Striking differences in proconvulsant-induced alterations of seizure threshold in two rat models - PubMed

Striking differences in proconvulsant-induced alterations of seizure threshold in two rat models

Marion Bankstahl et al. Neurotoxicology. 2012 Jan.

Abstract

During drug development, seizure threshold tests are widely used to identify potential proconvulsant activity of investigational drugs. The most commonly used tests in this respect are the timed intravenous pentylenetetrazole (PTZ) infusion seizure test and the maximal electroshock seizure threshold (MEST) test in mice or rats. To our knowledge, no study is available in which proconvulsant drug activities in these models are directly compared, which prompted us to perform such experiments in male Wistar rats. Five drugs with reported proconvulsant activity were tested in the two models: d-amphetamine, chlorpromazine, caffeine, theophylline, and tramadol. Furthermore, the anticonvulsant drug phenobarbital was included in the experiments. While phenobarbital exerted anticonvulsant activity in both models, the five proconvulsant drugs markedly differed in their effects. In the dose range tested, d-amphetamine significantly lowered the PTZ seizure threshold but increased the MEST, caffeine and theophylline did not alter the PTZ seizure threshold but decreased the MEST, and tramadol reduced the PTZ threshold but increased the MEST. These marked differences between seizure threshold tests are most likely a consequence of the mechanisms underlying seizure induction in these tests. Our data indicate that using only one seizure threshold model during preclinical drug development may pose the risk that potential proconvulsant activity of an investigational drug is overseen. However, the label "proconvulsant" may be misleading if such activity only occurs at doses high above the therapeutic range, but the drug is not proconvulsant or even exerts anticonvulsant effects at lower, therapeutically relevant doses.

Similar articles

• Preclinical assessment of proconvulsant drug activity and its relevance for predicting adverse events in humans.

  Löscher W. Löscher W. Eur J Pharmacol. 2009 May 21;610(1-3):1-11. doi: 10.1016/j.ejphar.2009.03.025. Epub 2009 Mar 16. Eur J Pharmacol. 2009. PMID: 19292981 Review.

• Anticonvulsant and proconvulsant actions of 2-deoxy-D-glucose.

  Gasior M, Yankura J, Hartman AL, French A, Rogawski MA. Gasior M, et al. Epilepsia. 2010 Aug;51(8):1385-94. doi: 10.1111/j.1528-1167.2010.02593.x. Epub 2010 May 17. Epilepsia. 2010. PMID: 20491877

• Isobolographic characterization of interactions between vigabatrin and tiagabine in two experimental models of epilepsy.

  Luszczki JJ, Czuczwar SJ. Luszczki JJ, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Mar 30;31(2):529-38. doi: 10.1016/j.pnpbp.2006.11.020. Epub 2007 Jan 3. Prog Neuropsychopharmacol Biol Psychiatry. 2007. PMID: 17204358

• The interaction between morphine and propranolol in chemical and electrical seizure models of mice.

  Shafaroodi H, Khosravani E, Fakhrzad A, Moezi L. Shafaroodi H, et al. Neurol Res. 2016 Feb;38(2):166-76. doi: 10.1080/01616412.2015.1136779. Epub 2016 Feb 26. Neurol Res. 2016. PMID: 26883739

• The Search for New Screening Models of Pharmacoresistant Epilepsy: Is Induction of Acute Seizures in Epileptic Rodents a Suitable Approach?

  Löscher W. Löscher W. Neurochem Res. 2017 Jul;42(7):1926-1938. doi: 10.1007/s11064-016-2025-7. Epub 2016 Aug 8. Neurochem Res. 2017. PMID: 27502939 Review.

Cited by

• [Convulsive crisis in Tramadol and caffeine abusers: about 8 cases and review of the literature].

  Maiga DD, Seyni H, Sidikou A, Azouma A. Maiga DD, et al. Pan Afr Med J. 2012;13:24. Epub 2012 Oct 3. Pan Afr Med J. 2012. PMID: 23308329 Free PMC article. Review. French.

• Caffeine and Its Interactions with Antiseizure Medications-Is There a Correlation between Preclinical and Clinical Data?

  Miziak B, Błaszczyk B, Chrościńska-Krawczyk M, Czuczwar SJ. Miziak B, et al. Int J Mol Sci. 2023 Dec 17;24(24):17569. doi: 10.3390/ijms242417569. Int J Mol Sci. 2023. PMID: 38139396 Free PMC article. Review.

• OV329, a novel highly potent γ-aminobutyric acid aminotransferase inactivator, induces pronounced anticonvulsant effects in the pentylenetetrazole seizure threshold test and in amygdala-kindled rats.

  Feja M, Meller S, Deking LS, Kaczmarek E, During MJ, Silverman RB, Gernert M. Feja M, et al. Epilepsia. 2021 Dec;62(12):3091-3104. doi: 10.1111/epi.17090. Epub 2021 Oct 7. Epilepsia. 2021. PMID: 34617595 Free PMC article.

• Advantages of repeated low dose against single high dose of kainate in C57BL/6J mouse model of status epilepticus: behavioral and electroencephalographic studies.

  Tse K, Puttachary S, Beamer E, Sills GJ, Thippeswamy T. Tse K, et al. PLoS One. 2014 May 6;9(5):e96622. doi: 10.1371/journal.pone.0096622. eCollection 2014. PLoS One. 2014. PMID: 24802808 Free PMC article.

• Levetiracetam Prevents Neurophysiological Changes and Preserves Cognitive Function in the Human Immunodeficiency Virus (HIV)-1 Transactivator of Transcription Transgenic Mouse Model of HIV-Associated Neurocognitive Disorder.

  Ewens AN, Pilski A, Hastings SD, Krook-Magnuson C, Graves SM, Krook-Magnuson E, Thayer SA. Ewens AN, et al. J Pharmacol Exp Ther. 2024 Sep 18;391(1):104-118. doi: 10.1124/jpet.124.002272. J Pharmacol Exp Ther. 2024. PMID: 39060163

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Elsevier Science

• Medical

  • MedlinePlus Health Information