, Volume 14, Issue 3, pp 407–415

Ovarian hormones elicit phosphorylation of akt and extracellular-signal regulated kinase in explants of the cerebral cortex



Estradiol and progesterone both have been demonstrated to afford neuroprotection against various insults. In an attempt to identify potential mechanisms underlying these neuroprotective effects, two key elements within signal transduction pathways linked to neuroprotection were evaluated. In mouse cerebral cortical explants, both estradiol and progesterone elicited the phosphorylation of Akt, a downstream effector of the phosphoinositide-3 (PI-3) kinase pathway. Progesterone also elicited the phosphorylation of extracellular-signal regulated kinase (ERK), a component of the mitogen-activated protein kinase (MAPK) pathway. These effects were not inhibited by the progesterone receptor antagonist, RU486. However, inhibition of either MAPK/ERK kinase with PD98059 or PI-3 kinase with LY294002 successfully inhibited progesterone's actions on ERK and Akt, respectively. Collectively, the data offer novel mechanisms for both progesterone and estrogen action in the central nervous system, demonstrating the functional and mechanistic diversity of gonadal hormones and supporting their neuroprotective potential for such neurodegenerative disorders as Alzheimer disease.

Key Words

Progesterone estrogen Akt extracellular-signal regulated kinase neuroprotection signal transduction 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Toran-Allerand, C. D. (1976). Brain Res. 106, 407–412.PubMedCrossRefGoogle Scholar
  2. 2.
    Toran-Allerand, C. D. (1980). Brain Res. 189, 413–427.PubMedCrossRefGoogle Scholar
  3. 3.
    Luine, V. N., Richards, S. T., Wu, V. Y., and Beck, K. D. (1998). Horm. Behav. 34, 149–162.PubMedCrossRefGoogle Scholar
  4. 4.
    Singh, M., Meyer, E. M., Millard, W. J., and Simpkins, J. W. (1994). Brain Res. 644, 305–312.PubMedCrossRefGoogle Scholar
  5. 5.
    Panickar, K. S., Guan, G., King, M. A., Rajakumar, G., and Simpkins, J. W. (1997). J. Neurobiol. 33, 961–967.PubMedCrossRefGoogle Scholar
  6. 6.
    Singer, C. A., Rogers, K. L., Strickland, T. M., and Dorsa, D. M. (1996). Neurosci. Lett. 212, 13–16.PubMedCrossRefGoogle Scholar
  7. 7.
    Green, P. S., Gridley, K. E., and Simpkins, J. W. (1996). Neurosci. Lett. 218, 165–168.PubMedCrossRefGoogle Scholar
  8. 8.
    Gridley, K. E., Green, P. S., and Simpkins, J. W. (1997). Brain Res. 778, 158–165.PubMedCrossRefGoogle Scholar
  9. 9.
    Goodman, Y., Bruce, A. J., Cheng, B., and Mattson, M. P. (1996). J. Neurochem. 66, 1836–1844.PubMedCrossRefGoogle Scholar
  10. 10.
    Simpkins, J. W., Rajakumar, G., Zhang, Y. Q., Simpkins, C. E., Greenwald, D., Yu, C. J., Bodor, N., and Day, A. L. (1997). J. Neurosurg. 87, 724–730.PubMedCrossRefGoogle Scholar
  11. 11.
    Hawk, T., Zhang, Y. Q., Rajakumar, G., Day, A. L., and Simpkins, J. W. (1998). Brain Res. 796, 296–298.PubMedCrossRefGoogle Scholar
  12. 12.
    Behl, C., Widmann, M., Trapp, T., and Holsboer, F. (1995). Biochem. Biophys. Res. Commun. 216, 473–482.PubMedCrossRefGoogle Scholar
  13. 13.
    Roof, R. L., Duvdevani R., Braswell, L., and Stein, D. G. (1994). Exp. Neurol. 129, 64–69.PubMedCrossRefGoogle Scholar
  14. 14.
    Asbury, E. T., Fritts, M. E., Horton, J. E., and Isaac, W. L. (1998). Behav. Brain Res. 97, 99–106.PubMedCrossRefGoogle Scholar
  15. 15.
    Roof, R. L., Hoffman, S. W., and Stein, D. G. (1997). Mol. Chem. Neuropathol. 31, 1–11.PubMedGoogle Scholar
  16. 16.
    Landers, J. P. and Spelsberg, T. C. (1992). Crit. Rev. Eukaryot. Gene Expr. 2 19–63.PubMedGoogle Scholar
  17. 17.
    Gronemeyer, H. (1992). FASEB J. 6, 2524–2529.PubMedGoogle Scholar
  18. 18.
    Aronica, S. M., Kraus, W. L., and Katzenellenbogen, B. S. (1994). Proc. Natl. Acad. Sci. USA 91, 8517–8521.PubMedCrossRefGoogle Scholar
  19. 19.
    Beyer, C. and Karolczak, M. (2000). J. Neurosci. Res. 59, 107–116.PubMedCrossRefGoogle Scholar
  20. 20.
    Watters, J. J. and Dorsa, D. M. (1998). J. Neurosci. 18, 6672–6680.PubMedGoogle Scholar
  21. 21.
    Morley, P., Whitfield, J. F., Vanderhyden, B. C., Tsang, B. K., and Schwartz, J. L. (1992). Endocrinology 131, 1305–1312.PubMedCrossRefGoogle Scholar
  22. 22.
    Pozzo-Miller, L. D., Inoue, T., and Murphy, D. D. (1999). J. Neurophysiol. 81, 1404–1411.PubMedGoogle Scholar
  23. 23.
    Buitrago, C., Massheimer, V., and de Boland, A. R. (2000). Cell Signal 12, 47–52.PubMedCrossRefGoogle Scholar
  24. 24.
    Migliaccio, A., Di Domenico, M., Castoria G., de Falco A., Bontempo, P., Nola, E., and Auricchio, F. (1996). EMBO J. 15, 1292–1300.PubMedGoogle Scholar
  25. 25.
    Singer, C. A., Figueroa-Masot, X. A., Batchelor, R. H., and Dorsa, D. M. (1999). J. Neurosci. 19, 2455–2463.PubMedGoogle Scholar
  26. 26.
    Singh, M., Setalo, G. Jr., Guan, X., Warren, M., and Toran-Allerand, C. D. (1999). J. Neurosci. 19, 1179–1188.PubMedGoogle Scholar
  27. 27.
    Singh, M., Setalo, G. Jr., Guan, X., Frail, D. E., and Toran-Allerand, C. D. (2000). J. Neurosci. 20, 1694–1700.PubMedGoogle Scholar
  28. 28.
    Desdouits-Magnen, J., Desdouits, F., Takeda, S., Syu, L. J., Saltiel, A. R., Buxbaum, J. D., Czernik, A. J., Nairn, A. C., and Greengard, P. (1998). J. Neurochem. 70, 524–530.PubMedCrossRefGoogle Scholar
  29. 29.
    Mills, J., Laurent Charest, D., Lam, F., Beyreuther, K., Ida, N., Pelech, S. L., and Reiner, P. B. (1997). J. Neurosci. 17, 9415–9422.PubMedGoogle Scholar
  30. 30.
    Datta, S. R., Brunet, A., and Greenberg, M. E. (1999). Genes Dev. 13, 2905–2927.PubMedCrossRefGoogle Scholar
  31. 31.
    Datta, S. R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, Y., and Greenberg, M. E. (1997). Cell 91, 231–241.PubMedCrossRefGoogle Scholar
  32. 32.
    Zha, J., Harada H., Yang, E., Jockel, J., and Korsmeyer, S. J. (1996). Cell 87, 619–628.PubMedCrossRefGoogle Scholar
  33. 33.
    D'Mello, S. R., Borodezt, K., and Soltoff, S. P. (1997). J. Neurosci. 17, 1548–1560.PubMedGoogle Scholar
  34. 34.
    Klesse, L. J. and Parada, L. F. (1998). J. Neurosci. 18, 10,420–10,428.Google Scholar
  35. 35.
    Dudek, H., Datta, S. R., Franke, T. F., Bimbaum, M. J., Yao, R., Cooper, G. M., Segal, R. A., Kaplan, D. R., and Greenberg, M. E. (1997). Science 275, 661–665.PubMedCrossRefGoogle Scholar
  36. 36.
    Marshall, C. (1995). Cell 80, 179–185.PubMedCrossRefGoogle Scholar
  37. 37.
    Jung-Testas, I., Do Thi, A., Koenig, H., Desarnaud, F., Shazand, K., Schumacher, M., and Baulieu, E. E. (1999). J. Steroid Biochem. Mol. Biol. 69, 97–107.PubMedCrossRefGoogle Scholar
  38. 38.
    Jung-Testas, I. and Baulieu, E. E. (1998). J. Steroid Biochem. Mol. Biol. 65, 243–251.PubMedCrossRefGoogle Scholar
  39. 39.
    Szeberenyi, J. (1996). Neurobiology (Budapest) 4, 1–11.Google Scholar
  40. 40.
    Vanhoutte, P., Barnier, J. V., Guibert, B., Pages, C., Besson, M. J., Hipskind, R. A., and Caboche, J. (1999). Mol. Cell. Biol. 19, 136–146.PubMedGoogle Scholar
  41. 41.
    Whitmarsh, A. J., Shore, P., Sharrocks, A. D., and Davis, R. J. (1995). Science 269, 403–407.PubMedCrossRefGoogle Scholar
  42. 42.
    Xing, J., Kornhauser, J. M., Xia, Z., Thiele, E. A., and Greenberg, M. E. (1998). Mol. Cell. Biol. 18, 1946–1955.PubMedGoogle Scholar
  43. 43.
    Sgambato, V., Pages, C., Rogard, M., Besson, M. J., and Caboche, J. (1998). J. Neurosci. 18, 8814–8825.PubMedGoogle Scholar
  44. 44.
    Szeberenyi, J. and Erhardt, P. (1994). Biochim. Biophys. Acta 1222, 187–202.PubMedCrossRefGoogle Scholar
  45. 45.
    Davis, R. J. (1995). Mol. Reprod. Dev. 42, 459–467.PubMedCrossRefGoogle Scholar
  46. 46.
    Frodin, M., and Gammeltoft, S. (1999). Mol. Cell. Endocrinol. 151, 65–77.PubMedCrossRefGoogle Scholar
  47. 47.
    Nguyen, T. T., Scimeca, J. C., Filloux, C., Peraldi, P., Carpentier, J. L., and Van Obberghen, E. (1993). J. Biol. Chem. 268, 9803–9810.PubMedGoogle Scholar
  48. 48.
    Yan, C. Y. I. and Greene, L. A. (1998). J. Neurosci. 18, 4042–4049.PubMedGoogle Scholar
  49. 49.
    Creedon, D. J., Johnson, E. M., and Lawrence, J. C. (1996). J. Biol. Chem. 271, 20,713–20,718.Google Scholar
  50. 50.
    Klesse, L. J., Meyers, K. A., Marshall, C. J., and Parada, L. F. (1999). Oncogene 18, 2055–2068.PubMedCrossRefGoogle Scholar
  51. 51.
    Guyton, K. Z., Liu, Y., Gorospe, M., Xu, Q., and Holbrook, N. J. (1996). J. Biol. Chem. 271, 4138–4142.PubMedCrossRefGoogle Scholar
  52. 52.
    Bi, R., Broutman, G., Foy, M. R., Thompson, R. F., and Baudry, M. (2000). Proc. Natl. Acad. Sci. USA. 97, 3602–3607.PubMedCrossRefGoogle Scholar
  53. 53.
    Franke, T. F., Kaplan, D. R., and Cantley, L. C. (1997). Cell, 88, 435–437.PubMedCrossRefGoogle Scholar
  54. 54.
    Yang, E., Zha, J., Jockel, J., Boise, L. H., Thompson, C. B., and Korsmeyer, S. J. (1995). Cell 80, 285–291.PubMedCrossRefGoogle Scholar
  55. 55.
    Honda, K., Sawada, H., Kihara, T., Urushitani, M., Nakamizo, T., Akaike, A., and Shimohama, S. (2000). J. Neurosci. Res. 60, 321–327.PubMedCrossRefGoogle Scholar
  56. 56.
    Zubenko, G. S., Stiffler, J. S., Hughes, H. B., and Martinez, A. J. (1999). Biol. Psychiatry 45, 731–736.PubMedCrossRefGoogle Scholar
  57. 57.
    Edwards, D. P., Altmann, M., DeMarzo A., Zhang, Y., Weigel, N. L., and Beck, C. A. (1995). J. Steroid Biochem. Mol. Biol. 53, 449–458.PubMedCrossRefGoogle Scholar
  58. 58.
    Beck, C. A., Zhang, Y., Weigel, N. L., and Edwards, D. P. (1996). J. Biol. Chem. 271, 1209–1217.PubMedCrossRefGoogle Scholar
  59. 59.
    Behl, C., Trapp, T., Skutella, T., and Holsboer, F. (1997). Eur. J. Neurosci. 9, 912–920.PubMedCrossRefGoogle Scholar
  60. 60.
    Tang, M. X., Jacobs, D., Stern, Y., Marder, K., Schofield, P., Gurland, B., Andrews, H., and Mayeux, R. (1996). Lancet 348, 429–432.PubMedCrossRefGoogle Scholar
  61. 61.
    Singh, M., Meyer, E. M., and Simpkins, J. W. (1995). Endocrinology 136, 2320–2324.PubMedCrossRefGoogle Scholar
  62. 62.
    Sohrabji, F., Miranda, R. C., and Toran-Allerand, C. D. (1995). Proc. Natl. Acad. Sci. USA 92, 11,110–11,114.CrossRefGoogle Scholar
  63. 63.
    Gahwiler, B. (1981). J. Neurosci. Methods 4, 329–342.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2001

Authors and Affiliations

  1. 1.Center for Reproductive SciencesColumbia University, College of Physicians and SurgeonsNew York
  2. 2.Department of Obstrics and GynecologyColumbia University, College of Physicians and SurgeonsNew York

Personalised recommendations