Structure-Nongenomic Neuroprotection Relationship of Estrogens and Estrogen-Derived Compounds

Hormones in Neurodegeneration, Neuroprotection, and Neurogenesis

Volumn , Issue , 2011, Pages 13-28

  Simpkins, James W ^a   Yi, Kun Don ^a   Perez, Evelyn ^b   Covey, Douglas ^c  

^a UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER   (United States)

^b NATIONAL INSTITUTE ON AGING   (United States)

^c WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Estradiol; Estratriene; Estrogen; Estrogen receptor; Estrone; Middle cerebral artery occlusion; Neuroprotection; Phenolic A ring; Signal transduction; Structure activity relationship

Indexed keywords

EID: 84885510257     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9783527633968.ch2     Document Type: Chapter

References (65)

1. Green, P.S. and Simpkins, J.W. (2000) Neuroprotective effects of estrogens: potential mechanisms of action. Int. J. Dev. Neurosci., 18, 347-358.
2. Alkayed, N.J., Harukuni, I., Kimes, A.S., London, E.D., Traystman, R.J., and Hurn, P.D. (1998) Gender-linked brain injury in experimental stroke. Stroke, 29, 159-165; discussion 166.
3. Dubal, D.B., Kashon, M.L., Pettigrew, L.C., Ren, J.M., Finklestein, S.P., Rau, S.W., and Wise, P.M. (1998) Estradiol protects against ischemic injury. J. Cereb. Blood Flow Metab., 18, 1253-1258.
4. Green, P.S., Bishop, J., and Simpkins, J.W. (1997) 17 alpha-estradiol exerts neuroprotective effects on SK-N-SH cells. J. Neurosci., 17, 511-515.
5. Green, P.S., Gordon, K., and Simpkins, J.W. (1997) Phenolic A ring requirement for the neuroprotective effects of steroids. J. Steroid Biochem. Mol. Biol., 63, 229-235.
6. Green, P.S., Gridley, K.E., and Simpkins, J.W. (1996) Estradiol protects against beta-amyloid (25-35)-induced toxicity in SK-N-SH human neuroblastoma cells. Neurosci. Lett., 218, 165-168.
7. Green, P.S., Gridley, K.E., and Simpkins, J.W. (1998) Nuclear ER-independent neuroprotection by estratrienes: a novel interaction with glutathione. Neuroscience, 84, 7-10.
8. Green, P.S., Yang, S.H., Nilsson, K.R., Kumar, A.S., Covey, D.F., and Simpkins, J.W. (2001) The nonfeminizing enantiomer of 17beta-estradiol exerts protective effects in neuronal cultures and a rat model of cerebral ischemia. Endocrinology, 142, 400-406.
9. Gridley, K.E., Green, P.S., and Simpkins, J.W. (1997) Low concentrations of estradiol reduce beta-amyloid (25-35)-induced toxicity, lipid peroxidation and glucose utilization in human SK-N-SH neuroblastoma cells. Brain Res., 778, 158-165.
10. Simpkins, J.W., Wang, J., Wang, X., Perez, E., Prokai, L., and Dykens, J.A. (2005) Mitochondria play a central role in estrogen-induced neuroprotection. Curr. Drug Targets CNS Neurol. Disord., 4, 69-83.
11. Sudo, S., Wen, T.C., Desaki, J., Matsuda, S., Tanaka, J., Arai, T., Maeda, N., and Sakanaka, M. (1997) Beta-estradiol protects hippocampal CA1 neurons against transient forebrain ischemia in gerbil. Neurosci. Res., 29, 345-354.
12. Yang, S.H., Shi, J., Day, A.L., and Simpkins, J.W. (2000) Estradiol exerts neuroprotective effects when administered after ischemic insult. Stroke, 31, 745-749; discussion 749-750.
13. Prokai, L., Prokai-Tatrai, K., Perjesi, P., Zharikova, A.D., Perez, E.J., Liu, R., and Simpkins, J.W. (2003) Quinol-based cyclic antioxidant mechanism in estrogen neuroprotection. Proc. Natl. Acad. Sci. U.S.A., 100, 11741-11746.
14. Prokai, L., Prokai-Tatrai, K., Perjesi, P., Zharikova, A.D., and Simpkins, J.W. (2003) Quinol-based metabolic cycle for estrogens in rat liver microsomes. Drug Metab. Dispos., 31, 701-704.
15. Dumas, J., Hancur-Bucci, C., Naylor, M., Sites, C., and Newhouse, P. (2008) Estradiol interacts with the cholinergic system to affect verbal memory in postmenopausal women: evidence for the critical period hypothesis. Horm. Behav., 53, 159-169.
16. Grodstein, F., Manson, J.E., and Stampfer, M.J. (2006) Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. J. Women's Health (Larchmt), 15, 35-44.
17. Harman, S.M. (2004) What do hormones have to do with aging? What does aging have to do with hormones. Ann. N. Y. Acad. Sci., 1019, 299-308.
18. Hodis, H.N., Mack, W.J., and Lobo, R.A. (2003) Randomized controlled trial evidence that estrogen replacement therapy reduces the progression of subclinical atherosclerosis in healthy postmenopausal women without preexisting cardiovascular disease. Circulation, 108, e5; author reply e5.
19. Sontag, E., Luangpirom, A., Hladik, C., Mudrak, I., Ogris, E., Speciale, S., and White, C.L. III (2004) Altered expression levels of the protein phosphatase 2A ABalphaC enzyme are associated with Alzheimer disease pathology. J. Neuropathol. Exp. Neurol., 63, 287-301.
20. Coker, L.H., Hogan, P.E., Bryan, N.R., Kuller, L.H., Margolis, K.L., Bettermann, K., Wallace, R.B., Lao, Z., Freeman, R., Stefanick, M.L., and Shumaker, S.A. (2009) Postmenopausal hormone therapy and subclinical cerebrovascular disease: the WHIMS-MRI study. Neurology, 72, 125-134.
21. Dubey, R.K., Imthurn, B., Barton, M., and Jackson, E.K. (2005) Vascular consequences of menopause and hormone therapy: importance of timing of treatment and type of estrogen. Cardiovasc. Res., 66, 295-306.
22. Maki, P.M. (2006) Potential importance of early initiation of hormone therapy for cognitive benefit. Menopause, 13, 6-7.
23. Manson, J.E., Allison, M.A., Rossouw, J.E., Carr, J.J., Langer, R.D., Hsia, J., Kuller, L.H., Cochrane, B.B., Hunt, J.R., Ludlam, S.E., Pettinger, M.B., Gass, M., Margolis, K.L., Nathan, L., Ockene, J.K., Prentice, R.L., Robbins, J., and Stefanick, M.L. (2007) Estrogen therapy and coronary-artery calcification. N. Engl. J. Med., 356, 2591-2602.
24. Resnick, S.M., Espeland, M.A., Jaramillo, S.A., Hirsch, C., Stefanick, M.L., Murray, A.M., Ockene, J., and Davatzikos, C. (2009) Postmenopausal hormone therapy and regional brain volumes: the WHIMS-MRI study. Neurology, 72, 135-142.
25. Salpeter, S.R., Walsh, J.M., Greyber, E., and Salpeter, E.E. (2006) Brief report: coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis. J. Gen. Intern. Med., 21, 363-366.
26. Zandi, P.P., Carlson, M.C., Plassman, B.L., Welsh-Bohmer, K.A., Mayer, L.S., Steffens, D.C., and Breitner, J.C. (2002) Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. J. Am. Med. Assoc., 288, 2123-2129.
27. Brinton, R.D. (2004) Requirements of a brain selective estrogen: advances and remaining challenges for developing a NeuroSERM. J. Alzheimers Dis., 6, S27-S35.
28. Shelly, W., Draper, M.W., Krishnan, V., Wong, M., and Jaffe, R.B. (2008) Selective estrogen receptor modulators: an update on recent clinical findings. Obstet. Gynecol. Surv., 63, 163-181.
29. Perez, E., Cai, Z.Y., Covey, D.F., and Simpkins, J.W. (2005) Neuroprotective effects of estratriene analogs: structure-activity relationships and molecular optimization. Drug Dev. Res., 66, 78-92.
30. Behl, C., Skutella, T., Lezoualc'h, F., Post, A., Widmann, M., Newton, C.J., and Holsboer, F. (1997) Neuroprotection against oxidative stress by estrogens: structure-activity relationship. Mol. Pharmacol., 51, 535-541.
31. Moosmann, B. and Behl, C. (1999) The antioxidant neuroprotective effects of estrogens and phenolic compounds are independent from their estrogenic properties. Proc. Natl. Acad. Sci. U.S.A., 96, 8867-8872.
32. Cegelski, L., Rice, C.V., O'Connor, R.D., Caruano, A.L., Tochtrop, G.P., Cai, Z.Y., Covey, D.F., and Schaefer, J. (2005) Mapping the locations of estradiol and potent neuroprotective analogues in phospholipid bilayers by REDOR NMR 2006. Drug Dev. Res., 66, 93-102.
33. Mooradian, A.D. (1993) Antioxidant properties of steroids. J. Steroid Biochem. Mol. Biol., 45, 509-511.
34. Romer, W., Oettel, M., Droescher, P., and Schwarz, S. (1997) Novel ''scavestrogens'' and their radical scavenging effects, iron-chelating, and total antioxidative activities: delta 8,9-dehydro derivatives of 17 alpha-estradiol and 17 beta-estradiol. Steroids, 62, 304-310.
35. Romer, W., Oettel, M., Menzenbach, B., Droescher, P., and Schwarz, S. (1997) Novel estrogens and their radical scavenging effects, iron-chelating, and total antioxidative activities: 17 alpha-substituted analogs of delta 9(11)-dehydro-17 beta-estradiol. Steroids, 62, 688-694.
36. Miller, C.P., Jirkovsky, I., Hayhurst, D.A., and Adelman, S.J. (1996) In vitro antioxidant effects of estrogens with a hindered 3-OH function on the copper-induced oxidation of low density lipoprotein. Steroids, 61, 305-308.
37. Ruiz-Larrea, B., Leal, A., Martin, C., Martinez, R., and Lacort, M. (1995) Effects of estrogens on the redox chemistry of iron: a possible mechanism of the antioxidant action of estrogens. Steroids, 60, 780-783.
38. Ruiz-Larrea, M.B., Martin, C., Martinez, R., Navarro, R., Lacort, M., and Miller, N.J. (2000) Antioxidant activities of estrogens against aqueous and lipophilic radicals; differences between phenol and catechol estrogens. Chem. Phys. Lipids, 105, 179-188.
39. Ryan, T.P., Steenwyk, R.C., Pearson, P.G., and Petry, T.W. (1993) Inhibition of in vitro lipid peroxidation by 21-aminosteroids. Evidence for differential mechanisms. Biochem. Pharmacol., 46, 877-884.
40. Dicko, A., Morissette, M., Ben Ameur, S., Pezolet, M., and Di Paolo, T. (1999) Effect of estradiol and tamoxifen on brain membranes: investigation by infrared and fluorescence spectroscopy. Brain Res. Bull., 49, 401-405.
41. Liang, Y., Belford, S., Tang, F., Prokai, L., Simpkins, J.W., and Hughes, J.A. (2001) Membrane fluidity effects of estratrienes. Brain Res. Bull., 54, 661-668.
42. Hughes, R.A., Harris, T., Altmann, E., McAllister, D., Vlahos, R., Robertson, A., Cushman, M., Wang, Z., and Stewart, A.G. (2002) 2-Methoxyestradiol and analogs as novel antiproliferative agents: analysis of three-dimensional quantitative structure-activity relationships for DNA synthesis inhibition and estrogen receptor binding. Mol. Pharmacol., 61, 1053-1069.
43. Liu, R., Yang, S.H., Perez, E., Yi, K.D., Wu, S.S., Eberst, K., Prokai, L., Prokai-Tatrai, K., Cai, Z.Y., Covey, D.F., Day, A.L., and Simpkins, J.W. (2002) Neuroprotective effects of a novel non-receptor-binding estrogen analogue: in vitro and in vivo analysis. Stroke, 33, 2485-2491.
44. Simpkins, J.W., Rajakumar, G., Zhang, Y.Q., Simpkins, C.E., Greenwald, D., Yu, C.J., Bodor, N., and Day, A.L. (1997) Estrogens may reduce mortality and ischemic damage caused by middle cerebral artery occlusion in the female rat. J. Neurosurg., 87, 724-730.
45. Watters, J.J., Campbell, J.S., Cunningham, M.J., Krebs, E.G., and Dorsa, D.M. (1997) Rapid membrane effects of steroids in neuroblastoma cells: effects of estrogen on mitogen activated protein kinase signalling cascade and c-fos immediate early gene transcription. Endocrinology, 138, 4030-4033.
46. Xia, S., Cai, Z.Y., Thio, L.L., Kim-Han, J.S., Dugan, L.L., Covey, D.F., and Rothman, S.M. (2002) The estrogen receptor is not essential for all estrogen neuroprotection: new evidence from a new analog. Neurobiol. Dis., 9, 282-293.
47. Yang, S.H., He, Z., Wu, S.S., He, Y.J., Cutright, J., Millard, W.J., Day, A.L., and Simpkins, J.W. (2001) 17-beta estradiol can reduce secondary ischemic damage and mortality of subarachnoid hemorrhage. J. Cereb. Blood Flow Metab., 21, 174-181.
48. Perez, E., Liu, R., Yang, S.H., Cai, Z.Y., Covey, D.F., and Simpkins, J.W. (2005) Neuroprotective effects of an estratriene analog are estrogen receptor independent in vitro and in vivo. Brain Res., 1038, 216-222.
49. Migliaccio, A., Di Domenico, M., Castoria, G., de Falco, A., Bontempo, P., Nola, E., and Auricchio, F. (1996) Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells. EMBO J., 15, 1292-1300.
50. Kelly, M.J., Lagrange, A.H., Wagner, E.J., and Ronnekleiv, O.K. (1999) Rapid effects of estrogen to modulate G protein-coupled receptors via activation of protein kinase A and protein kinase C pathways. Steroids, 64, 64-75.
51. Singer, C.A., Figueroa-Masot, X.A., Batchelor, R.H., and Dorsa, D.M. (1999) The mitogen-activated protein kinase pathway mediates estrogen neuroprotection after glutamate toxicity in primary cortical neurons. J. Neurosci., 19, 2455-2463.
52. Singh, M., Setalo, G. Jr., Guan, X., Warren, M., and Toran-Allerand, C.D. (1999) Estrogen-induced activation of mitogen-activated protein kinase in cerebral cortical explants: convergence of estrogen and neurotrophin signaling pathways. J. Neurosci., 19, 1179-1188.
53. Toran-Allerand, C.D., Singh, M., and Setalo, G. Jr. (1999) Novel mechanisms of estrogen action in the brain: new players in an old story. Front. Neuroendocrinol., 20, 97-121.
54. Zhang, L., Rubinow, D.R., Xaing, G., Li, B.S., Chang, Y.H., Maric, D., Barker, J.L., and Ma, W. (2001) Estrogen protects against beta-amyloid-induced neurotoxicity in rat hippocampal neurons by activation of Akt. Neuroreport, 12, 1919-1923.
55. Lee, S.J. and McEwen, B.S. (2001) Neurotrophic and neuroprotective actions of estrogens and their therapeutic implications. Annu. Rev. Pharmacol. Toxicol., 41, 569-591.
56. Yi, K.D., Cai, Z.Y., Covey, D.F., and Simpkins, J.W. (2008) Estrogen receptor-independent neuroprotection via protein phosphatase preservation and attenuation of persistent extracellular signal-regulated kinase 1/2 activation. J. Pharmacol. Exp. Ther., 324, 1188-1195.
57. Zhu, X., Lee, H.G., Raina, A.K., Perry, G., and Smith, M.A. (2002) The role of mitogen-activated protein kinase pathways in Alzheimer's disease. Neurosignals, 11, 270-281.
58. Ferrer, I., Friguls, B., Dalfo, E., and Planas, A.M. (2003) Early modifications in the expression of mitogen-activated protein kinase (MAPK/ERK), stressactivated kinases SAPK/JNK and p38, and their phosphorylated substrates following focal cerebral ischemia. Acta Neuropathol., 105, 425-437.
59. Zhu, J.H., Kulich, S.M., Oury, T.D., and Chu, C.T. (2002) Cytoplasmic aggregates of phosphorylated extracellular signal-regulated protein kinases in Lewy body diseases. Am. J. Pathol., 161, 2087-2098.
60. Slevin, M., Krupinski, J., Slowik, A., Rubio, F., Szczudlik, A., and Gaffney, J. (2000) Activation of MAP kinase (ERK-1/ERK-2), tyrosine kinase and VEGF in the human brain following acute ischaemic stroke. Neuroreport, 11, 2759-2764.
61. Sarkar, S.N., Huang, R.Q., Logan, S.M., Yi, K.D., Dillon, G.H., and Simpkins, J.W. (2008) Estrogens directly potentiate neuronal L-type Ca2+ channels. Proc. Natl. Acad. Sci. U.S.A., 105, 15148-15153.
62. Yi, K.D., Covey, D.F., and Simpkins, J.W. (2009) Mechanism of okadaic acid-induced neuronal death and the effect of estrogens. J. Neurochem., 108, 732-740.
63. Yi, K.D., Chung, J., Pang, P., and Simpkins, J.W. (2005) Role of protein phosphatases in estrogen-mediated neuroprotection. J. Neurosci., 25, 7191-7198.
64. Yi, K.D. and Simpkins, J.W. (2008) Protein phosphatase 1, protein phosphatase 2A, and calcineurin play a role in estrogen-mediated neuroprotection. Endocrinology, 149, 5235-5243.
65. Perez, E., Cai, Z.Y., Covey, D.F., and Simpkins, J.W. (2006) Neuroprotective effects of estratriene analogs: structureactivity relationships and molecular optimization. Drug Dev. Res., 68, 1-15.