Journal of Molecular Neuroscience

, Volume 49, Issue 1, pp 172–181 | Cite as

Protective Effect of Carbamazepine on Kainic Acid-induced Neuronal Cell Death Through Activation of Signal Transducer and Activator of Transcription-3

  • Hae Jeong Park
  • Su Kang Kim
  • Joo-Ho Chung
  • Jong Woo Kim


Studies have shown that the protective effect of carbamazepine (CBZ) on seizure-induced neuronal injury. However, its precise mechanisms remain unknown. Here, to investigate the neuroprotective mechanism of CBZ against seizure-induced neuronal cell death, we identified the change of gene expressions by CBZ in the hippocampus of kainic acid (KA)-treated mice using microarray method, and studied the involvement of candidate gene in neuroprotective action of CBZ. KA (15 mg/kg) and/or CBZ (30 mg/kg, 0.5 h after KA exposure) were injected intraperitoneally into mice. Through microarray analysis, we found that signal transducer and activator of transcription-3 (Stat3) gene expression was upregulated in the hippocampal CA3 region, 24 h after KA injection (15 mg/kg), and that CBZ further elevated Stat3 expression in KA-treated mice. KA also increased the protein level and phosphorylation of Stat3, and CBZ further increased the Stat3 phosphorylation, without changing Stat3 protein level in KA-treated mice. In particular, phospho-Stat3 immunoreactivity (IR) by KA was shown in astrocytes rather than in neurons; whereas phospho-Stat3 IR by CBZ in KA-treated mice was observed predominantly in neurons, and also in neuroprotective protein Bcl-xL-expression cells. These results indicate that Stat3 may play an important role in neuroprotective action of CBZ on seizure-induced neuronal injury.


Carbamazepine Kainic acid Seizure Signal transducer and activator of transcription-3 Neuroprotection 

Supplementary material

12031_2012_9854_MOESM1_ESM.doc (97 kb)
ESM 1(DOC 97 kb)
12031_2012_9854_MOESM2_ESM.doc (310 kb)
ESM 2(DOC 310 kb)


  1. Almgren M, Nyengaard JR, Persson B, Lavebratt C (2008) Carbamazepine protects against neuronal hyperplasia and abnormal gene expression in the megencephaly mouse. Neurobiol Dis 32:364–376PubMedCrossRefGoogle Scholar
  2. Bambrick L, Kristian T, Fiskum G (2004) Astrocyte mitochondrial mechanisms of ischemic brain injury and neuroprotection. Neurochem Res 29:601–608PubMedCrossRefGoogle Scholar
  3. Benoit ME, Tenner AJ (2011) Complement protein C1q-mediated neuroprotection is correlated with regulation of neuronal gene and miRNA expression. J Neurosci 31:3459–3269PubMedCrossRefGoogle Scholar
  4. Bernier M, Paul RK, Martin-Montalvo A et al (2011) Negative regulation of STAT3 protein-mediated cellular respiration by SIRT1 protein. J Biol Chem 286:19270–19279PubMedCrossRefGoogle Scholar
  5. Bolte S, Cordelières FP (2006) A guided tour into subcellular colocalization analysis in light microscopy. J Microsc 224:213–232PubMedCrossRefGoogle Scholar
  6. Chang YC, Rapoport SI, Rao JS (2009) Chronic administration of mood stabilizers upregulates BDNF and bcl-2 expression levels in rat frontal cortex. Neurochem Res 34:536–541PubMedCrossRefGoogle Scholar
  7. Choi JS, Kim SY, Cha JH et al (2003) Upregulation of gp130 and STAT3 activation in the rat hippocampus following transient forebrain ischemia. Glia 41:237–246PubMedCrossRefGoogle Scholar
  8. Costa C, Belcastro V, Tozzi A et al (2008) Electrophysiology and pharmacology of striatal neuronal dysfunction induced by mitochondrial complex I inhibition. J Neurosci 28:8040–8052PubMedCrossRefGoogle Scholar
  9. Coyle JT (1987) Kainic acid: insights into excitatory mechanisms causing selective neuronal degeneration. Ciba Found Symp 126:186–203PubMedGoogle Scholar
  10. Dziennis S, Alkayed NJ (2008) Role of signal transducer and activator of transcription 3 in neuronal survival and regeneration. Rev Neurosci 19:341–361PubMedGoogle Scholar
  11. Dziennis S, Jia T, Rønnekleiv OK, Hum PD, Alkayed NJ (2007) Role of signal transducer and activator of transcription-3 in estradiol-mediated neuroprotection. J Neurosci 27:7268–7274PubMedCrossRefGoogle Scholar
  12. Farkas I, Takahashi M, Fukuda A et al (2003) Complement C5a receptor-mediated signaling may be involved in neurodegeneration in Alzheimer's disease. J Immunol 170:5764–5771PubMedGoogle Scholar
  13. Fearnley IM, Carroll J, Shannon RJ, Runswick MJ, Walker JE, Hirst J (2001) GRIM-19, a cell death regulatory gene product, is a subunit of bovine mitochondrial NADH:ubiquinone oxidoreductase (complex I). J Biol Chem 276:38345–38348PubMedCrossRefGoogle Scholar
  14. Gardner J, Ghorpade A (2003) Tissue inhibitor of metalloproteinase (TIMP)-1: the TIMPed balance of matrix metalloproteinases in the central nervous system. J Neurosci Res 74:801–806PubMedCrossRefGoogle Scholar
  15. Gouder N, Fritschy JM, Boison D (2003) Seizure suppression by adenosine A1 receptor activation in a mouse model of pharmacoresistant epilepsy. Epilepsia 44:877–885PubMedCrossRefGoogle Scholar
  16. Grabenstatter HL, Clark S, Dudet FE (2007) Anticonvulsant effects of carbamazepine on spontaneous seizures in rats with kainate-induced epilepsy: comparison of intraperitoneal injections with drug-in-food protocols. Epilepsia 48:2287–2295PubMedGoogle Scholar
  17. Grad JM, Zeng XR, Boise LH (2000) Regulation of Bcl-xL: a little bit of this and a little bit of STAT. Curr Opin Oncol 12:543–549PubMedCrossRefGoogle Scholar
  18. Greenamyre JT, Sherer TB, Betarbet R, Panov AV (2001) Complex I and Parkinson's disease. I U B M B Life 52:135–141Google Scholar
  19. Hattori R, Maulik N, Otani H et al (2001) Role of STAT3 in ischemic preconditioning. J Mol Cell Cardiol 33:1929–1936PubMedCrossRefGoogle Scholar
  20. Jaworski DM (2000) Differential regulation of tissue inhibitor of metalloproteinase mRNA expression in response to intracranial injury. Glia 30:199–208PubMedCrossRefGoogle Scholar
  21. Kalakonda S, Nallar SC, Lindner DJ, Hu J, Reddy SP, Kalvakolanu DV (2007) Tumor-suppressive activity of the cell death activator GRIM-19 on a constitutively active signal transducer and activator of transcription 3. Cancer Res 67:6212–6220PubMedCrossRefGoogle Scholar
  22. Kitano Y, Komiyama C, Makino M et al (2005) Anticonvulsant and neuroprotective effects of the novel nootropic agent nefiracetam on kainic acid-induced seizures in rats. Brain Res 1057:168–176PubMedCrossRefGoogle Scholar
  23. Kovacs GG, Gasque P, Ströbel T et al (2004) Complement activation in human prion disease. Neurobiol Dis 15:21–28PubMedCrossRefGoogle Scholar
  24. Levy DE, Darnell JE Jr (2002) Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3:651–662PubMedCrossRefGoogle Scholar
  25. Li Q, Zhang R, Guo YL, Mei YW (2009) Effect of neuregulin on apoptosis and expressions of STAT3 and GFAP in rats following cerebral ischemic reperfusion. J Mol Neurosci 37:67–73PubMedCrossRefGoogle Scholar
  26. Löscher W (1998) Pharmacology of glutamate receptor antagonists in the kindling model of epilepsy. Prog Neurobiol 54:721–741PubMedCrossRefGoogle Scholar
  27. Lund IV, Hu Y, Raol YH et al (2008) BDNF selectively regulates GABAA receptor transcription by activation of the JAK/STAT pathway. Sci Signal 1:1–14CrossRefGoogle Scholar
  28. MacDonald RL, Kelly KM (1993) Antiepileptic drug mechanisms of action. Epilepsia 34:S1–S8PubMedCrossRefGoogle Scholar
  29. Merry DE, Korsmeyer SJ (1997) Bcl-2 gene family in the nervous system. Annu Rev Neurosci 20:245–267PubMedCrossRefGoogle Scholar
  30. Minato H, Kikuta C, Fujitani B, Masuda Y (1997) Protective effect of zonisamide, an antiepileptic drug, against transient focal cerebral ischemia with middle cerebral artery occlusion-reperfusion in rats. Epilepsia 38:975–980PubMedCrossRefGoogle Scholar
  31. Morrison RS, Wenzel HJ, Kinoshita Y, Robbins CA, Donehower LA, Schwartzkroin PA (1996) Loss of the p53 tumor suppressor gene protects neurons from kainate-induced cell death. J Neurosci 16:1337–1345PubMedGoogle Scholar
  32. Nadler JV (1981) Minireview. Kainic acid as a tool for the study of temporal lobe epilepsy. Life Sci 29:2031–2042PubMedCrossRefGoogle Scholar
  33. Natale JE, Ahmed F, Cernak I, Stoica B, Faden AI (2003) Gene expression profile changes are commonly modulated across models and species after traumatic brain injury. J Neurotrauma 20:907–927PubMedCrossRefGoogle Scholar
  34. Nedergaard M, Dirnagl U (2005) Role of glial cells in cerebral ischemia. Glia 50:281–286PubMedCrossRefGoogle Scholar
  35. Ng YP, Cheung ZH, Ip NY (2006) STAT3 as a downstream mediator of Trk signaling and functions. J Biol Chem 281:15636–15644PubMedCrossRefGoogle Scholar
  36. Noh HS, Kim YS, Kim YH et al (2006) Ketogenic diet protects the hippocampus from kainic acid toxicity by inhibiting the dissociation of bad from 14-3-3. J Neurosci Res 84:1829–1836PubMedCrossRefGoogle Scholar
  37. Olayioye MA, Beuvink I, Horsch K, Daly JM, Hynes NE (1999) ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases. J Biol Chem 274:17209–17218PubMedCrossRefGoogle Scholar
  38. Parsadanian AS, Cheng Y, Keller-Peck CR, Holtzman DM, Snider WD (1998) Bcl-xL is an antiapoptotic regulator for postnatal CNS neurons. J Neurosci 18:1009–1019PubMedGoogle Scholar
  39. Pisalyaput K, Tenner AJ (2008) Complement component C1q inhibits beta-amyloid- and serum amyloid Pinduced neurotoxicity via caspase- and calpain-independent mechanisms. J Neurochem 104:696–707PubMedGoogle Scholar
  40. Schirrmacher K, Mayer A, Walden J, Düsing R, Bingmann D (1993) Effects of carbamazepine on action potentials and calcium currents in rat spinal ganglion cells in vitro. Neuropsychobiology 27:176–179PubMedCrossRefGoogle Scholar
  41. Shulga N and Pastorino JG (2012) GRIM-19 Mediated Translocation of STAT3 to Mitochondria is Necessary for TNF Induced Necroptosis. J. Cell Sci. doi:10.1242/jcs.103093
  42. Sperk G (1994) Kainic acid seizures in the rat. Prog Neurobiol 42:1–32PubMedCrossRefGoogle Scholar
  43. Stephanou A, Brar BK, Knight RA, Latchman DS (2000) Opposing actions of STAT-1 and STAT-3 on the Bcl-2 and Bcl-x promoters. Cell Death Differ 7:329–330PubMedCrossRefGoogle Scholar
  44. Stevens B, Allen NJ, Vazquez LE et al (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–1178PubMedCrossRefGoogle Scholar
  45. Suzuki S, Tanaka K, Nogawa S, Dembo T, Kosakai A, Fukuuchi Y (2001) Phosphorylation of signal transducer and activator of transcription-3 (Stat3) after focal cerebral ischemia in rats. Exp Neurol 170:63–71PubMedCrossRefGoogle Scholar
  46. Tejima E, Guo S, Murata Y et al (2009) Neuroprotective effects of overexpressing tissue inhibitor of metalloproteinase TIMP-1. J Neurotrauma 26:1935–1941PubMedCrossRefGoogle Scholar
  47. Thomas MA, Joshi PP, Klaper RD (2012) Gene-class analysis of expression patterns induced by psychoactive pharmaceutical exposure in fathead minnow (Pimephales promelas) indicates induction of neuronal systems. Comp Biochem Physiol C Toxicol Pharmacol 155:109–120PubMedCrossRefGoogle Scholar
  48. Vignais ML, Sadowski HB, Watling D, Rogers NC, Gilman M (1996) Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins. Mol Cell Biol 16:1759–1769PubMedGoogle Scholar
  49. Wang L, Zuo CH, Zhao DY, Wu XR (2000) Brain distribution and efficacy of carbamazepine in kainic acid induced seizure in rats. Brain Dev 22:154–157PubMedCrossRefGoogle Scholar
  50. Wang T, Yan XB, Zhao JJ et al (2011) Gene associated with retinoid-interferon-induced mortality-19 suppresses growth of lung adenocarcinoma tumor in vitro and in vivo. Lung Cancer 72:287–293PubMedCrossRefGoogle Scholar
  51. Xuan YT, Guo Y, Han H, Zhu Y, Bolli R (2001) An essential role of the JAK-STAT pathway in ischemic preconditioning. Proc Natl Acad Sci USA 98:9050–9055PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Hae Jeong Park
    • 1
  • Su Kang Kim
    • 1
  • Joo-Ho Chung
    • 1
  • Jong Woo Kim
    • 2
  1. 1.Kohwang Medical Research Institute, School of MedicineKyung Hee UniversitySeoulRepublic of Korea
  2. 2.Department of Neuropsychiatry, School of MedicineKyung Hee UniversitySeoulRepublic of Korea

Personalised recommendations