title: The neuroprotective effect of losartan through inhibiting AT1/ASK1/MKK4/JNK3 pathway following cerebral I/R in rat hippocampal CA1 region.
abstract: OBJECTIVE
  It has been well documented that angiotensin II type 1 (AT(1) ) receptor blockers (ARBs) are known to attenuate neural damage and the c-Jun N-terminal protein kinase 3 (JNK3) pathway and caspase-3 signal are involved in neuronal cell death following cerebral ischemia/reperfusion (I/R). In this study, we first showed that losartan could protect neurons against cerebral I/R-induced injury.
  
  
  METHODS
  Cerebral ischemia model was induced by four-vessel occlusion. Antisense oligodeoxynucleotides (ODNs) against AT1 receptor and losartan were used to detect whether the AT1 receptor implicated in cerebral I/R. Immunoprecipitation (IP) and immunoblotting (IB) were used to detect the interactions between β-arrestin-2 and AT1/apoptosis signal-regulating kinase 1 (ASK1)/MAP kinase kinase 4 (MKK4) signaling module following cerebral I/R.
  
  
  RESULTS
  First, losartan decreased cerebral I/R-induced neuronal death. Second, losartan depressed the β-arrestin-2-assembled AT1/ASK1/MKK4 signaling module. Third, losartan depressed the activation of c-jun, JNK3, Bcl-2, caspase-3 and the release of cytochrome c from mitochondria to cytoplasm.
  
  
  CONCLUSIONS
  Taken together, losartan could attenuate neural damage following the cerebral I/R via inhibiting the β-arrestin-2-assembled AT1/ASK1/MKK4 signaling module and depressing the activation of c-jun, JNK3, and caspase-3 and the release of cytochrome c.
authors.affiliation: Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Tian-Ling
authors.initials: TL
authors.lastname: Zhang
authors.forename: Jian-Liang
authors.initials: JL
authors.lastname: Fu
authors.forename: Zhi
authors.initials: Z
authors.lastname: Geng
authors.forename: Jia-Jun
authors.initials: JJ
authors.lastname: Yang
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Sun
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002545:Brain Ischemia / Q000473:pathology*; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D019808:Losartan / Q000627:therapeutic use*; D048670:MAP Kinase Kinase 4; D048848:MAP Kinase Kinase Kinase 5; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D048057:Mitogen-Activated Protein Kinase 10; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015427:Reperfusion Injury / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D018696:Neuroprotective Agents; D020319:Oligodeoxyribonucleotides, Antisense; D044140:Receptor, Angiotensin, Type 1; D048057:Mitogen-Activated Protein Kinase 10; D048848:MAP Kinase Kinase Kinase 5; D048670:MAP Kinase Kinase 4; D019808:Losartan