Neuroprotection by the stable nitroxide 3-carbamoyl-proxyl during reperfusion in a rat model of transient focal ischemia.
OBJECTIVE
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.
Hu
Guohan
G
Department of Neurological Surgery, University of California at Davis, Sacramento, California 95817, USA.
Lyeth
Bruce G
BG
Zhao
Xueren
X
Mitchell
James B
JB
Watson
Joe C
JC
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D002546:Ischemic Attack, Transient / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors
D003497:Cyclic N-Oxides; D018696:Neuroprotective Agents; D011759:Pyrrolidines; C077426:3-carbamoyl-2,2,5,5-tetramethyl-1-pyrrolidinyl-N-oxyl