title: Characterization of neuroprotective effects of biphalin, an opioid receptor agonist, in a model of focal brain ischemia.
abstract: Approximately 795,000 people experience a new or recurrent stroke in the United States annually. The purpose of this study was to assess the protective effect of a nonselective opioid receptor agonist, biphalin, in brain edema and infarct damage by using both in vitro and in vivo models of stroke. In an in vivo model of ischemia, biphalin significantly decreased edema (66.6 and 58.3%) and infarct (52.2 and 56.4%) ratios in mouse transient (60-min occlusion/24-h reperfusion) and permanent (6 h) middle cerebral artery occlusion models, respectively. Biphalin administration also showed decreased neurodegeneration in hippocampal, cortical, and striatal brain tissue after ischemia, evidenced by reduced Fluoro-Jade C staining. In addition, biphalin improved neurological function after stroke injury evidenced by neurological score and locomotor activity evaluation. Biphalin significantly decreased penumbral expression of Na(+), K(+), 2Cl(-) cotransporter (NKCC) and the translocation of the conventional isoforms of protein kinase C (PKC). It also reversed the activation of PKC-induced cell volume increase during ischemia in primary neuronal cell cultures exposed to 1 h of oxygen glucose deprivation. These data suggest that opioid receptor activation provides neuroprotection during stroke, and a possible explanation of this mechanism could be the inhibition of NKCC function via the regulation of PKC-dependent cell signaling.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S. Coulter, Amarillo, TX 79016, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Kaushik
authors.initials: K
authors.lastname: Shah
authors.forename: Hezhen
authors.initials: H
authors.lastname: Wang
authors.forename: Vardan T
authors.initials: VT
authors.lastname: Karamyan
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Abbruscato
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004745:Enkephalins / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D011957:Receptors, Opioid / Q000819:agonists*; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
chemical_list: D004745:Enkephalins; D018696:Neuroprotective Agents; D011957:Receptors, Opioid; D028021:Sodium-Potassium-Chloride Symporters; C053673:biphalin; D011493:Protein Kinase C