Selective estrogen receptor modulators as brain therapeutic agents

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   Figure 1

   Summary of the neuroprotective effects of SERMs reported in animal models of neurodegenerative, cognitive, and affective disorders.
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   Figure 2

   SERMs prevent excitotoxic neuronal death in vivo after kainic acid administration. High magnification of the hilus of the dentate gyrus of ovariectomized rats stained with toluidine blue after the i.p. injection of vehicle (Control); kainic acid (KA; 7 mg/kg); tamoxifen (1 mg/kg) and kainic acid; raloxifene (1 mg/kg) and kainic acid; lasofoxifene (1 mg/kg) and kainic acid; bazedoxifene (2 mg/kg) and kainic acid. Kainic acid results in the loss of hilar neurons (large cells). Small cell nuclei correspond to glial cells. Some SERMs, such as tamoxifen, raloxifene, and bazedoxifene, prevent the excitotoxic effect of kainic acid. Adapted, with permission, from Ciriza I, Carrero P, Azcoitia I, Lundeen SG & Garcia-Segura LM 2004 Selective estrogen receptor modulators protect hippocampal neurons from kainic acid excitotoxicity: differences with the effect of estradiol. Journal of Neurobiology 61 209–221. © 2004 Wiley Periodicals, Inc.
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   Figure 3

   SERMs reduce microglia activation after the administration of LPS in vivo. Representative images of the central white matter of the cerebellum of male rats showing immunoreactivity for MHC-II, a marker of activated microglia, after the i.p. injection of (A) vehicles for SERMs (DMSO) and LPS (phosphate buffer); (B) LPS; (C) 1 mg/kg tamoxifen and LPS; (D) 1 mg/kg raloxifene and LPS. Insets show details of the morphology of MHC-II immunoreactive cells at high magnification. LPS increases the number of MHC-II immunoreactive microglial cells and induces a reactive phenotype in microglia, with thicker and shorter cell processes. SERMs revert the effect of LPS. Scale bar 100 μm. In the insets, the scale bar represents 25 μm. Adapted, with permission, from Tapia-Gonzalez S, Carrero P, Pernia O, Garcia-Segura LM & Diz-Chaves Y 2008 Selective oestrogen receptor (ER) modulators reduce microglia reactivity in vivo after peripheral inflammation: potential role of microglial ERs. Journal of Endocrinology 198 219–230. © 2008 Society for Endocrinology.
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   Figure 4

   Summary of the molecular mechanisms involved in the neuroprotective effects of SERMs. SERMs act in the nervous system through classical ERs or by ER-independent mechanisms and activate a variety of signaling molecules, including MAPK, PI3K, Akt, CREB, and NF-κB. These molecules, in turn, trigger different coordinated mechanisms to promote neuronal survival and regulate mood and cognition.

• © 2011 Society for Endocrinology