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Vol. 77, No. 1, 2003
Issue release date: January 2003
Neuroendocrinology 2003;77:44–50

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

Mehta S.H. · Dhandapani K.M. · De Sevilla L.M. · Webb R.C. · Mahesh V.B. · Brann D.W.
aDepartment of Physiology, and bInstitute of Molecular Medicine and Genetics, Neurobiology Program, and Department of Neurology, Medical College of Georgia, Augusta, Ga., USA

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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.

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  1. Dhandapani K, Brann DW: Protective effects of estrogen and SERMs in the brain. Biol Reprod 2002;67:1379–1385.
  2. Hall ED, Pazara KE, Linserman KL: Sex differences in postischemic neuronal necrosis in gerbils. J Cereb Blood Flow Metab 1991;11:292–298.
  3. Alkayed NJ, Harukuni I, Kimes AS, London ED, Traystman RJ, Hurn PD: Gender-linked brain injury in experimental stroke. Stroke 1998;29:159–166.
  4. Dubal DB, Kashon ML, Pettigrew LC, Ren JM, Finklestein SP, Rau SW, Wise PM: Estradiol protects against ischemic injury. J Cereb Blood Flow Metab 1998;18:1253–1258.
  5. Simpkins JW, Rajakumar G, Zhang YQ, Simpkins CE, Greenwald D, Yu CJ, Bodor N, Day AL: Estrogens may reduce mortality and ischemic damage caused by middle cerebral artery occlusion in the female rat. J Neurosurg 1997;87:724–730.
  6. Zhang YQ, Shi J, Rajakumar G, Day AL, Simpkins JW: Effects of gender and estradiol treatment on focal brain ischemia. Brain Res 1998;784:321–324.

    External Resources

  7. Rusa R, Alkayed NJ, Crain BJ, Traystman RJ, Kimes AS, London ED, Klaus JA, Hurn PD: 17β-Estradiol reduces stroke injury in estrogen-deficient animals. Stroke 1999;30:1665–1670.
  8. Shi J, Panickar KS, Yang SH, Rabbani O, Day AL, Simpkins JW: Estrogen attenuates over-expression of β-amyloid precursor protein messenger RNA in an animal model of focal ischemia. Brain Res 1998;810:87–92.
  9. Dubal DB, Wise PM: Neuroprotective effects of estradiol in middle-aged female rats. Endocrinology 2001;142:43–48.
  10. Alkayed NJ, Crain BJ, Traystman RJ, Hurn PD: Estrogen-mediated neuroprotection in reproductively senescent rats. Stroke 1999;30:274–279.
  11. Brann DW, Mahesh VB: Endogenous excitatory amino acid involvement in the preovulatory and steroid-induced surge of gonadotropins in the female rat. Endocrinology 1991;128:1541–1547.
  12. D’Mello D, Mehta D, Pereira J, Rao CV: A toxicity study of simultaneous administration of tamoxifen and diazepam to female Wistar rats. Exp Toxicol Pathol 1999;51:549–553.
  13. Daniel CP, Gaskell SJ, Bishop H, Nicholson RI: Determination of tamoxifen and a hydroxylated metabolite in plasma from patients with advanced breast cancer using gas chromatography-mass spectrometry. J Endocrinol 1979;83:401–408.
  14. Delozier Y, Spielmann M, Mace-Lesec’h J, Janvier M, Hill C, Asselain B, Julien J, Weber B, Mauriac L, Petit J, Kerbrat P, Malhaire J, Vennin P, Leduc B, Namer M: Tamoxifen adjuvant treatment duration in early breast cancer: Initial results of a randomized study comparing short-term treatment with long-term treatment. J Clin Oncol 2000;18:3507–3512.
  15. Jordan VC, Bain RR, Brown RR, Gosden B, Santos MA: Determination and pharmacology of a new hydroxylated metabolite of tamoxifen observed in patient sera during therapy for advanced breast cancer. Cancer Res 1983;43:1446–1450.
  16. Zea-Longa E, Weinstein PR, Carlson S, Cummins R: Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 1989;20:84–91.
  17. Burger HG: The endocrinology of the menopause. Maturitas 1996;23:129–136.
  18. Brown RD, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO: Stroke incidence, prevalence, and survival: Secular trends in Rochester, Minnesota, through 1989. Stroke 1996;27:373–380.
  19. Mercuro G, Zoncu S, Cherchi A, Rosano G: Can menopause be considered an independent risk factor for cardiovascular disease? Ital Heart J 2001;2:719–727.
  20. Kimelberg H, Feustel P, Jin Y, Paquette J, Boulos A, Keller RW, Trammer BI: Acute treatment with tamoxifen reduces ischemic damage following middle cerebral artery occlusion. Neuroreport 2000;11:2675–2679.
  21. Dubal D, Zhu H, Yu J, Rau S, Shughrue P, Merchenthaler I, Kindy M, Wise PM: Estrogen receptor α, not β, is a critical link in estradiol-mediated protection against brain injury. Proc Natl Acad Sci USA 2001;98:1952–1957.
  22. Toung T, Hurn P, Traystman R, Sieber F: Estrogen decreases infarct size after temporary focal ischemia in a genetic model of type 1 diabetes mellitus. Stroke 2000;31:2701–2706.
  23. Obata T, Kubota S: Protective effect of tamoxifen on 1-methyl-4-phenylpyridine-induced hydroxyl radical generation in the rat striatum. Neurosci Lett 2001;308:87–90.
  24. Dluzen D, McDermott JL, Anderson LI: Tamoxifen diminishes methamphetamine-induced striatal dopamine depletion in intact female and male mice. J Neuroendocrinol 2001;13:618–624.
  25. Cheng CM, Cohen M, Wang J, Bondy CA: Estrogen augments glucose transporter and IGF1 expression in primate cerebral cortex. FASEB J 2001;15:907–915.
  26. Cyr M, Thibault C, Morissette M, Landry M, Di Paolo T: Estrogen-like activity of tamoxifen and raloxifene on NMDA receptor binding and expression of its subunits in rat brain. Neuropsychopharmacology 2001;25:242–257.
  27. Cyr M, Morissette M, Landry M, Di Paolo T: Estrogenic activity of tamoxifen and raloxifene on rat brain AMPA receptors. Neuroreport 2001;12:535–539.
  28. Ernst T, Chang L, Cooray D, Salvador C, Jovicich J, Walot I, Boone K, Chebowski R: The effect of tamoxifen and estrogen on brain metabolism in elderly women. J Natl Cancer Inst 2002;94:592–597.
  29. Wu X, Glinn M, Ostrowski N, Su Y, Ni B, Cole H, Bryant H, Paul SM: Raloxifene and estradiol benzoate both fully restore hippocampal choline acetyltransferase activity in ovariectomized rats. Brain Res 1999;847:98–104.
  30. Pinilla L, Gonzalez L, Tena-Sempere M, Aguilar E: Evidence for an estrogen-like action of raloxifene upon the hypothalamic-pituitary unit: raloxifene inhibits luteinizing hormone secretion and stimulates prolactin secretion in ovariectomized female rats. Neurosci Lett 2001;311:149–152.
  31. Rossberg M, Murphy S, Traystman R, Hurn PD: LY353381.HCl, a selective estrogen receptor modulator, and experimental stroke. Stroke 2000;31:3041–3046.
  32. Toran-Allerand CD, Miranda R, Hochberg R, MacLusky NJ: Cellular variations in estrogen receptor mRNA translation in the developing brain: evidence from combined [125I]estrogen autoradiography and non-isotopic in situ hybridization histochemistry. Brain Res 1992;576:25–41.
  33. Kuppers E, Beyer C: Expression of estrogen receptor-α and -β mRNA in the developing and adult mouse striatum. Neurosci Lett 1999;276:95–98.

    External Resources

  34. Sawada M, Alkayed N, Goto S, Crain B, Traystman R, Shaivitz A, Nelson R, Hurn PD: Estrogen receptor antagonist ICI182,780 exacerbates ischemic injury in female mouse. J Cereb Blood Flow Metab 2000;20:112–118.
  35. Ahotupa M, Mantyla E, Kangas L: Antioxidant properties of the triphenylethylene antiestrogen drug toremifene. Arch Pharmacol 1997;356:297–302.
  36. Kuohung W, Shwaery GT, Keaney JF Jr: Tamoxifen, esterified estradiol, and physiologic concentrations of estradiol inhibit oxidation of low-density lipoprotein by endothelial cells. Am J Obstet Gynecol 2001;184:1060–1063.
  37. Phillis JW, Song D, O’Regan MH: Tamoxifen, a chloride channel blocker, reduces glutamate and aspartate release from ischemic cerebral cortex. Brain Res 1998;780:352–355.
  38. Osuka K, Feustel PJ, Mongin AA, Tranmer BI, Kimelberg HL: Tamoxifen inhibits nitrotyrosine formation after reversible middle cerebral artery occlusion in the rat. J Neurochem 2001;76:1842–1850.

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