title: Blockade of endothelin B receptor improves the efficacy of levetiracetam in chronic epileptic rats.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chunchon 200-702, South Korea; Institute of Epilepsy Research, College of Medicine, Hallym University, Chunchon 200-702, South Korea.
authors.forename: Ah-Reum
authors.initials: AR
authors.lastname: Ko
authors.affiliation: Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chunchon 200-702, South Korea; Institute of Epilepsy Research, College of Medicine, Hallym University, Chunchon 200-702, South Korea. Electronic address: tckang@hallym.ac.kr.
authors.forename: Tae-Cheon
authors.initials: TC
authors.lastname: Kang
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D065131:Endothelin B Receptor Antagonists / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000188:drug therapy* / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D000077287:Levetiracetam; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy / Q000503:physiopathology; D016896:Treatment Outcome; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D065131:Endothelin B Receptor Antagonists; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009842:Oligopeptides; D010880:Piperidines; D011725:Pyridines; D044023:Receptor, Endothelin B; C086539:BQ 788; D000077287:Levetiracetam; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; D010889:Piracetam
keywords: Endothelin-1, Endothelin B receptor, Epilepsy, Levetiracetam, P-glycoprotein; p38 mitogen-activated protein kinase