) 52:186–193Google Scholar
  82. 82.
    Karp JM, Leng Teo GS (2009) Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell 4:206–216PubMedGoogle Scholar
  83. 83.
    Parekkadan B, Milwid JM (2010) Mesenchymal stem cells as therapeutics. In: Yarmush ML, Duncan JS, Gray ML (eds) Annual review of biomedical engineering, vol 12. Annual Reviews, Palo Alto, pp 87–117Google Scholar
  84. 84.
    Tsai LK, Leng Y, Wang Z, Leeds P, Chuang DM (2010) The mood stabilizers valproic acid and lithium enhance mesenchymal stem cell migration via distinct mechanisms. Neuropsychopharmacology 35:2225–2237PubMedCentralPubMedGoogle Scholar
  85. 85.
    Tsai LK, Wang Z, Munasinghe J, Leng Y, Leeds P, Chuang DM (2011) Mesenchymal stem cells primed with valproate and lithium robustly migrate to infarcted regions and facilitate recovery in a stroke model. Stroke 42:2932–2939PubMedCentralPubMedGoogle Scholar
  86. 86.
    Yu F, Wang Z, Tanaka M, Chiu CT, Leeds P, Zhang Y, Chuang DM (2013) Posttrauma cotreatment with lithium and valproate: reduction of lesion volume, attenuation of blood-brain barrier disruption, and improvement in motor coordination in mice with traumatic brain injury. J Neurosurg 119:766–773Google Scholar
  87. 87.
    Jin G, Duggan M, Imam A, Demoya MA, Sillesen M, Hwabejire J, Jepsen CH, Liu B, Mejaddam AY, Lu J, Smith WM, Velmahos GC, Socrate S, Alam HB (2012) Pharmacologic resuscitation for hemorrhagic shock combined with traumatic brain injury. J Trauma Acute Care Surg 73:1461–1470PubMedGoogle Scholar
  88. 88.
    Imam AM, Jin G, Duggan M, Sillesen M, Hwabejire JO, Jepsen CH, Deperalta D, Liu B, Lu J, Demoya MA, Socrate S, Alam HB (2013) Synergistic effects of fresh frozen plasma and valproic acid treatment in a combined model of traumatic brain injury and hemorrhagic shock. Surgery 154:388–396PubMedGoogle Scholar
  89. 89.
    Hwabejire JO, Jin G, Imam AM, Duggan M, Sillesen M, Deperalta D, Jepsen CH, Lu J, Li Y, Demoya MA, Alam HB (2013) Pharmacologic modulation of cerebral metabolic derangement and excitotoxicity in a porcine model of traumatic brain injury and hemorrhagic shock. Surgery 154:234–243PubMedGoogle Scholar
  90. 90.
    Abdanipour A, Schluesener HJ, Tiraihi T (2012) Effects of valproic acid, a histone deacetylase inhibitor, on improvement of locomotor function in rat spinal cord injury based on epigenetic science. Iran Biomed J 16:90–100PubMedCentralPubMedGoogle Scholar
  91. 91.
    Hao HH, Wang L, Guo ZJ, Bai L, Zhang RP, Shuang WB, Jia YJ, Wang J, Li XY, Liu Q (2013) Valproic acid reduces autophagy and promotes functional recovery after spinal cord injury in rats. Neurosci Bull 29:484–492PubMedGoogle Scholar
  92. 92.
    Lee JY, Kim HS, Choi HY, Oh TH, Ju BG, Yune TY (2012) Valproic acid attenuates blood-spinal cord barrier disruption by inhibiting matrix metalloprotease-9 activity and improves functional recovery after spinal cord injury. J Neurochem 121:818–829PubMedGoogle Scholar
  93. 93.
    Lv L, Han X, Sun Y, Wang X, Dong Q (2012) Valproic acid improves locomotion in vivo after SCI and axonal growth of neurons in vitro. Exp Neurol 233:783–790PubMedGoogle Scholar
  94. 94.
    Biermann J, Grieshaber P, Goebel U, Martin G, Thanos S, Di Giovanni S, Lagreze WA (2010) Valproic acid-mediated neuroprotection and regeneration in injured retinal ganglion cells. Invest Ophthalmol Vis Sci 51:526–534PubMedGoogle Scholar
  95. 95.
    Zhang Z, Tong N, Gong Y, Qiu Q, Yin L, Lv X, Wu X (2011) Valproate protects the retina from endoplasmic reticulum stress-induced apoptosis after ischemia-reperfusion injury. Neurosci Lett 504:88–92PubMedGoogle Scholar
  96. 96.
    Zhang Z, Qin X, Tong N, Zhao X, Gong Y, Shi Y, Wu X (2012) Valproic acid-mediated neuroprotection in retinal ischemia injury via histone deacetylase inhibition and transcriptional activation. Exp Eye Res 94:98–108PubMedGoogle Scholar
  97. 97.
    Symington GR, Leonard DP, Shannon PJ, Vajda FJ (1978) Sodium valproate in Huntington’s disease. Am J Psychiatry 135:352–354PubMedGoogle Scholar
  98. 98.
    Piepers S, Veldink JH, de Jong SW, van der Tweel I, van der Pol WL, Uijtendaal EV, Schelhaas HJ, Scheffer H, de Visser M, de Jong JM, Wokke JH, Groeneveld GJ, van den Berg LH (2009) Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis. Ann Neurol 66:227–234PubMedGoogle Scholar
  99. 99.
    Chiu CT, Wang Z, Hunsberger JG, Chuang DM (2013) Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder. Pharmacol Rev 65:105–142PubMedCentralPubMedGoogle Scholar
  100. 100.
    Koenig S, Gerstner T, Keller A, Teich M, Longin E, Dempfle CE (2008) High incidence of vaproate-induced coagulation disorders in children receiving valproic acid: a prospective study. Blood Coagul Fibrinolysis 19:375–382PubMedGoogle Scholar
  101. 101.
    Kreuz W, Linde R, Funk M, Meyer-Schrod R, Foll E, Nowak-Gottl U, Jacobi G, Vigh Z, Scharrer I (1990) Induction of von Willebrand disease type I by valproic acid. Lancet 335:1350–1351PubMedGoogle Scholar
  102. 102.
    Pohlmann-Eden B, Peters CN, Wennberg R, Dempfle CE (2003) Valproate induces reversible factor XIII deficiency with risk of perioperative bleeding. Acta Neurol Scand 108:142–145PubMedGoogle Scholar
  103. 103.
    Cannizzaro E, Albisetti M, Wohlrab G, Schmugge M (2007) Severe bleeding complications during antiepileptic treatment with valproic acid in children. Neuropediatrics 38:42–45PubMedGoogle Scholar
  104. 104.
    Frey LC (2003) Epidemiology of posttraumatic epilepsy: a critical review. Epilepsia 44(Suppl 10):11–17PubMedGoogle Scholar
  105. 105.
    Hamer HM (2009) Seizures and epilepsies after stroke. Nervenarzt 80:405–414PubMedGoogle Scholar
  106. 106.
    Leng Y, Liang MH, Ren M, Marinova Z, Leeds P, Chuang DM (2008) Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons: roles of glycogen synthase kinase-3 inhibition. J Neurosci 28:2576–2588PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Sheng Chen
    • 1
  • Haijian Wu
    • 1
  • Damon Klebe
    • 2
  • Yuan Hong
    • 1
  • Jianmin Zhang
    • 1
  1. 1.Department of Neurosurgery, Second Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
  2. 2.Departments of Physiology and PharmacologyLoma Linda UniversityLoma LindaUSA

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