Skip to main content
SpringerLink
Log in

Effect of Rufinamide on the kainic acid-induced excitotoxic neuronal death in the mouse hippocampus

  • Research Article
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Rufinamide (RUF) is a structurally unique anti-epileptic drug, used in the treatment of seizure disorders such as Lennox-Gastaut syndrome. In the present study, we investigated whether RUF protected against excitotoxic neuronal damage in the mouse hippocampal CA3 region after intraperitoneal kainic acid (KA) injection. Treatment with 25, 50 and 100 mg/kg RUF significantly decreased the KA-induced neuronal death in the hippocampal CA3 region in a dose-dependent manner. In addition, 100 mg/kg RUF treatment reduced the KA-induced oxidative stress-related increase of MDA level and decrease of total SOD activity in the hippocampus. KA-induced increases of pro-inflammatory cytokines, TNF-α and IL-1β, levels as well as KA-induced microglial activation were also suppressed by RUF treatment. These results indicate that RUF displays a neuroprotective effect against KA-induced excitotoxic neuronal death in the mouse hippocampus through anti-oxidant and anti-inflammatory activities.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Allan SM, Tyrrell PJ, Rothwell NJ (2005) Interleukin-1 and neuronal injury. Nat Rev Immunol 5:629–640

    Article  PubMed  CAS  Google Scholar 

  • Bahn S, Volk B, Wisden W (1994) Kainate receptor gene expression in the developing rat brain. J Neurosci 14:5525–5547

    Article  PubMed  CAS  Google Scholar 

  • Ben-Ari Y, Cossart R (2000) Kainate, a double agent that generates seizures: two decades of progress. Trends Neurosci 23:580–587

    Article  PubMed  CAS  Google Scholar 

  • Cho IH, Hong J, Suh EC, Kim JH, Lee H, Lee JE, Lee S, Kim CH, Kim DW, Jo EK, Lee KE, Karin M, Lee SJ (2008) Role of microglial IKKbeta in kainic acid-induced hippocampal neuronal cell death. Brain 131:3019–3033

    Article  PubMed  PubMed Central  Google Scholar 

  • Choi HS, Park JH, Ahn JH, Hong S, Cho JH, Won MH, Lee CH (2015) The anti-inflammatory activity of duloxetine, a serotonin/norepinephrine reuptake inhibitor, prevents kainic acid-induced hippocampal neuronal death in mice. J Neurol Sci 358:390–397

    Article  PubMed  CAS  Google Scholar 

  • Das A, Mcdowell M, O’dell CM, Busch ME, Smith JA, Ray SK, Banik NL (2010) Post-treatment with voltage-gated Na(+) channel blocker attenuates kainic acid-induced apoptosis in rat primary hippocampal neurons. Neurochem Res 35:2175–2183

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gall Z, Orban-Kis K, Szilagyi T (2017) Differential effects of sodium channel blockers on in vitro induced epileptiform activities. Arch Pharm Res 40:112–121

    Article  PubMed  CAS  Google Scholar 

  • Gilchrist J, Dutton S, Diaz-Bustamante M, Mcpherson A, Olivares N, Kalia J, Escayg A, Bosmans F (2014) Nav1.1 modulation by a novel triazole compound attenuates epileptic seizures in rodents. ACS Chem Biol 9:1204–1212

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gluck MR, Jayatilleke E, Shaw S, Rowan AJ, Haroutunian V (2000) CNS oxidative stress associated with the kainic acid rodent model of experimental epilepsy. Epilepsy Res 39:63–71

    Article  PubMed  CAS  Google Scholar 

  • Hakimian S, Cheng-Hakimian A, Anderson GD, Miller JW (2007) Rufinamide: a new anti-epileptic medication. Expert Opin Pharmacother 8:1931–1940

    Article  PubMed  CAS  Google Scholar 

  • Han JY, Ahn SY, Kim CS, Yoo SK, Kim SK, Kim HC, Hong JT, Oh KW (2012) Protection of apigenin against kainate-induced excitotoxicity by anti-oxidative effects. Biol Pharm Bull 35:1440–1446

    Article  PubMed  CAS  Google Scholar 

  • Jin Y, Lim CM, Kim SW, Park JY, Seo JS, Han PL, Yoon SH, Lee JK (2009) Fluoxetine attenuates kainic acid-induced neuronal cell death in the mouse hippocampus. Brain Res 1281:108–116

    Article  PubMed  CAS  Google Scholar 

  • Kim DH, Yoon BH, Jung WY, Kim JM, Park SJ, Park DH, Huh Y, Park C, Cheong JH, Lee KT, Shin CY, Ryu JH (2010) Sinapic acid attenuates kainic acid-induced hippocampal neuronal damage in mice. Neuropharmacology 59:20–30

    Article  PubMed  CAS  Google Scholar 

  • Kitano Y, Komiyama C, Makino M, Takasuna K, Satoh H, Aoki T, Kinoshita M, Takazawa A, Yamauchi T, Sakurada S (2005) Anticonvulsant and neuroprotective effects of the novel nootropic agent nefiracetam on kainic acid-induced seizures in rats. Brain Res 1057:168–176

    Article  PubMed  CAS  Google Scholar 

  • Lee J, Lim E, Kim Y, Li E, Park S (2010) Ghrelin attenuates kainic acid-induced neuronal cell death in the mouse hippocampus. J Endocrinol 205:263–270

    Article  PubMed  CAS  Google Scholar 

  • Li SY, Jia YH, Sun WG, Tang Y, An GS, Ni JH, Jia HT (2010) Stabilization of mitochondrial function by tetramethylpyrazine protects against kainate-induced oxidative lesions in the rat hippocampus. Free Radic Biol Med 48:597–608

    Article  PubMed  CAS  Google Scholar 

  • Malva JO, Carvalho AP, Carvalho CM (1998) Kainate receptors in hippocampal CA3 subregion: evidence for a role in regulating neurotransmitter release. Neurochem Int 32:1–6

    Article  PubMed  CAS  Google Scholar 

  • Mantegazza M, Curia G, Biagini G, Ragsdale DS, Avoli M (2010) Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurol 9:413–424

    Article  PubMed  CAS  Google Scholar 

  • Park HJ, Kim HJ, Park HJ, Ra J, Zheng LT, Yim SV, Chung JH (2008) Protective effect of topiramate on kainic acid-induced cell death in mice hippocampus. Epilepsia 49:163–167

    Article  PubMed  CAS  Google Scholar 

  • Park HJ, Kim SK, Chung JH, Kim JW (2013) Protective effect of carbamazepine on kainic acid-induced neuronal cell death through activation of signal transducer and activator of transcription-3. J Mol Neurosci 49:172–181

    Article  PubMed  CAS  Google Scholar 

  • Park SH, Sim YB, Lee JK, Lee JY, Suh HW (2016) Characterization of temporal expressions of FOXO and pFOXO proteins in the hippocampus by kainic acid in mice: involvement of NMDA and non-NMDA receptors. Arch Pharm Res 39:660–667

    Article  PubMed  CAS  Google Scholar 

  • Scharfman HE (2007) The neurobiology of epilepsy. Curr Neurol Neurosci Rep 7:348–354

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Si PP, Zhen JL, Cai YL, Wang WJ, Wang WP (2016) Salidroside protects against kainic acid-induced status epilepticus via oxidative stress. Neurosci Lett 618:19–24

    Article  PubMed  CAS  Google Scholar 

  • Somera-Molina KC, Robin B, Somera CA, Anderson C, Stine C, Koh S, Behanna HA, Van Eldik LJ, Watterson DM, Wainwright MS (2007) Glial activation links early-life seizures and long-term neurologic dysfunction: evidence using a small molecule inhibitor of proinflammatory cytokine upregulation. Epilepsia 48:1785–1800

    Article  PubMed  CAS  Google Scholar 

  • Tak E, Park GC, Kim SH, Jun DY, Lee J, Hwang S, Song GW, Lee SG (2016) Epigallocatechin-3-gallate protects against hepatic ischaemia-reperfusion injury by reducing oxidative stress and apoptotic cell death. J Int Med Res 44:1248–1262

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tan DX, Manchester LC, Reiter RJ, Qi W, Kim SJ, El-Sokkary GH (1998) Melatonin protects hippocampal neurons in vivo against kainic acid-induced damage in mice. J Neurosci Res 54:382–389

    Article  PubMed  CAS  Google Scholar 

  • Taniwaki Y, Kato M, Araki T, Kobayashi T (1996) Microglial activation by epileptic activities through the propagation pathway of kainic acid-induced hippocampal seizures in the rat. Neurosci Lett 217:29–32

    Article  PubMed  CAS  Google Scholar 

  • Wang Q, Yu S, Simonyi A, Rottinghaus G, Sun GY, Sun AY (2004) Resveratrol protects against neurotoxicity induced by kainic acid. Neurochem Res 29:2105–2112

    Article  PubMed  CAS  Google Scholar 

  • Wang Q, Yu S, Simonyi A, Sun GY, Sun AY (2005) Kainic acid-mediated excitotoxicity as a model for neurodegeneration. Mol Neurobiol 31:3–16

    Article  PubMed  CAS  Google Scholar 

  • Wang B, Dawson H, Wang H, Kernagis D, Kolls BJ, Yao L, Laskowitz DT (2013) Lacosamide improves outcome in a murine model of traumatic brain injury. Neurocrit Care 19:125–134

    Article  PubMed  CAS  Google Scholar 

  • Wang CH, Hsiao CJ, Lin YN, Wu JW, Kuo YC, Lee CK, Hsiao G (2014) Carbamazepine attenuates inducible nitric oxide synthase expression through Akt inhibition in activated microglial cells. Pharm Biol 52:1451–1459

    Article  PubMed  CAS  Google Scholar 

  • White HS, Franklin MR, Kupferberg HJ, Schmutz M, Stables JP, Wolf HH (2008) The anticonvulsant profile of rufinamide (CGP 33101) in rodent seizure models. Epilepsia 49:1213–1220

    Article  PubMed  CAS  Google Scholar 

  • Xie C, Sun J, Qiao W, Lu D, Wei L, Na M, Song Y, Hou X, Lin Z (2011) Administration of simvastatin after kainic acid-induced status epilepticus restrains chronic temporal lobe epilepsy. PLoS ONE 6:e24966

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zheng H, Zhu W, Zhao H, Wang X, Wang W, Li Z (2010) Kainic acid-activated microglia mediate increased excitability of rat hippocampal neurons in vitro and in vivo: crucial role of interleukin-1beta. NeuroImmunoModulation 17:31–38

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education (NRF-2017R1D1A1B03029311).

Author information

Authors and Affiliations

  1. Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, 31116, Republic of Korea

    Jin-A Park & Choong-Hyun Lee

Authors
  1. Jin-A Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Choong-Hyun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Choong-Hyun Lee.

Ethics declarations

Conflict of interest

The authors have declared that there is no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Park, JA., Lee, CH. Effect of Rufinamide on the kainic acid-induced excitotoxic neuronal death in the mouse hippocampus. Arch. Pharm. Res. 41, 776–783 (2018). https://doi.org/10.1007/s12272-018-1043-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-018-1043-1

Keywords

Search

Navigation