Abstract
Overian hormones can protect against brain injury, neurodegeneration, and cognitive decline. Most attention has focused on estrogens and accumulating data demonstrate that estrogen seems to specifically protect cortical and hippocampal neurons from ischemic injury and from damage due to severe seizures. Although multiple studies demonstrate protection by estrogen, in only a few instances is the issue of how the steroid confers protection known. Here, we first review data evaluating the neuroprotective effects of estrogens, a selective estrogen receptor modulator (SERM), and estrogen receptor α-and β-selective ligands in animal models of focal and global ischemia. Using focal ischemia in ovariectomized ERαKO, ERβKO, and wild-type mice, we clearly established that the ERα subtype is the critical ER mediating neuroprotection in mouse focal ischemia. In rats and mice, the middle cerebral artery occlusion (MCAO) model was used to represent cerebrovascular stroke, while in gerbils the two-vessel occlusion model, representing global ischemia, was used. The gerbil global ischemia model was used to evaluate the neuroprotective effects of estrogen, SERMs, and ERα-and ERβ-selective compounds in the hippocampus. Analysis of neurogranin mRNA, a marker of viability of hippocampal neurons, with in situ hybridization, revealed that estrogen treatment protected the dorsal CA1 regions not only when administered before, but also when given 1 h after occlusion. Estrogen rarely is secreted alone and studies of neuroprotection have been less extensive for a second key ovarian hormone progesterone. In the second half of this review, we present data on neuroprotection by estrogen and progesterone in animal model of epilepsy followed by exploration into ovarian steroid effects on neuronal damage in models of multiple sclerosis and traumatic brain injury.
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Behl, C. (2002). Nat. Rev. Neurosci. 3, 433–442.
Garcia-Segura, L. M., Azcoitia, I., and DonCarlos, L. L. (2001). Prog. Neurobiol. 63, 29–60.
Wise, P. M., Dubal, D. B., Wilson, M. E., Rau, S. W., and Bottner, M. (2001). Endocrinology 142, 969–973.
Hoffman, G. E., Moore, N., Fiskum, G., and Murphy, A. Z. (2003). Exp. Neurol. 182, 124–134.
Veliskova, J., Velisek, L., Galanopoulou, A. S., and Sperber E. F. (2000). Epilepsia 41 (Suppl. 6), S30-S35.
Backstrom, T. (1976). Acta Neurolog. Scand. 54, 321–347.
Ramsay, R. E. (1987). J. Clin. Neurophysiol. 4, 23–25.
Schachter, S. C. (1988). Arch. Neurol. 45, 1267–1270.
Morrell, M. J. (1992). Epilepsia 33, S49–61.
Morrell, M. J. (1999). Neurology 53(4 Suppl. 1), S42–48.
Morrell, M. J., Sarto, G. E., Shafer, P. O., Borda, E. A., Herzog, A., and Callanan, M. (2000). J. Womens Health Gend. Based Med. 9, 959–965.
Huang, Z., Huang, P. L., Panahian, N., Dalkara, T., Fishman, M. C., and Moskowitz, M. A. (1994). Science 265, 1883–1885.
Alkayed, N. J., Harukuni, I., Kimes, A. S., London, E. D., Traystman, R. J., and Hurn, P. D. (1998). Stroke 29, 159–165; discussion 166.
Dubal, D. B., Kashon, M. L., Pettigrew, L. C., et al. (1998). J. Cereb. Blood Flow Metab. 18, 1253–1258.
Dubal, D. B., Shughrue, P. J., Wilson, M. E., Merchenthaler, I., and Wise, P. M. (1999). J. Neurosci 19, 6385–6393.
Dubal, D. B., and Wise, P. M. (2001). Endocrinology, 142, 43–48.
Simpkins, J. W., Green, P. S., Gridley, K. E., Singh, M., de Fiebre, N. C., and Rajakumar, G. (1997). Am. J. Med. 103, 19S-25S.
Dubal, D. B., Zhu, H., Yu. J., et al. (2001). Proc. Natl. Acad. Sci. USA 98, 1952–1957.
Yang, S. H., Shi, J., Day, A. L., and Simpkins, J. W. (2000). Stroke 31, 745–749; discussion 749-750.
Merchenthaler, I., Dellovade, T. L., and Shughrue, P. J. (2003). Ann. NY Acad. Sci. 1007, 89–100.
Shughrue, P. J., Stumpf, W. E., MacLusky, N. J., Zielinski, J. E., and Hochberg, R. B. (1990). Endocrinology 126, 1112–1124.
Choi, D. W. (1996). Curr. Opin. Neurobiol. 6, 667–672.
Leker R. R. and Shohami, E. (2002). Brain Res. Brain Res. Rev. 39, 55–73.
Teixeira, C., Reed, J. C. and Pratt, M. A. (1995). Cancer Res., 55, 3902–3907.
Bredesen D. E. (1995). Ann. Neurol. 38, 839–851.
MacManus, J. P. and Buchan, A. M. (2000). J. Neurotrauma 17, 899–914.
Merry, D. E. and Korsmeyer, S. J. (1997). Ann. Rev. Neurosci. 20, 245–267.
Tanaka, H., Grooms, S. Y., Bennett, M. V., and Zukin, R. S. (2000). Brain Res. 886, 190–207.
Graham, S. H. and Chen, J. (2001). J. Cereb. Blood Flow Metabol. 21, 99–109.
Shughrue, P. J. and Merchenthaler, I. (2003). Neuroscience 116, 851–861.
Green, P. S., Gordon, K., and Simpkins, J. W. (1997). J. Steroid Biochem. Mol. Biol. 63, 229–235.
Toran-Allerand, C. D. (2000). Novartis Found. Symp. 230, 56–69 discussion 69-73.
Asimiadou, S., Bittigau, P., Felderhoff-Mueser, U., et al. (2005). Ann. Neurol. 58, 266–276.
Balthazart, J., Baillien, M., and Ball, G. F. (2005). J. Neuroendocrinol. 17, 553–559.
Bryant, D. N., Bosch, M. A., Ronnekleiv, O. K., and Dorsa, D. M. (2005). Neuroscience 133, 343–352.
Foster, T. C. (2005). Front. Neuroendocrinol. 26, 51–64.
Guerra, B., Diaz, M., Alonso, R., and Marin, R. (2004). J. Neurochem. 91, 99–109.
Hilke, S., Theodorsson, A., Fetissov, S., et al. (2005) Eur. J. Neurosci. 21, 2089–2099.
Malyala, A., Kelly, M. J., and Ronnekleiv, O. K. (2005). Steroids 70, 397–406.
Marin, R., Guerra, B., Alonso, R., Ramirez, C. M., and Diaz, M. (2005). Curr. Neurovasc. Res. 2, 287–301.
Qiu, J., Bosch, M. A., Tobias, S. C., et al. (2003). J. Neurosci. 23, 9529–9540.
Moosmann, B. and Behl, C. (1999). Proc. Natl. Acad. Sci. USA 96, 8867–8872.
Wu, T. W., Wang, J. M., Chen, S., and Brinton, R. D. (2005). Neuroscience 135, 59–72.
Roof, R. L., Duvdevani, R., Heyburn, J. W., and Stein, D. G. (1996). Exp. Neurol. 138, 246–251.
Grossman, K. J., Goss, C. W. and Stein, D. G. (2004). Brain Res. 1008, 29–39.
He, J., Evans, C. O., Hoffman, S. W., Oyesiku, N. M., and Stein, D. G. (2004). Exp. Neurol. 189, 404–412.
Roof, R. L., Duvdevani, R., and Stein, D. L. (1993). Brain Res. 607, 333–336.
Gonzalez Deniselle, M. C., Lopez-Costa, J. J., Saavedra, J. P. et al. (2002). Neurobiol. Dis. 11, 457–468.
Chen, J., Chopp, M., and Li, Y. (1999). J. Neurol. Sci. 171, 24–30.
Jiang, N., Chopp, M., Stein, D., and Feit, H. (1996) Brain Res. 735, 101–107.
Murphy, S. J., Littleton-Kearney, M. T., and Hurn, P. D. (2002) J. Cereb. Blood Flow Metab. 22, 1181–1188.
Gibson, C. L., Constantin, D., Prior, M. J., Bath, P. M., and Murphy, S. P. (2005). Exp. Neurol. 193, 522–530.
Murphy, S. J., Traystman, R. J., Hurn, P. D., and Duckles, S. P. (2000). Stroke 31, 1173–1178.
Miller, L., Alley, E. W., Murphy, W. J., Russell, S. W., and Hunt, J. S. (1996). J. Leuk. Biol. 59, 442–450.
Murphy, S., Simmons, M. L., Agullo, L. et al. (1993) Trends Neurosci. 16, 323–328.
Polan, M. L., Loukides, J., Nelson, P., et al. (1989). J. Clin. Endocrinol. Metab. 69, 1200–1206.
Betz, A. L. (1986). Fed. Proc. 45, 2050–2054.
Chaplin, E. R., Free, R. G., and Goldstein, G. W. (1981). Biochem. Pharmacol. 30, 241–245.
Herkes, G. K., Eadie, M. J., Sharbrough, F., and Moyer, T. (1993). Epilepsy Res. 15, 47–52.
Herzog, A. G., Klein, P., and Ransil, B. J. (1997). Epilepsia 38, 1082–1088.
Murri, L. and Galli, R. (1997). Cephalalgia 17 (Suppl. 20), 46–47.
Beyenburg, S., Stoffel-Wagner, B., Bauer, J., et al. (2001). Epilepsy Res. 44, 141–153.
Bonuccelli, U., Melis, G. B., Paoletti, A. M., Fioretti, P., Murri, L., and Muratorio, A. (1989). Epilepsy Res. 3, 100–106.
Buterbaugh G. G. (1987). Pharmacol. Biochem. Behav. 28, 291–297.
Buterbaugh, G. G. (1989). Epilepsy Res. 4, 207–215.
Edwards, H. E., Burnham, W. M., Mendonca A., Bowlby, D. A., and MacLusky, N. J. (1999). Brain Res. 838, 136–150.
Hom, A. C., Leppik, I. E., and Rask, C. A. (1993). Neurology 43, 198–204.
Hom, A. C. and Buterbaugh, G. G. (1986). Epilepsia 27, 103–108.
Buterbaugh, G. G. and Hudson, G. M. (1991). Exp. Neurol. 111, 55–64.
Bauer, J. (2001). Epilepsia 42, 20–22.
Herzog, A. G. (1995). Neurology 45, 1660–1662.
Holmes, G. L. and Weber, D. A. (1984). Dev. Brain Res. 16, 45–53.
Kalviainen, R., Salmenpera, T., Partanen, K., Vainio, P., Riekkinen, P. and Pitkanen A. (1998). Neurology 50, 1377–1382.
Mathern, G. W., Price, G., Rosales, C., Pretorius, J. K., Lozada, A., and Mendoza, D. (1998). Epilepsy Res. 30, 133–151.
Moshe, S. L. (1988). J. Child Neurol. 13 (Suppl. 1), S3–6; discussion S30-32.
Salmenpera, T., Kalviainen, R., Partanen, K., and Pitkanen, A. (2001). Epilepsy Res. 46, 69–82.
Tasch, E., Cendes, F., Li, L. M., Dubeau, F., Andermann, F., and Arnold, D. L. (1999). Ann. Neurol. 45, 568–576.
Gayoso, M. J., Primo, C., al-Majdalawj, A., Fernandez, J. M., Garrosa, M., and Iniguez, C. (1994). Brain Res. 653, 92–100.
Jarrard, L. E. and Meldrum, B. S. (1993). Neuropathol. Appl. Neurobiol. 19, 381–389.
Lothman, E. W. and Collins, R. C. (1981). Brain Res. 218, 299–318.
Olney, J. W., Collins, R. C., and Sloviter, R. S. (1986). Adv. Neurol. 44, 857–877.
Olney, J. W., Fuller, T., and de Gubareff, T. (1979). Brain Res. 176, 91–100.
Sperk, G., Lassmann, H., Baran, H., Kish, S. J., Seitelberger, F., and Hornykiewicz O. (1983). Neuroscience 10, 1301–1315.
Frye, C. A., Manjarrez, J., and Camacho-Arroyo, I. (2000). Brain Res. 881, 98–102.
Tauboll, E. and Lindstrom, S. (1993). Epilepsy Res. 14, 17–30.
Baulieu, E. E., Schumacher, M., Koenig, H., Jung-Testas, I., and Akwa, Y. (1996). Cell Mol. Neurobiol. 16, 143–154.
Frye, C. A. (1995). Brain Res. 696, 113–120.
Frye, C. A., Murphy R. E., and Platek, S. M. (2000). Behav. Brain Res. 115, 55–64.
Frye, C. A., Scalise, T. J., and Bayon, L. E. (1998). J. Neuroendocrinol. 10, 291–296.
Galli, R., Luisi, M., Pizzanelli, C. et al. (2001). Epilepsia 42, 216–219.
Barbaccia, M. L., Roscetti, G., Trabucchi, M., et al. (1996). Neuroendocrinology 63, 166–172.
Friedman, L., Gibbs, T. T. and Farb, D. H. (1993). Mol. Pharmacol. 44, 191–197.
Gulinello, M., Gong, Q. H., Li, X., and Smith, S. S. (2001). Brain Res. 910, 55–66.
Wohlfarth, K. M., Bianchi, M. T., and Macdonald, R. L. (2002). J. Neurosci. 22, 1541–1549.
Azcoitia, I., Sierra, A., and Garcia-Segura, L. M. (1998). Neuroreport 9, 3075–3079.
Fujikawa, D. G., Shinmei, S. S., and Cai, B. (2000). Epilepsia 41, S9–13.
Kondo, T., Sharp, F. R., Honkaniemi, J., Mikawa, S., Epstein, C. J., and Chan, P. H. (1997). J. Cereb. Blood Flow Metab. 17, 241–256.
Kondratyev, A. and Gale, K. (2001). Neurosci. Lett. 310, 13–16.
Liu, W., Liu, R., Chun, J. T., et al. (2001). Brain Res. 916, 239–248.
Pollard, H., Cantagrel, S., Charriaut-Marlangue, C., Moreau, J., and Ben Ari, Y. (1994). Neuroreport 5, 1053–1055.
Pollard, H., Charriaut-Marlangue, C., Cantagrel, S., et al. (1994). Neuroscience 63, 7–18.
Venero, J. L., Revuelta, M., Machado, A., and Cano, J. (1999). Neuroscience 94, 1071–1081.
Gillardon, F., Wickert, H., and Zimmermann, M. (1995). Neurosci. Lett. 192, 85–88.
Choi, K. C., Kang, S. K., Tai, C. J., Auersperg, N., and Leung, P. C. (2001). Endocrinology 142, 2351–2360.
Harms, C., Lautenschlager, M., Bergk, A., et al. (2001). J. Neurosci. 21, 2600–2609.
Pike, C. J. (1999). J. Neurochem. 72, 1552–1563.
Sawada, H., Ibi, M., Kihara, T., et al. (2000) FASEB J. 14, 1202–1214.
Goodman, Y., Bruce, A., Cheng, B., and Mattson, M. (1996). J. Neurochem. 66, 1836–1844.
Bramlett, H. M. and Dietrich W. D. (2001). J. Neurotrauma 18, 891–900.
Roof, R. L., Duvdevani, R., Braswell, L., and Stein, D. G. (1994). Exp. Neurol. 129, 64–69.
Robertson, C. L., Puskar, A., Hoffman, G. E., Murphy, A. Z., Saraswati, M., and Fiskum, G. (2006). Exp. Neurol. 197, 235–243.
Cutler, S. M., Pettus, E. H., Hoffman, S. W., and Stein, D. G. (2005). Exp. Neurol. 195, 423–429.
Meffre, D., Delespierre, B., Gouezou, M. et al. (2005). J. Neurochem. 93, 1314–1326.
Suzuki, T., Bramlett, H. M., Ruenes, G., and Dietrich, W. D. (2004). J. Neurotrauma 21, 842–853.
Stein, D. G. and Hoffman S. W. (2003). Pediatr. Rehabil. 6, 13–22.
Perry, V. H., and Anthony, D. C. (1999). Philos. Trans. R. Soc. Lond. B Biol. Sci. 354, 1641–1647.
Peterson, J. W., Bo, L., Mork, S., Chang, A., and Trapp, B. D. (2001). Ann. Neurol. 50, 389–400.
Alcazar, A., Regidor, I., Masjuan, J., Salinas, M., and Alvarez-Cermeno, J. C. (1998). Neurosci. Lett. 255, 75–78.
Alcazar, A., Regidor, I., Masjuan, J., Salinas, M., and Alvarez-Cermeno, J. C. (2000). J. Neuroimmunol. 104, 58–67.
Oren, A., White, L. R., and Aasly, J. (2001) J. Neurol. Sci. 186, 31–36.
Whitacre, C. C. (2001). Nat. Immunol. 2, 777–780.
Duquette, P. and Girard, M. (1993). Curr. Opin. Neurol. Neurosurg. 6, 195–201.
Runmarker, B. and Andersen, O. (1995). Brain 118, 253–261.
Siiteri, P. K. and Stites, D. P. (1982). Biol. Reprod. 26, 1–14.
Arnason, B. G. and Richman, D. P. (1969). Trans. Am. Neurol. Assoc. 94, 54–58.
Bebo, B. F. Jr., Fyfe-Johnson, A., Adlard K., Beam, A. G., Vandenbark, A. A., and Offner, H. (2001). J. Immunol. 166, 2080–2089.
Gilmore, W., Weiner, L. P., and Correale, J. (1997) J. Immunol. 158, 446–451.
Ito, A., Bebo, B. F. Jr., Matejuk, A. et al. (2001). J. Immunol. 167, 542–552.
Kim, S., Liva, S. M., Dalal, M. A., Verity, M. A., and Voskuhl, R. R. (1999). Neurology 52, 1230–1238.
Marzi, M., Vigano, A., Trabattoni, D., et al., (1996). Clin. Exp. Immunol. 106, 127–133.
Trooster, W. J., Teelken, A. W., Gerrits, P. O., et al. (1996) Clin. Neurol. Neurosurg. 98, 222–226.
Piccinni, M. P., Giudizi, M. G., Biagiotti, R., et al. (1995) J. Immunol. 155, 128–133.
Hoffman, G. E., Le, W. W., Murphy, A. Z., and Koski, C. L. (2001). Exp. Neurol. 171, 272–284.
Venters, H. D., Dantzer, R., and Kelley, K. W. (2000). Trends Neurosci. 23, 175–180.
Koski, C. L., Hila, S., and Hoffman, G. E. (2004) Endocrinology 145, 95–103.
Green, P. S. and Simpkins, J. W. (2000). Int. J. Dev. Neurosci. 18, 347–358.
Jellinger, K. A., and Bancher, C. (1998). J. Neural. Transm. Suppl. 54, 77–95.
MacLusky, N. J., Chalmers-Redman, R., Kay, G., Ju, W., Nethrapalli, I. S., and Tatton, W. G. (2003). Neuroscience 118, 741–754.
Wilson, M. E., Dubal, D. B., and Wise, P. M. (2000). Brain Res. 873, 235–242.
Formby, B. and Wiley, T. S. (1998). Ann. Clin. Lab. Sci. 28, 360–369.
Gompel, A., Somai, S., Chaouat, M., et al. (2000). Steroids 65, 593–598.
Bernauer, S., Wehling, M., Gerdes, D., and Falkenstein, E. (2001). DNA Seq. 12, 13–25.
Krippner-Heidenreich, A., Tubing, F., Bryde, S., Willi, S. Zimmermann, G., and Scheurich, P. (2002). J. Biol. Chem. 277, 44155–44163.
Littlejohn, A. F., Tucker, S. J., Mohamed, A. A. et al. (2003). Biochem. Pharmacol. 65, 91–99.
Mielke, K. and Herdegen, T. (2000). Prog. Neurobiol. 61, 45–60
reen, D. R. (1998). Cell 94, 695–698.
Mielke, K. and Herdegen, T. (2002). Mol. Cell. Neurosci. 20, 211–224.
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Hoffman, G.E., Merchenthaler, I. & Zup, S.L. Neuroprotection by ovarian hormones in animal models of neurological disease. Endocr 29, 217–231 (2006). https://doi.org/10.1385/ENDO:29:2:217
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DOI: https://doi.org/10.1385/ENDO:29:2:217