title: Delta opioid receptor agonist BW373U86 attenuates post-resuscitation brain injury in a rat model of asphyxial cardiac arrest.
abstract: OBJECTIVE
  The aim of this study was to investigate whether the DOR agonist BW373U86 conferred neuroprotection following ACA when given after resuscitation and to determine the long-term effects of chronic BW373U86 treatment on ACA-elicited brain injury.
  
  
  METHODS
  Animals were divided into acute and chronic treatment groups. Each group consisted of four sub-groups, including Sham, ACA, BW373U86 (BW373U86+ACA), and Naltrindole groups (Naltrindole and BW373U86+ACA). The DOR antagonist Naltrindole was used to confirm the possible receptor-dependent effects of BW373U86. ACA was induced by 8min of asphyxiation followed by resuscitation. All drugs were administered either immediately after the restoration of spontaneous circulation (ROSC) in acute-treatment groups or over 6 consecutive days in chronic-treatment groups. Alterations of cAMP response element-binding protein (CREB) and phosphorylated CREB (pCREB) were analyzed by western blot and immunohistochemistry. Neurological functions were assessed by neurological deficit score (NDS) and Morris Water Maze performance. Neurodegeneration was monitored by immunofluorescence and Nissl staining.
  
  
  RESULTS
  ACA induced massive neuron loss and serious neurological function deficits. BW373U86 significantly reduced both of these negative effects and increased CREB and pCREB expression in the hippocampus; these effects were reversed with acute Naltrindole treatment. The protective effects of BW373U86 persisted until 28d post-ROSC with chronic treatment, but these effects were not reversed by Naltrindole.
  
  
  CONCLUSIONS
  BW373U86 attenuates global cerebral ischemic injury induced by ACA through both DOR-dependent and DOR-independent mechanisms. CREB might be an important molecule in mediating these neuroprotective effects.
authors.affiliation: Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province 710038, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province 710038, China.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province 710038, China.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province 710038, China.
authors.forename: Xude
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province 710038, China.
authors.forename: Linong
authors.initials: L
authors.lastname: Yao
authors.affiliation: Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province 710038, China.
authors.forename: Daihua
authors.initials: D
authors.lastname: Yu
authors.affiliation: Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province 710038, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province 710038, China. Electronic address: gaocj74@163.com.
authors.forename: Changjun
authors.initials: C
authors.lastname: Gao
authors.affiliation: Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province 710038, China. Electronic address: tdmzka@fmmu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Chai
mesh_terms: D000818:Animals; D001237:Asphyxia / Q000628:therapy*; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D001925:Brain Damage, Chronic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050882:CREB-Binding Protein / Q000378:metabolism; D016887:Cardiopulmonary Resuscitation; D004195:Disease Models, Animal; D006323:Heart Arrest / Q000628:therapy*; D007124:Immunoenzyme Techniques; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley
chemical_list: D001549:Benzamides; D018696:Neuroprotective Agents; D010879:Piperazines; C083877:BW 373U86; D009271:Naltrexone; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; C055382:naltrindole
keywords: Asphyxial cardiac arrest; Delta opioid receptor; Neuroprotection; cAMP response element-binding protein