Tamoxifen, a selective estrogen receptor modulator, reduces ischemic damage caused by middle cerebral artery occlusion in the ovariectomized female rat.
Previous work has demonstrated that physiological concentrations of 17beta-estradiol can protect the female rat brain against middle cerebral artery occlusion (MCAO)-induced ischemic damage. The present study examined whether therapeutic doses of the clinically relevant selective estrogen receptor modulator (SERM), tamoxifen, can similarly protect the female rat brain against ischemic stroke damage. Adult female rats were bilaterally ovariectomized and implanted subcutaneously with either a placebo or tamoxifen time-release pellet (0.1, 0.8 or 2.4 mg/kg/day). One week later, the animals underwent permanent MCAO to assess the protective ability of the different tamoxifen doses on brain infarct size. As expected, MCAO produced a large infarct ( approximately 53%) of the affected cerebral hemisphere in placebo (control) animals. The 0.1 mg/kg/day dose of tamoxifen did not exhibit any significant protective effects, however; the 0.8 and 2.4 mg/kg/day doses of tamoxifen, which are in the therapeutic range, dramatically reduced infarct of the affected cerebral hemisphere ( approximately 70% reduction) as compared to the controls. The reduction of infarct size was primarily due to protection of two major structures, the cerebral cortex and striatum. Laser Doppler analysis further revealed that tamoxifen had no significant effect on cerebral blood flow either before or after MCAO, suggesting that tamoxifen protection is independent of cerebral blood flow changes. Further studies showed that tamoxifen pellets implanted at the time of MCAO did not reduce infarct size, suggesting that pretreatment with tamoxifen is necessary to observe a protective effect. These studies suggest that clinically important SERMs may have an additional unrecognized beneficial effect of protection of the female brain.
Mehta
Shyamal H
SH
Department of Physiology, Medical College of Georgia, Augusta, Ga 30912, USA.
Dhandapani
Krishnan M
KM
De Sevilla
Liesl M
LM
Webb
R Clinton
RC
Mahesh
Virendra B
VB
Brann
Darrell W
DW
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D005260:Female; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*; D013629:Tamoxifen / Q000627:therapeutic use*
D018696:Neuroprotective Agents; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen