Delta 2-specific opioid receptor agonist and hibernating woodchuck plasma fraction provide ischemic neuroprotection.

Abstract

OBJECTIVES:

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.

• Authors: Meera Govindaswami, Stephan A Brown, Jin Yu, Hong Zhu, Paul D Bishop, Mark S Kindy, Peter R Oeltgen
• Journal: Academic emergency medicine : official journal of the Society for Academic Emergency Medicine (Acad Emerg Med) Vol. 15 Issue 3 Pg. 250-7 (Mar 2008) ISSN: 1553-2712 [Electronic] United States
• PMID: 18304055 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Neuroprotective Agents
• Oligopeptides
• Receptors, Opioid, delta
• Nitric Oxide

Topics

• Animals
• Brain Ischemia (blood, prevention & control)
• Cells, Cultured
• Disease Models, Animal
• Hibernation (physiology)
• Male
• Marmota
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neuroprotective Agents (blood, pharmacology)
• Nitric Oxide (metabolism)
• Oligopeptides (blood, pharmacology)
• Receptors, Opioid, delta (agonists)
• Reference Values