Neuroprotective activity of tamoxifen in permanent focal ischemia.
OBJECTIVE
The authors have previously shown that tamoxifen is effective in protecting brain tissue from ischemic injury in a rat model of reversible focal ischemia. In this study the authors tested whether similar protective effects are found in a rat model of permanent focal ischemia (permanent middle cerebral artery [MCA] occlusion).


METHODS
Tamoxifen (20 mg/kg) was given either before or at 1, 3, or 6 hours after permanent MCA occlusion in rats, with sustaining doses given every 12 hours thereafter. The median infarct volume measured after 72 hours was 113 mm3 for the vehicle (dimethyl sulfoxide) groups, compared with 31 mm3 for pretreatment, and 14, 27, and 98 mm3 for treatment beginning at 1, 3, and 6 hours, respectively, after permanent MCA occlusion. The infarct reductions in the pretreated and 1- and 3-hour post-MCA occlusion treatment groups were statistically significant (p < 0.05). At 3 hours after permanent MCA occlusion, tamoxifen also significantly reduced the infarct size at a lower dose of 5 mg/kg but not at 1 mg/kg; the same sustaining doses of 5 and 1 mg/kg were given every 12 hours.


CONCLUSIONS
Tamoxifen is as effective in a permanent model of focal ischemia as it is in the reversible model, and the therapeutic window of 3 hours after initiation of ischemia is identical. This effectiveness is likely due to several properties of the drug, including its known ability to cross the blood-brain barrier. Because tamoxifen has been administered safely in humans for treatment of gliomas at similarly high doses to those used in this study, it may be clinically useful as a treatment for ischemic stroke.
Kimelberg
Harold K
HK
Center for Neuropharmacology and Neuroscience, and Division of Neurosurgery, Albany Medical College, Albany, New York 12208, USA. kimelbh@mail.amc.edu
Jin
Yiqiang
Y
Charniga
Carol
C
Feustel
Paul J
PJ
D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D018696:Neuroprotective Agents; D013629:Tamoxifen