Objectives: The authors present evidence that the d 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 lL 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 d-or l-specific opioids and HWP or SAWP prior to activation with lipopolysaccharide and interferon-c. 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 behav-ioral 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 d-and l-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. ACADEMIC EMERGENCY MEDICINE 2008; 15:250-257 ª

No abstract