Tamoxifen, a Selective Estrogen Receptor Modulator, Reduces Ischemic Damage Caused by Middle Cerebral Artery Occlusion in the Ovariectomized Female Rat

Abstract

Previous work has demonstrated that physiological concentrations of 17β-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 (∼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 (∼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.

Acute inhibition of TAK1 protects against neuronal death in cerebral ischemia

“…25 Because tamoxifen affects ischemic brain damage, 26 we postponed MCAO to 6 weeks after tamoxifen treatment. With this regimen, tamoxifen had no effect on the infarct size (data not shown).…”

Neurotrophic and neuroprotective actions of estrogen: Basic mechanisms and clinical implications

“…LY353381.HCl did not affect cerebral blood flow, suggesting a potential direct neuroprotective effect of this SERM in the brain. Additionally, several studies have shown that the SERM, tamoxifen also significantly reduces infarct size in both transient and permanent occlusion/ reperfusion models of cerebral ischemia [40][41][42][43]. Like the raloxifene analogue, the protective effect of tamoxifen was independent of cerebral blood flow changes, indicating a potential direct neuroprotective effect of this SERM in the brain.…”

Tamoxifen Neuroprotection in Cerebral Ischemia Involves Attenuation of Kinase Activation and Superoxide Production and Potentiation of Mitochondrial Superoxide Dismutase

“…Along these lines, work by our laboratory and others has shown that the selective estrogen receptor modulator tamoxifen can significantly reduce infarct size in both transient and permanent occlusion/reperfusion models of cerebral ischemia (7)(8)(9)(10). Kimelberg and colleagues (7) were the first to report a neuroprotective action of tamoxifen after stroke in male animals, an effect later extended to female animals by our laboratory (9). The effect of tamoxifen was shown to be independent of cerebral blood flow changes, indicating a potential direct neuroprotective effect in the brain by tamoxifen.…”

“…pMCAO was used in all experiments, as described previously by our laboratory (9). Briefly, rats were anesthetized by im injection of ketamine/xylazine (60 mg/ml and 8 mg/ml, respectively).…”