Blockade of endothelin B receptor improves the efficacy of levetiracetam in chronic epileptic rats. (September 2015)

• Record Type: Journal Article
• Authors: Ko, Ah-Reum; Kang, Tae-Cheon
• Is Part Of: Seizure. Volume 31(2015)
• Page Start: 133
• Page End: 140
• Publication Date: 2015-09
• Subjects: Endothelin-1, Endothelin B receptor, Epilepsy, Levetiracetam, P-glycoprotein -- p38 mitogen-activated protein kinase; Epilepsy -- Periodicals; Epilepsy -- Periodicals; Seizures -- Periodicals; Épilepsie -- Périodiques; Electronic journals; Electronic journals; 616.853
• DOI: 10.1016/j.seizure.2015.07.019
• Languages: English
• ISSNs: 1059-1311

Abstract

Highlights: LEV did not reduce seizure activity in ∼40% of epileptic rats. Neither SB202190 nor BQ788 affected the seizure activity in epileptic rats. LEV + SB202190 reduced seizure duration, but not seizure frequency. LEV + BQ788 alleviated seizure frequency and seizure duration. ETB receptor will be an important therapeutic target for intractable epilepsy. Abstract: Purpose: To elucidate the mechanisms that regulate p-glycoprotein (PGP) expression and function in pharmacoresistant epilepsy, we investigated the effect of an ETB receptor antagonist (BQ788) and a p38 mitogen-activated protein kinase (p38MAPK) inhibitor (SB202190) on intractable seizures in chronic epileptic rats. Methods: Lithium-pilocarpine-induced chronic epileptic rats were used in the present study. Animals were given levetiracetam (LEV), LEV + SB202190, LEV + BQ788, SB202190 or BQ788 over a 3-day period using an osmotic pump. Seizure activity was recorded by video-EEG monitoring with 2 h of recording per day at the same time of day. We also performed western blot after EEG analysis. Results: Compared to control animals, PGP, ETB receptor and p38MAPK expression was increased in the hippocampus of epileptic animals. Neither SB202190 nor BQ788 affected the spontaneous seizure activity in epileptic rats. Three of ten rats were responders and achieved complete seizure control or significant reduction in seizure activity by LEV. In four of ten rats, seizure frequency was unaltered by LEV (non-responders). LEV + SB202190 reduced seizure duration, but not seizure frequency, in both responders and non-responders. LEV + BQ788 alleviated seizure frequency and seizure duration in both responders and non-responders. Compared to responders, PGP and ETB receptor expression was enhanced in the hippocampus of non-responders. Conclusion: To the best of our knowledge, these findings are the first indications of the role of ETB receptor in pharmacoresistant epilepsy. Therefore, the present data suggest that the regulation of the ETB receptor-mediated signaling pathway may be important for identification of new therapeutic strategies for improving antiepileptic drug efficacy.