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.
Footnotes
This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant RO1-NSO46526] (to T.J.A.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.184127.
-
ABBREVIATIONS:
- OR
- opioid receptor
- DOR
- δ-opioid receptor
- MOR
- μ-opioid receptor
- KOR
- κ-opioid receptor
- NKCC
- Na+, K+, 2Cl− cotransporter
- OGD
- oxygen glucose deprivation
- TTC
- 2,3,5-triphenyltetrazolium chloride
- CCA
- common carotid artery
- MCA
- middle cerebral artery
- MCAO
- MCA occlusion
- tMCAO
- transient MCAO
- pMCAO
- permanent MCAO
- DAPI
- 4′-6-diamidino-2-phenylindole
- FJC
- Fluoro-Jade C
- DHE
- dihydroethidium
- PKC
- protein kinase C
- PVDF
- polyvinylidene difluoride
- TBS
- Tris-buffered saline
- TBST
- TBS containing 0.1% Tween 20
- PMA
- phorbol 12-myristate 13-acetate
- HBSS
- Hanks' balanced salt solution
- U-50488
- 2-(3,4-dichlorophenyl)-N-methyl-N-[(1R,2R)-2-pyrrolidin-1-ylcyclohexyl]acetamid.
- Received May 22, 2011.
- Accepted August 16, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|