Neuroprotection by the stable nitroxide 3-carbamoyl-proxyl during reperfusion in a rat model of transient focal ischemia.

Abstract

OBJECT:

Nitroxides mimic superoxide dismutase (SOD) biochemically and may prevent free radical oxidative injury in settings in which endogenous SOD is overwhelmed. The authors have previously shown the efficacy of a nitroxide, Tempol, in reducing stroke infarct size. Of the nitroxides, 3-carbamoyl-proxyl (3-CP) is especially promising for clinical use, because it does not cause hypotension in animals. Its efficacy in brain ischemia, however, is untested. The goal of this study was to ascertain whether 3-CP would reduce brain damage in a rat ischemia-reperfusion model.

METHODS:

The authors performed a blinded, dose-response study of the effect of different amounts of 3-CP (1, 10, and 100 mg/kg) on infarct size at 24 hours after focal ischemia and reperfusion. The 3-CP was given intravenously during reperfusion, which followed 1 hour of reversible ischemia induced by a thread placed intraluminally in the middle cerebral artery of rats. Brain infarcts, measured with 2,3,5-triphenyltetrazolium chloride staining in six 3-CP groups, were compared with those measured in controls (animals given an equal volume of saline). Edema-corrected infarct sizes (mean +/- standard deviation) were as follows: 146 +/- 64 mm3 in controls; 107 +/- 18 mm3 in rats given 1 mg/kg 3-CP; 40 +/- 20 mm3 in those given 10 mg/kg 3-CP; and 44 +/- 17 mm3 in those given 100 mg/kg 3-CP. A statistically significant reduction in infarct size was achieved in the 10- and 100-mg/kg 3-CP-treated groups (p < 0.01). A reduction in infarct size was also seen in the 1 mg/kg 3-CP-treated group, but this did not reach statistical significance. The authors observed no effects of 3-CP on blood pressure or brain temperature.

CONCLUSIONS:

Given at reperfusion, 3-CP significantly decreases brain infarct size at doses of 10 and 100 mg/kg without causing hypotension. The authors found that 3-CP is well suited for further laboratory and clinical use in brain ischemia and reperfusion.

• Authors: Guohan Hu, Bruce G Lyeth, Xueren Zhao, James B Mitchell, Joe C Watson
• Journal: Journal of neurosurgery (J Neurosurg) Vol. 98 Issue 2 Pg. 393-6 (Feb 2003) ISSN: 0022-3085 [Print] United States
• PMID: 12593628 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cyclic N-Oxides
• Neuroprotective Agents
• Pyrrolidines
• 3-carbamoyl-2,2,5,5-tetramethyl-1-pyrrolidinyl-N-oxyl

Topics

• Animals
• Blood Pressure (drug effects, physiology)
• Cyclic N-Oxides (administration & dosage, therapeutic use)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Ischemic Attack, Transient (complications, drug therapy, physiopathology)
• Male
• Neuroprotective Agents (administration & dosage, therapeutic use)
• Pyrrolidines (administration & dosage, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (etiology, physiopathology, prevention & control)
• Time Factors