Cox-2 inhibition can lead to adverse effects in a rat model for temporal lobe epilepsy

Holtman, Linda; van Vliet, Erwin A.; Edelbroek, Peter M.; Aronica, Eleonora; Gorter, Jan A.

doi:10.1016/j.eplepsyres.2010.06.011

« Previous Next »Epilepsy Research
Volume 91, Issue 1 , Pages 49-56, September 2010

Cox-2 inhibition can lead to adverse effects in a rat model for temporal lobe epilepsy

Linda Holtman
- Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands
Erwin A. van Vliet
- Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands
- Epilepsy Institute in The Netherlands Foundation (SEIN), Achterweg 5, 2103 SW Heemstede, The Netherlands
Peter M. Edelbroek
- Epilepsy Institute in The Netherlands Foundation (SEIN), Achterweg 5, 2103 SW Heemstede, The Netherlands
Eleonora Aronica
- Academic Medical Center, Department of (Neuro)Pathology, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Jan A. Gorter
- Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands
- Epilepsy Institute in The Netherlands Foundation (SEIN), Achterweg 5, 2103 SW Heemstede, The Netherlands
- Corresponding author at: Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands. Tel.: +31 205257893; fax: +31 205257709.

Received 23 March 2010; received in revised form 2 June 2010; accepted 23 June 2010.

Summary

Purpose

Status epilepticus (SE) leads to upregulation of pro-inflammatory proteins including cyclooxygenase-2 (cox-2) which could be implicated in the epileptogenic process and epileptic seizures. Recent studies show that cox-2 can regulate expression of P-glycoprotein (P-gp) during epileptogenesis and epilepsy. P-gp could cause pharmacoresistance by reducing brain entry of anti-epileptic drugs such as phenytoin (PHT). Here we have investigated the effects of cox-2 inhibition on epileptogenesis, spontaneous seizures and PHT treatment in a rat model for temporal lobe epilepsy (TLE).

Methods

A 3-day treatment with the cox-2 inhibitor SC-58236 (SC) was started 1 day before electrically induced SE. Chronic epileptic rats were treated with SC for 14 days, which was followed by a 7-day period of SC/PHT combination treatment. Seizure activity was monitored continuously using electroencephalography.

Results

SC treatment did not affect SE duration, but led to an increased number of rats that died during the first 2 weeks after SE. Cox-2 inhibition during the chronic period led to an increased number of seizures in the 2nd week of treatment in 50% of the rats. SC/PHT treatment reduced seizures significantly for only 2 days.

Conclusions

Both SC treatment that started before SE and the 14-day treatment in chronic epileptic rats led to adverse effects in the TLE rat model. Despite a temporal reduction in seizure frequency with SC/PHT treatment, SC does not seem to be a suitable approach for anti-epileptogenic or anti-epileptic therapy.

Keywords: Status epilepticus, Neuroinflammation, Temporal lobe epilepsy, P-glycoprotein, Pharmacoresistance