title: Opioids modulate post-ischemic progression in a rat model of stroke.
abstract: Alterations in the opioidergic system have been found in cerebral ischemia. Neuroprotection studies have demonstrated the involvement of the opioidergic system in cerebral ischemia/reperfusion (I/R). However, the neuroprotective mechanisms remain largely unclear. This study was conducted to investigate whether intracerebroventricular administration of opioidergic agonists has a neuroprotective effect against cerebral ischemia in rats and, if this proved to be the case, to determine the potential neuroprotective mechanisms. Using a focal cerebral I/R rat model, we demonstrated that the opioidergic agents, BW373U86 (delta agonist) and Dynorphin A 1-13 (kappa agonist), but not TAPP (mu agonist), attenuated cerebral ischemic injury as manifested in the reduction of cerebral infarction and preservation of neurons. The antagonism assay showed that the neuroprotective effect of Dynorphin A was attenuated by nor-Binaltorphimine (kappa antagonist). Surprisingly, BW373U86-induced neuroprotection was not changed by Naltrindole (delta antagonist). These findings indicate that BW373U86 and Dynorphin A exerted distinct neuroprotection against ischemia via opioid-independent and -dependent mechanisms, respectively. The post-ischemic protection in beneficial treatments was accompanied by alleviations in brain edema, inflammatory cell infiltration, and pro-inflammatory cytokine interleukin 6 (IL-6) expression. In vitro cell study further demonstrated that the opioidergic agonists, delta and kappa, but not mu, attenuated IL-6 production from stimulated glial cells. Our findings indicate that opioidergic agents have a role in post-ischemic progression through both opioid-dependent and -independent mechanisms. In spite of the distinct-involved action mechanism, the potential neuroprotective effect of opioidergic compounds was associated with immune suppression. Taken together, these findings suggest a potential role for opioidergic agents in the therapeutic consideration of neuroinflammatory diseases. However, a better understanding of the mechanisms involved is necessary before this therapeutic potential can be realized.
authors.affiliation: Department of Nursing, Tajen Institute of Technology, Pingtung 907, Taiwan.
authors.forename: Tsung-Kuei
authors.initials: TK
authors.lastname: Kao
authors.forename: Yen-Chuan
authors.initials: YC
authors.lastname: Ou
authors.forename: Su-Lan
authors.initials: SL
authors.lastname: Liao
authors.forename: Wen-Ying
authors.initials: WY
authors.lastname: Chen
authors.forename: Chun-Chiang
authors.initials: CC
authors.lastname: Wang
authors.forename: Shih-Yun
authors.initials: SY
authors.lastname: Chen
authors.forename: An-Na
authors.initials: AN
authors.lastname: Chiang
authors.forename: Chun-Jung
authors.initials: CJ
authors.lastname: Chen
mesh_terms: D000578:Amidines / Q000494:pharmacology / Q000627:therapeutic use; D000701:Analgesics, Opioid / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D019610:Cytoprotection / Q000187:drug effects* / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D004399:Dynorphins / Q000494:pharmacology / Q000627:therapeutic use; D004660:Encephalitis / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008297:Male; D009292:Narcotic Antagonists / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000578:Amidines; D000701:Analgesics, Opioid; D001549:Benzamides; D015850:Interleukin-6; D009292:Narcotic Antagonists; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010879:Piperazines; D011957:Receptors, Opioid; C034807:tetra-4-amidinophenoxypropane; C050138:dynorphin A (1-13), Ala(2)-Trp(4)-; C083877:BW 373U86; D004399:Dynorphins