Neuroprotective activity of tamoxifen in permanent focal ischemia

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Object. 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.

Article Information

Address reprint requests to: Harold K. Kimelberg, Ph.D., Division of Neurosurgery, A-60, Albany Medical College, 47 New Scotland Avenue, Albany, New York 12208. email: kimelbh@mail.amc.edu.

© AANS, except where prohibited by US copyright law.

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    Box plot showing time window for effects of tamoxifen on infarct volume measured using TTC 72 hours after permanent MCA occlusion (pMCAo). The times shown on the abscissa refer to the start of tamoxifen administration (20 mg/kg), measured from initiation of MCA occlusion; “pre-pMCAo” refers to animals infused with 20 mg/kg tamoxifen over a period of 15 minutes beginning 25 minutes before the start of ischemia. The boxes labeled 1 hour, 3 hour, and 6 hour pMCAo show infarct volumes measured in animals that received vehicle or 20 mg/kg tamoxifen starting at 1, 3, or 6 hours, respectively, after permanent MCA occlusion. As described in detail in Materials and Methods, the first two doses, for pretreatment and 1 hour after MCA occlusion, were given intravenously, whereas in the 3- and 6-hour permanent MCA occlusion groups all doses were administered intraperitoneally. All animals received additional 20-mg/kg intraperitoneal injections at 12-hour intervals measured from the first dose until death. The vehicle (control) groups received dimethyl sulfoxide injected at the same times via the same routes but are combined here for clarity and because there were no statistically significant differences among them. Box plots show the median value (horizontal line in box), and the interquartile range (25–75%) is represented by the box. Whiskers encompass the 5 to 95% range and the black squares indicate the means. Values from individual animals are plotted to the right of the box plots. *p < 0.05 compared with corresponding vehicle-treated controls (Mann—Whitney U-test).

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    Photographs of representative slices of rat brain stained with TTC for determination of infarct volume in a vehicle-treated animal (upper) and an animal receiving 20 mg/kg tamoxifen intravenously before MCA occlusion and intraperitoneally at 12-hour intervals thereafter (lower). The unstained (white) area in the cortex indicates the area of infarction.

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    Box plot showing effect of tamoxifen given intraperitoneally at doses of 1, 5, and 20 mg/kg 3 hours after permanent MCA occlusion with the same dose given intraperitoneally every 12 hours until death, on infarct size measured at 72 hours. Tamoxifen significantly reduces the volume of infarction at 5 mg/kg (*p < 0.05, Mann—Whitney U-test), as well as at 20 mg/kg (the 20 mg/kg data are the same as in Fig. 1).

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