Neurological Sciences

, Volume 35, Issue 10, pp 1561–1566 | Cite as

Proconvulsant effects of estriol, the third estrogen, in the mouse PTZ-kindling model

Original Article
First Online:
Received:
Accepted:

Abstract

The effect of estriol, the third estrogen, was evaluated for its effect on pentylenetetrazole (PTZ)-kindling model of epileptogenesis in mice followed by evaluation on kindling-induced changes in cognitive and motor functions. Kindling was induced by once every 2 days treatment with PTZ (25 mg/kg, i.p.) for 5 weeks. The seizure severity during induction of kindling and percentage incidence of animals kindled at the end of 5 weeks was recorded. Motor function was assessed using a grip strength meter while spatial memory was assessed in a cross maze. Estriol (0.005 and 0.01 mg/kg i.p.) reduced the time for induction of kindling from 5 weeks to 3 and 2 weeks for male and female mice respectively and enhanced the percentage incidence of seizures. Clomiphene (0.9 mg/kg i.p.) delayed the development of kindling and produced anticonvulsant effects. It also partially reversed the proconvulsant effects of estriol. On grip strength test and spontaneous alternation behaviour, a significant decline was observed in kindled mice which was further reduced by pre-treatment with estriol. Both clomiphene and diazepam were unable to reverse the reduced GS of PTZ-kindled mice but enhanced the percentage alternation of such animals. The study shows that estriol has powerful proconvulsant effects. Its administration in hormone replacement therapy or other indications, thus, requires careful monitoring in patients susceptible to epileptic seizures. The anticonvulsant effects of clomiphene requires further investigations.

Keywords

Estriol Clomiphene citrate Diazepam PTZ kindling Grip strength Spontaneous alternation behaviour 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

The work was carried out in Neurobehavioral Pharmacology Laboratory with a support from Special Assistance Programme of University Grants Commission, New Delhi. We are thankful to Dr. Abhay Sharma, CSIR-IGIB, New Delhi for providing the drugs for the study.

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    Nicoletti F, Speciale C, Sortino MA, Summa G, Caruso G, Patti F et al (1985) Comparative effects of estradiol benzoate, the antiestrogen clomiphene citrate, and the progestin medroxyprogesterone acetate on kainic acid-induced seizures in male and female rats. Epilepsia 26:252–257PubMedCrossRefGoogle Scholar
  2. 2.
    Rogawski MA, Reddy DS (2004) Neurosteroids: endogenous modulators of seizure susceptibility. In: Rho JM, Sankar R, Cavazos J (eds) Epilepsy: scientific foundations of clinical practice. Marcel Dekker, New York, pp 319–355Google Scholar
  3. 3.
    Lason W (2000) Effects of estrogens on seizures and neurotoxicity. Pol J Pharmacol 52:59–62PubMedCrossRefGoogle Scholar
  4. 4.
    Saberi M, Pourgholami MH, Jorjani M (2001) The acute effects of estradiol benzoate on amygdala-kindled seizures in male rats. Brain Res 891:1–6PubMedCrossRefGoogle Scholar
  5. 5.
    Kalkbrenner KA, Standley CA (2003) Estrogen modulation of NMDA-induced seizures in ovariectomized and non-ovariectomized rats. Brain Res 28:244–249CrossRefGoogle Scholar
  6. 6.
    Veliskiova J (2007) Estrogens and epilepsy: why are we so excited? Neuroscientist 13:77–88CrossRefGoogle Scholar
  7. 7.
    Ledoux VA, Smejkalova T, May RM, Cooke BM, Woolley CS (2009) Estradiol facilitates the release of neuropeptide Y to suppress hippocampus-dependent seizures. J Neurosci 29:1457–1468PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Marcus EM, Watson CW, Goldman PL (1966) Effects of steroids on cerebral electrical activity. Epileptogenic effects of conjugated estrogens and related compounds in the cat and rabbit. Arch Neurol 15:521–532PubMedCrossRefGoogle Scholar
  9. 9.
    Horn AC, Buterbaugh GG (1986) Estrogen alters the acquisition of seizures kindled by repeated amygdala stimulation or pentylenetetrazol administration in ovariectomized female rats. Epilepsia 27:103–108CrossRefGoogle Scholar
  10. 10.
    Buterbaugh GG (1989) Estradiol replacement facilitates the acquisition of seizures kindled from the anterior neocortex in female rats. Epilepsy Res 4:207–215PubMedCrossRefGoogle Scholar
  11. 11.
    Woolley S (2000) Estradiol facilitates kainic acid-induced, but not fluorothyl-induced, behavioral seizure activity in adult female rats. Epilepsia 41:510–515PubMedCrossRefGoogle Scholar
  12. 12.
    Reddy DS (2009) The role of neurosteroids in the pathophysiology and treatment. Epilepsy Res 85:1–30PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Veliskova J, Velisek L, Galanopoulou AS, Sperber EF (2000) Neuroprotective effects of estrogen on hippocampal cells in adult female rats after status epilepticus. Epilepsia 41:30–35CrossRefGoogle Scholar
  14. 14.
    Barha CK, Galea LA (2010) Influence of different estrogens on neuroplasticity and cognition in the hippocampus. Biochimica Biophysica Acta 1800:1056–1067CrossRefGoogle Scholar
  15. 15.
    Budziszewska B, Leśkiewicz M, Kubera M, Jaworska-Feil L, Kajta M, Lasoń W (2001) Estrone but not 17 beta-estradiol, attenuates kainate-induced seizures and toxicity in male mice. Exp Clin Endo Diab 109:168–173CrossRefGoogle Scholar
  16. 16.
    Scharfman HE, MacLusky NJ (2006) The influence of gonadal hormones on neuronal excitability, seizures, and epilepsy in the female. Epilepsia 47:1423–1440PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Ali A, Ahmad FJ, Pillai KK, Vohora D (2005) Amiloride protects against pentylenetetrazole-induced kindling in mice. Br J Pharmacol 145:884–888CrossRefGoogle Scholar
  18. 18.
    Nasir SA, Sharma A, Khanam R, Vohora D (2012) Effect of medroxyprogesterone on development of pentylenetetrazole-induced kindling in mice. Neuroscience. doi: 10.1016/j.neuroscience.2012.01.031 (e-pub ahead of print)PubMedCentralGoogle Scholar
  19. 19.
    Ali A, Ahmad FJ, Pillai KK, Vohora D (2004) Evidence of the anti-epileptic potential of amiloride with neuropharmacological benefits in rodent models of epilepsy and behaviour. Epilepsy Behav 145:880–884Google Scholar
  20. 20.
    Vohora D, Pal SN, Pillai KK (2005) Modulation of spontaneous alternation behavior of mice treated with thioperamide and tacrine in a cross maze task. Fund Clin Pharmacol 19:531–532CrossRefGoogle Scholar
  21. 21.
    Takahashi K, Okada M, Ozaki T, Kurioka H, Manabe A, Kanasaki H, Miyazaki K (2000) Safety and efficacy of estriol for symptoms natural or surgically induced menopause. Hum Reprod 15:1028–1036PubMedCrossRefGoogle Scholar
  22. 22.
    Draca S (2006) Estriol and progesterone: a new role for sex hormones. Int J Biomed Sci 2:305–307PubMedPubMedCentralGoogle Scholar
  23. 23.
    Zemlyak I, Sheila MB, Robert MS (2002) Protection against gp120-induced neurotoxicity by an array of estrogenic steroids. Brain Res 958:272–276PubMedCrossRefGoogle Scholar
  24. 24.
    DaSilva LF, Pereira P, Elisabetsky E (1998) A neuropharmacological analysis of PTZ-induced kindling in mice. Gen Pharmacol 31:47–50CrossRefGoogle Scholar
  25. 25.
    Cain DP (1989) Long-term potentiation and kindling: how similar are the mechanisms? Trends Neurosci 57:37–43Google Scholar
  26. 26.
    Scharfman HE, Mercurio TC, Goodman JH, Wilson MA, MacLusky NJ (2003) Hippocampal excitability increases during the estrous cycle in the rat: a potential role for brain-derived neurotrophic factor. J Neurosci 23:11641–11652PubMedPubMedCentralGoogle Scholar
  27. 27.
    Wahnschaffe U, Loscher W (1992) Lack of changes in seizure susceptibility during the estrous cycle in kindled rats. Epilepsy Res 13:199–204PubMedCrossRefGoogle Scholar
  28. 28.
    McEwen BS (2001) Estrogens effects on brain: multiple sites and molecular mechanism. J Appl Physiol 91:2785–2801PubMedGoogle Scholar
  29. 29.
    Herzog AG (1988) Seizure control with clomiphene therapy: a case report. Arch Neurol 45:209–210PubMedCrossRefGoogle Scholar
  30. 30.
    Check MD, Jerome H, Fred D, Lublin MD, Martin M, Mandel MD (1982) Clomiphene as an anticonvulsant drug. Arch Neurol 39:784PubMedCrossRefGoogle Scholar
  31. 31.
    Herzog AG (1999) Psychoneuroendocrine aspects of temporolimbic epilepsy. Psychosomatics 40:102–108PubMedCrossRefGoogle Scholar
  32. 32.
    Herzog AG (1991) Reproductive endocrine considerations and hormonal therapy for men with epilepsy. Epilepsia 32(Suppl. 6):34–37CrossRefGoogle Scholar
  33. 33.
    Brann DW, Dhandapani K, Wakade C, Virendra B, Khan MM (2007) Neurotrophic and neuroprotective actions of estrogen: basic mechanisms and clinical implications. Steroids 72:381–405PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Gibbs RB, Gabor R (2003) Estrogen and cognition: applying preclinical findings to clinical perspectives. J Neurosci Res 74:637–643PubMedCrossRefGoogle Scholar
  35. 35.
    Tan RS, Pu SJ, Culberson JW (2003) Role of androgens in mild cognitive impairment and possible interventions during andropause. Med Hypotheses 60:448–452PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2014

Authors and Affiliations

  1. 1.Neurobehavioral Pharmacology Laboratory, Department of Pharmacology, Faculty of PharmacyJamia Hamdard (Hamdard University)New DelhiIndia

Personalised recommendations