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Vol. 77, No. 4, 2003
Issue release date: April 2003
Neuroendocrinology 2003;77:223–231

Repeated Estradiol Treatment Prevents MPTP-Induced Dopamine Depletion in Male Mice

Ramirez A.D. · Liu X. · Menniti F.S.
CNS Discovery, Pfizer Global Research and Development, Groton, Conn., USA

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Epidemiological data suggest that the steroid hormone 17β-estradiol plays an important role in protecting the brain from neurodegenerative processes, including that causing the loss of dopamine (DA) neurons in Parkinson’s disease. Determining the mechanisms of neuroprotection in experimental systems may facilitate the development of estrogenic therapies for these diseases. The present study sought to further investigate the mechanism of the neuroprotective effect of 17β-estradiol in a murine model of Parkinson’s disease, i.e. 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced striatal DA depletion. Consistent with previous findings, 17β-estradiol was found to inhibit MPTP-induced DA depletion under a dosing regimen (repeated daily administration) that mimicked physiological levels of the steroid. However, high doses of the steroid administered repeatedly or acutely failed to inhibit toxicity, as did 17α- estradiol. These data suggest that the neuroprotective effect of 17β-estradiol was mediated through an interaction with one of the nuclear estrogen receptors, and is not the result of an antioxidant action. In order to realize the therapeutic potential of the neuroprotective effect of 17β-estradiol for Parkinson’s disease, it will be necessary to identify synthetic estrogen receptor modulators that lack the activity of the steroid on peripheral tissue. In this study, raloxifene failed to mimic the neuroprotective effect of 17β-estradiol against MPTP toxicity. Thus, exploration of new compounds with different pharmacological and/or physiochemical properties is warranted.

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  1. Moghal S, Rajput AH, D’Arcy C, Rajput R: Prevalence of movement disorders in elderly community residents. Neuroepidemiology 1994;13:175–178.
  2. Lang AE: Manipulating the dopaminergic system in Parkinson’s disease. Phamacol Ther 1987;32:51–76.
  3. Langston JW, Irwin I, Ricaurte GA: Neurotoxins, parkinsonism and Parkinson’s disease. Pharmacol Ther 1987;32:19–49.
  4. Marek K, Seibyl J, Shoulson I, Holloway R, Kieburtz K, McDermott M, Kamp C, Shinaman A, Fahn S, Lang A, Weiner W, Welsh M: Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002;287:1653–1660.
  5. Ball J: Current advances in Parkinson’s disease. Trends Neurosci 2001;24:367–369.
  6. Dluzen DE: Neuroprotective effects of estrogen upon the nigrostriatal dopaminergic system. J Neurocytol 2000;29:387–399.

    External Resources

  7. Dluzen DE, McDermott JL, Liu B: Estrogen as a neuroprotectant against MPTP-induced neurotoxicity in C57/Bl mice. Neurotoxicol Teratol 1996;18:603–606.

    External Resources

  8. Giovanni A, Sieber BA, Heikkila RE, Sonsalla PK: Studies on species sensitivity to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. I. Systemic administration. J Pharmacol Exp Ther 1994;270:1008–1014.
  9. Gerlach M, Riederer P, Przuntek H, Youdim MB: MPTP mechanisms of neurotoxicity and their implications for Parkinson’s disease. Eur J Pharmacol 1991;208:273–286.
  10. Greenamyre JT, Sherer TB, Betarbet R, Panov AV: Complex I and Parkinson’s disease. IUBMB Life 2001;52:135–141.
  11. Wilson ME, Dubal DB, Wise PM: Estradiol protects against injury-induced cell death in cortical explant cultures: A role for estrogen receptors. Brain Res 2000;873:235–242.
  12. Alkayed NJ, Harakuni I, Kimes AS, London ED, Traystman RJ, Hurn PD: Gender-linked brain injury in experimental stroke. Stroke 1998;29:159–166.
  13. 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.
  14. Marder K, Tang MX, Mejia H, Alfaro B, Cote L, Louis E, Groves J, Mayeux R: Risk of Parkinson’s disease among first-degree relatives: A community-based study. Neurology 1996;47:155–160.
  15. Lyons KE, Hubble JP, Troster AI, Pahwa R, Koller WC: Gender differences in Parkinson’s disease. Clin Neuropharmacol 1998;21:118–121.
  16. Miller DB, Ali SF, O’Callaghan JP, Laws SC: The impact of gender and estrogen on striatal dopaminergic neurotoxicity. Ann NY Acad Sci 1998;844:153–165.
  17. Dluzen DE, McDermott JL: Estrogen, anti-estrogen and gender: Differences in methamphetamine neurotoxicity. Ann NY Acad Sci 2002;965:136–156.
  18. Saunders-Pullman R, Gordon-Elliott J, Parides M, Fahn S, Saunders HR, Bressman S: The effect of estrogen replacement on early Parkinson’s disease. Neurology 1999;7:141–149.
  19. Ekue A, Boulanger JF, Morissette M, Di Paolo T: Lack of effect of testosterone and dihydrotestosterone compared to 17β-oestradiol in 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine mice. J Neuroendocrinol 2002;14:731–736.
  20. Dluzen DE, McDermott JL, Anderson LI: Tamoxifen eliminates estrogen’s neuroprotective effect upon MPTP-induced neurotoxicity of the nigrostriatal dopaminergic system. Neurotoxicity Res 2001;3:291–300.
  21. Callier S, Morissette M, Grandbois M, Di Paolo T: Stereospecific prevention by 17β-estradiol of MPTP-induced dopamine depletion in mice. Synapse 2000;37:245–251.
  22. Jones CD, Jevnikar MG, Pike AJ, Peters MK, Black LJ, Thompson AR, Falcone JF, Clemens JA: Antiestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives leading to [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride (LY 156758), a remarkably effective estrogen antagonist with only minimal intrinsic estrogenicity. J Med Chem 1984;27:1057–1066.
  23. Paxinos G, Franklin KBJ: The Mouse Brain in Stereotaxic Coordinates, 2nd ed. San Diego, Academic Press, 2001.
  24. Callier S, Morissette M, Grandbois M, Pelaprat D, Di Paolo T: Neuroprotective properties of 17β-estradiol, progesterone, and raloxifene in MPTP C57Bl/6 mice. Synapse 2001;41:131–138.
  25. Grandbois M, Morissette M, Callier S, Di Paolo T: Ovarian steroids and raloxifene prevent MPTP-induced dopamine depletion in mice. Neuroreport 2000;11:343–346.
  26. Becker JB, Ramirez VD: Sex differences in the amphetamine stimulated release of catecholamines from rat striatal tissue in vitro. Brain Res 1981;204:361–372.
  27. Zhou W, Koldzic-Zivanovic N, Clarke CH, De Beun R, Wassermann K, Bury PS, Cunningham KA, Thomas ML: Selective estrogen receptor modulator effects in the rat brain. Neuroendocrinology 2002;75:24–33.
  28. Behl C, Skutella T, Lezoualc’h F, Post A, Widmann M, Newton CJ, Holsboer F: Neuroprotection against oxidative stress by estrogens: Structure-activity relationship. Mol Pharmacol 1997;51:535–541.
  29. Green PS, Bishop J, Simpkins JW: 17β-Estradiol exerts neuroprotective effects on SK-N-SH cells. J Neurosci 1997;17:511–515.
  30. Green PS, Gordon K, Simpkins JW: Phenolic A ring requirement for the neuroprotective effects of steroids. J Steroid Biochem Mol Biol 1997;63:229–235.
  31. Zhang JQ, Cai WQ, Zhou DS, Su BY: Distribution and differences of estrogen receptor beta immunoreactivity in the brain of adult male and female rats. Brain Res 2002;935:73–80.
  32. Dubal DB, Zhu H, Yu J, Rau SW, Shughrue PJ, Merchenthaler I, Kindy MS, 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.
  33. Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster WJ, Draper M, Christiansen C: Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997;337:1641–1647.
  34. Wakeling AE, Valcaccia B, Newboult E, Green LR: Non-steroidal antioestrogens – receptor binding and biological response in rat uterus, rat mammary carcinoma and human breast cancer cells. J Steroid Biochem 1984;20:111–120.
  35. Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M, Lawrence JB, Shah AS, Anderson PW: Effects of rolaxifene on serum lipid and coagulation factors in healthy postmenopausal women. JAMA 1998;279:1445–1451.
  36. Wu X, Glinn MA, Ostrowski NL, Su Y, Ni B, Cole HW, Bryant HU, Paul SM: Raloxifene and estradiol benzoate both fully restore hippocampal choline acetyltransferase activity in ovariectomized rats. Brain Res 1999;847:98–104.

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