title: Neuroprotection by the stable nitroxide 3-carbamoyl-proxyl during reperfusion in a rat model of transient focal ischemia.
abstract: 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.
authors.affiliation: Department of Neurological Surgery, University of California at Davis, Sacramento, California 95817, USA.
authors.forename: Guohan
authors.initials: G
authors.lastname: Hu
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Lyeth
authors.forename: Xueren
authors.initials: X
authors.lastname: Zhao
authors.forename: James B
authors.initials: JB
authors.lastname: Mitchell
authors.forename: Joe C
authors.initials: JC
authors.lastname: Watson
mesh_terms: 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
chemical_list: D003497:Cyclic N-Oxides; D018696:Neuroprotective Agents; D011759:Pyrrolidines; C077426:3-carbamoyl-2,2,5,5-tetramethyl-1-pyrrolidinyl-N-oxyl