title: δ-Opioid receptor activation rescues the functional TrkB receptor and protects the brain from ischemia-reperfusion injury in the rat.
abstract: OBJECTIVE
  δ-opioid receptor (DOR) activation reduced brain ischemic infarction and attenuated neurological deficits, while DOR inhibition aggravated the ischemic damage. The underlying mechanisms are, however, not well understood yet. In this work, we asked if DOR activation protects the brain against ischemic injury through a brain-derived neurotrophic factor (BDNF) -TrkB pathway.
  
  
  METHODS
  We exposed adult male Sprague-Dawley rats to focal cerebral ischemia, which was induced by middle cerebral artery occlusion (MCAO). DOR agonist TAN-67 (60 nmol), antagonist Naltrindole (100 nmol) or artificial cerebral spinal fluid was injected into the lateral cerebroventricle 30 min before MCAO. Besides the detection of ischemic injury, the expression of BDNF, full-length and truncated TrkB, total CREB, p-CREB, p-ATF and CD11b was detected by Western blot and fluorescence immunostaining.
  
  
  RESULTS
  DOR activation with TAN-67 significantly reduced the ischemic volume and largely reversed the decrease in full-length TrkB protein expression in the ischemic cortex and striatum without any appreciable change in cerebral blood flow, while the DOR antagonist Naltrindole aggregated the ischemic injury. However, the level of BDNF remained unchanged in the cortex, striatum and hippocampus at 24 hours after MCAO and did not change in response to DOR activation or inhibition. MCAO decreased both total CREB and pCREB in the striatum, but not in the cortex, while DOR inhibition promoted a further decrease in total and phosphorylated CREB in the striatum and decreased pATF-1 expression in the cortex. In addition, MCAO increased CD11b expression in the cortex, striatum and hippocampus, and DOR activation specifically attenuated the ischemic increase in the cortex but not in the striatum and hippocampus.
  
  
  CONCLUSIONS
  DOR activation rescues TrkB signaling by reversing ischemia/reperfusion induced decrease in the full-length TrkB receptor and reduces brain injury in ischemia/reperfusion.
authors.affiliation: State Key Laboratory of Medical Neurobiology, Department of Integrative Medicine and Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Tian
authors.forename: Jingchun
authors.initials: J
authors.lastname: Guo
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: Minwei
authors.initials: M
authors.lastname: Li
authors.forename: Gencheng
authors.initials: G
authors.lastname: Wu
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
mesh_terms: D051697:Activating Transcription Factor 1 / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000378:metabolism; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism*
chemical_list: D051697:Activating Transcription Factor 1; D019208:Brain-Derived Neurotrophic Factor; D039481:CD11b Antigen; D017362:Cyclic AMP Response Element-Binding Protein; D011804:Quinolines; D017465:Receptors, Opioid, delta; C094142:TAN 67; D009271:Naltrexone; D020813:Receptor, trkB; C055382:naltrindole