title: Endothelin-1 induces LIMK2-mediated programmed necrotic neuronal death independent of NOS activity.
abstract: BACKGROUND
  Recently, we have reported that LIM kinase 2 (LIMK2) involves programmed necrotic neuronal deaths induced by aberrant cyclin D1 expression following status epilepticus (SE). Up-regulation of LIMK2 expression induces neuronal necrosis by impairment of dynamin-related protein 1 (DRP1)-mediated mitochondrial fission. However, we could not elucidate the upstream effecter for LIMK2-mediated neuronal death. Thus, we investigated the role of endothelin-1 (ET-1) in LIMK2-mediated neuronal necrosis, since ET-1 involves neuronal death via various pathways.
  
  
  RESULTS
  Following SE, ET-1 concentration and its mRNA were significantly increased in the hippocampus with up-regulation of ETB receptor expression. BQ788 (an ETB receptor antagonist) effectively attenuated SE-induced neuronal damage as well as reduction in LIMK2 mRNA/protein expression. In addition, BQ788 alleviated up-regulation of Rho kinase 1 (ROCK1) expression and impairment of DRP1-mediated mitochondrial fission in CA1 neurons following SE. BQ788 also attenuated neuronal death and up-regulation of LIMK2 expression induced by exogenous ET-1 injection.
  
  
  CONCLUSIONS
  These findings suggest that ET-1 may be one of the upstream effectors for programmed neuronal necrosis through abnormal LIMK2 over-expression by ROCK1.
authors.affiliation: Department of Anatomy & Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chunchon, Kangwon-Do, 200-702, South Korea.
authors.forename: Ah-Reum
authors.initials: AR
authors.lastname: Ko
authors.affiliation: Department of Anatomy & Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chunchon, Kangwon-Do, 200-702, South Korea.
authors.forename: Hye-Won
authors.initials: HW
authors.lastname: Hyun
authors.affiliation: Department of Anatomy & Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chunchon, Kangwon-Do, 200-702, South Korea.
authors.forename: Su-Ji
authors.initials: SJ
authors.lastname: Min
authors.affiliation: Department of Anatomy & Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chunchon, Kangwon-Do, 200-702, South Korea. jieunkim@hallym.ac.kr.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Anatomy & Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chunchon, Kangwon-Do, 200-702, South Korea. tckang@hallym.ac.kr.
authors.forename: Tae-Cheon
authors.initials: TC
authors.lastname: Kang
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology; D051242:Caveolin 1 / Q000494:pharmacology; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000473:pathology; D054461:Lim Kinases / Q000378:metabolism*; D008297:Male; D063154:Mitochondrial Dynamics / Q000187:drug effects; D008954:Models, Biological; D009336:Necrosis; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism; D013226:Status Epilepticus / Q000235:genetics / Q000473:pathology; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D000577:Amides; D051242:Caveolin 1; D019332:Endothelin-1; D009842:Oligopeptides; D010455:Peptides; D010880:Piperidines; D011725:Pyridines; D012333:RNA, Messenger; D017466:Receptors, Endothelin; C108830:Y 27632; C086539:BQ 788; D052248:Nitric Oxide Synthase Type I; D054461:Lim Kinases; C490644:Limk2 protein, rat; D054460:rho-Associated Kinases