Skip to main content
SpringerLink
Log in

Effect of minocycline on pentylenetetrazol-induced chemical kindled seizures in mice

  • Original Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Inflammation is one of the mechanisms involved in seizure induction. In this study, the effect of minocycline, an anti-inflammatory drug, was investigated on kindling acquisition. Chemical kindling was induced by injection of a subthreshold dose of pentylenetetrazol (PTZ; 37.5 mg/kg) in mice on every other day. Two groups of animals received minocycline (25 mg/kg) at 1 h before or 1 h after PTZ injection. Following the last PTZ injection, the changes in gene expression of TNF-α receptor, γ2 subunit of GABAA receptor and NR2A subunit of NMDA receptor were assessed in the hippocampus and piriform cortex. Injection of minocycline before PTZ increased the latency to stage 4 seizure, and decreased the duration of stages 4 and 5 seizure. It also prevented the increase in the mRNA of NR2A subunit of NMDA receptor in the hippocampus and removed the PTZ-induced increase in mRNA of γ2 subunit of GABAA receptor in piriform cortex of PTZ kindled mice. Minocycline also prevented the increase in TNF-α receptor gene expression in both hippocampus and piriform cortex. Injection of minocycline after PTZ had no significant effect on measured parameters. Therefore, it can be concluded that minocycline may exert an anticonvulsant effect through preventing the increase in GABAA and NMDA receptor subunits. These effects are accompanied by a reduction in an important inflammation index, TNF-α receptor.

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

Access this article

Log in via an institution

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

Similar content being viewed by others

References

  1. Kwan P, Brodie MJ (2006) Combination therapy in epilepsy: when and what to use. Drugs 66:1817–1829

    Article  CAS  PubMed  Google Scholar 

  2. Vezzani A (2005) Inflammation and epilepsy. Epilepsy Curr 5:1–6

    Article  PubMed Central  PubMed  Google Scholar 

  3. Lucas SM, Rothwell NJ, Gibson RM (2006) The role of inflammation in CNS injury and disease. Br J Pharmacol 147(Suppl 1):S232–S240

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Vezzani A, Granata T (2005) Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia 46:1724–1743

    Article  CAS  PubMed  Google Scholar 

  5. Pitkanen A, Sutula TP (2002) Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy. Lancet Neurol 1:173–181

    Article  PubMed  Google Scholar 

  6. Meli DN, Loeffler JM, Baumann P, Neumann U, Buhl T, Leppert D, Leib SL (2004) In pneumococcal meningitis a novel water-soluble inhibitor of matrix metalloproteinases and TNF-alpha converting enzyme attenuates seizures and injury of the cerebral cortex. J Neuroimmunol 151:6–11

    Article  CAS  PubMed  Google Scholar 

  7. Balosso S, Ravizza T, Perego C, Peschon J, Campbell IL, De Simoni MG, Vezzani A (2005) Tumor necrosis factor-alpha inhibits seizures in mice via p75 receptors. Ann Neurol 57:804–812

    Article  CAS  PubMed  Google Scholar 

  8. Stirling DP, Koochesfahani KM, Steeves JD, Tetzlaff W (2005) Minocycline as a neuroprotective agent. Neuroscientist 11:308–322

    Article  CAS  PubMed  Google Scholar 

  9. Lee SM, Yune TY, Kim SJ, Park DW, Lee YK, Kim YC, Oh YJ, Markelonis GJ, Oh TH (2003) Minocycline reduces cell death and improves functional recovery after traumatic spinal cord injury in the rat. J Neurotrauma 20:1017–1027

    Article  PubMed  Google Scholar 

  10. Gonzalez JC, Egea J, Del Carmen Godino M, Fernandez-Gomez FJ, Sanchez-Prieto J, Gandia L, Garcia AG, Jordan J, Hernandez-Guijo JM (2007) Neuroprotectant minocycline depresses glutamatergic neurotransmission and Ca(2 +) signalling in hippocampal neurons. Eur J Neurosci 26:2481–2495

    Article  PubMed  Google Scholar 

  11. Abraham J, Fox PD, Condello C, Bartolini A, Koh S (2012) Minocycline attenuates microglia activation and blocks the long-term epileptogenic effects of early-life seizures. Neurobiol Dis 46:425–430

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Nowak M, Strzelczyk A, Reif PS, Schorlemmer K, Bauer S, Norwood BA, Oertel WH, Rosenow F, Strik H, Hamer HM (2012) Minocycline as potent anticonvulsant in a patient with astrocytoma and drug resistant epilepsy. Seizure 21:227–228

    Article  CAS  PubMed  Google Scholar 

  13. Wang DD, Englot DJ, Garcia PA, Lawton MT, Young WL (2012) Minocycline- and tetracycline-class antibiotics are protective against partial seizures in vivo. Epilepsy Behav 24:314–318

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Lason W, Turchan J, Przewlocka B, Labuz D, Machelska H, Przewlocki R (1998) Effects of pentylenetetrazol kindling on glutamate receptor genes expression in the rat hippocampus. Brain Res 785:355–358

    Article  CAS  PubMed  Google Scholar 

  15. Lukomskaya NY, Lavrent’eva VV, Starshinova LA, Zhabko EP, Gorbunova LV, Tikhonova TB, Gmiro VE, Magazanik LG (2007) Effects of ionotropic glutamate receptor channel blockers on the development of pentylenetetrazol kindling in mice. Neurosci Behav Physiol 37:75–81

    Article  CAS  PubMed  Google Scholar 

  16. Ghasemi M, Schachter SC (2011) The NMDA receptor complex as a therapeutic target in epilepsy: a review. Epilepsy Behav 22:617–640

    Article  PubMed  Google Scholar 

  17. Treiman DM (2001) GABAergic mechanisms in epilepsy. Epilepsia 42(Suppl 3):8–12

    Article  PubMed  Google Scholar 

  18. Cremer CM, Palomero-Gallagher N, Bidmon HJ, Schleicher A, Speckmann EJ, Zilles K (2009) pentylenetetrazol-induced seizures affect binding site densities for GABA, glutamate and adenosine receptors in the rat brain. Neuroscience 163:490–499

    Article  CAS  PubMed  Google Scholar 

  19. Grecksch G, Ruethrich H, Bernstein HG, Becker A (1995) PTZ-kindling after colchicine lesion in the dentate gyrus of the rat hippocampus. Physiol Behav 58:695–698

    Article  CAS  PubMed  Google Scholar 

  20. Vezzani A, Friedman A (2011) Brain inflammation as a biomarker in epilepsy. Biomark Med 5:607–614

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Vezzani A, Friedman A, Dingledine RJ (2013) The role of inflammation in epileptogenesis. Neuropharmacol 69:16–24

    Google Scholar 

  22. Vezzani A, Aronica E, Mazarati A, Pittman QJ (2013) Epilepsy and brain inflammation. Exp Neurol 244:11–21

    Google Scholar 

  23. Walsh LA, Li M, Zhao TJ, Chiu TH, Rosenberg HC (1999) Acute pentylenetetrazol injection reduces rat GABAA receptor mRNA levels and GABA stimulation of benzodiazepine binding with no effect on benzodiazepine binding site density. J Pharmacol Exp Ther 289:1626–1633

    CAS  PubMed  Google Scholar 

  24. Plata-Salaman CR, Ilyin SE, Turrin NP, Gayle D, Flynn MC, Romanovitch AE, Kelly ME, Bureau Y, Anisman H, McIntyre DC (2000) Kindling modulates the IL-1beta system, TNF-alpha, TGF-beta1, and neuropeptide mRNAs in specific brain regions. Brain Res Mol Brain Res 75:248–258

    Article  CAS  PubMed  Google Scholar 

  25. Zhang XM, Zhu J (2011) Kainic Acid-induced neurotoxicity: targeting glial responses and glia-derived cytokines. Curr Neuropharmacol 9:388–398

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Al-Shorbagy MY, El Sayeh BM, Abdallah DM (2012) Diverse effects of variant doses of dexamethasone in lithium-pilocarpine induced seizures in rats. Can J Physiol Pharmacol 90:13–21

    Article  CAS  PubMed  Google Scholar 

  27. Franke H, Kittner H (2001) Morphological alterations of neurons and astrocytes and changes in emotional behavior in pentylenetetrazol-kindled rats. Pharmacol Biochem Behav 70:291–303

    Article  CAS  PubMed  Google Scholar 

  28. Becker A, Braun H, Schröder H, Grecksch G, Höllt V (1999) Effects of enadoline on the development of pentylenetetrazol kindling, learning performance, and hippocampal morphology. Brain Res 823:191–197

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from Vice Chancellor for Research Affairs of Tarbiat Modares University, Tehran, Iran.

Conflict of interest

The authors declare that there is no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, P.O. Box 14115-331, Tehran, Islamic Republic of Iran

    Nooshin Ahmadirad, Amir Shojaei, Mohammad Javan & Javad Mirnajafi-Zadeh

  2. Cancer Research Laboratories, Department of Surgery, St. George Hospital, University of New South Wales, Sydney, Australia

    Mohammad H. Pourgholami

Authors
  1. Nooshin Ahmadirad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amir Shojaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohammad Javan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammad H. Pourgholami
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Javad Mirnajafi-Zadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Javad Mirnajafi-Zadeh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ahmadirad, N., Shojaei, A., Javan, M. et al. Effect of minocycline on pentylenetetrazol-induced chemical kindled seizures in mice. Neurol Sci 35, 571–576 (2014). https://doi.org/10.1007/s10072-013-1552-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-013-1552-0

KeyWords

Search

Navigation