Delta 2-specific opioid receptor agonist and hibernating woodchuck plasma fraction provide ischemic neuroprotection.
OBJECTIVE
The authors present evidence that the delta opioid receptor agonist Deltorphin-D(variant) (Delt-D(var)) and hibernating woodchuck plasma (HWP), but not summer-active woodchuck plasma (SAWP), can provide significant neuroprotection from focal ischemia in mice by a mechanism that relies in part on reducing nitric oxide (NO) release in ischemic tissue.


METHODS
Cerebral ischemia was produced in wild-type and NO synthase-deficient (NOS(-/-)) mice by transient, 1-hour middle cerebral artery occlusion (MCAO). Behavioral deficits were determined at 22 hours and infarct volume was assessed at 24 hours after MCAO. Mice were treated with saline or Delt-D(var) at 2.0 and 4.0 mg/kg, or 200 microL of HWP or SAWP. NOS(-/-) mice were treated with either saline or Delt-D(var) at 4.0 mg/kg. NO release was determined using an N9 microglial cell line pretreated with delta- or mu-specific opioids and HWP or SAWP prior to activation with lipopolysaccharide and interferon-gamma. Nitrate in the medium was measured as an indicator of NO production.


RESULTS
Infusion of Delt-D(var) or HWP (but not SAWP) decreased infarct volume and improved behavioral deficits following 1 hour of MCAO and 24 hours of reperfusion. In NOS(-/-) mice, endothelial NOS(+/+) is required to provide Delt-D(var)-induced neuroprotection. Delt-D(var) and HWP dose-dependently decreased NO release in cell culture, while SAWP and other delta- and mu-specific opioids did not.


CONCLUSIONS
Delt-D(var) and HWP, but not SAWP, are effective neuroprotectant agents in a mouse model of transient MCAO. In cell culture, the mechanism of this ischemic neuroprotection may rely in part on their ability to block NO release.
Govindaswami
Meera
M
Department of Pathology, University of Kentucky College of Medicine and Veterans Affairs Medical Center, Lexington, KY 40536, USA.
Brown
Stephan A
SA
Yu
Jin
J
Zhu
Hong
H
Bishop
Paul D
PD
Kindy
Mark S
MS
Oeltgen
Peter R
PR
D000818:Animals; D002545:Brain Ischemia / Q000097:blood* / Q000517:prevention & control*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006605:Hibernation / Q000502:physiology; D008297:Male; D008392:Marmota; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000097:blood / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D009842:Oligopeptides / Q000097:blood / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000819:agonists*; D012016:Reference Values
D018696:Neuroprotective Agents; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D009569:Nitric Oxide