Blockade of endothelin B receptor improves the efficacy of levetiracetam in chronic epileptic rats.

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 2h 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.

• Authors: Ah-Reum Ko, Tae-Cheon Kang
• Journal: Seizure (Seizure) Vol. 31 Pg. 133-40 (Sep 2015) ISSN: 1532-2688 [Electronic] England
• PMID: 26362390 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Anticonvulsants
• Endothelin B Receptor Antagonists
• Enzyme Inhibitors
• Imidazoles
• Oligopeptides
• Piperidines
• Pyridines
• Receptor, Endothelin B
• BQ 788
• Levetiracetam
• p38 Mitogen-Activated Protein Kinases
• 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole
• Piracetam

Topics

• Animals
• Anticonvulsants (pharmacology)
• Brain (drug effects, physiopathology)
• Chronic Disease
• Disease Models, Animal
• Endothelin B Receptor Antagonists (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Epilepsy (drug therapy, physiopathology)
• Imidazoles (pharmacology)
• Levetiracetam
• Male
• Oligopeptides (pharmacology)
• Piperidines (pharmacology)
• Piracetam (analogs & derivatives, pharmacology)
• Pyridines (pharmacology)
• Rats, Sprague-Dawley
• Receptor, Endothelin B (metabolism)
• Seizures (drug therapy, physiopathology)
• Treatment Outcome
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)