Neuroprotective properties of 17β-estradiol, progesterone, and raloxifene in MPTP C57Bl/6 mice

Authors

  • Sophie Callier,

    1. Oncology and Molecular Endocrinology Research Center, and Faculty of Pharmacy, Laval University, Québec, Qc, G1K 7P4, Canada
    2. INSERM Unit 339, St.-Antoine Hospital, 75012 Paris, France
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  • Marc Morissette,

    1. Oncology and Molecular Endocrinology Research Center, and Faculty of Pharmacy, Laval University, Québec, Qc, G1K 7P4, Canada
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  • Michelle Grandbois,

    1. Oncology and Molecular Endocrinology Research Center, and Faculty of Pharmacy, Laval University, Québec, Qc, G1K 7P4, Canada
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  • Didier Pélaprat,

    1. INSERM Unit 339, St.-Antoine Hospital, 75012 Paris, France
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  • Thérèse Di Paolo

    Corresponding author
    1. Oncology and Molecular Endocrinology Research Center, and Faculty of Pharmacy, Laval University, Québec, Qc, G1K 7P4, Canada
    • Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (CHUL), 2705, Laurier Boulevard, Sainte-Foy, Québec, Qc, Canada, G1V 4G2
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Abstract

Previous work from our laboratory showed prevention of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) induced dopamine depletion in striatum of C57Bl/6 mice by 17β-estradiol, progesterone, and raloxifene, whereas 17α-estradiol had no effect. The present study investigated the mechanism by which these compounds exert their neuroprotective activity. The hormonal effect on the dopamine transporter (DAT) was examined to probe the integrity of dopamine neurons and glutamate receptors in order to find a possible excitotoxic mechanism. Drugs were injected daily for 5 days before MPTP (four injections, 15 mg/kg ip at 2-h intervals) and drug treatment continued for 5 more days. MPTP induced a decrease of striatal DAT-specific binding (50% of control) and DAT mRNA in the substantia nigra (20% of control), suggesting that loss of neuronal nerve terminals was more extensive than cell bodies. This MPTP-induced decrease of striatal [125I]RTI-121 specific binding was prevented by 17β-estradiol (2 μg/day), progesterone (2 μg/day), or raloxifene (5 mg/kg/day) but not by 17α-estradiol (2 μg/day) or raloxifene (1 mg/kg/day). No treatment completely reversed the decreased levels of DAT mRNA in the substantia nigra. Striatal [125I]RTI-121 specific binding was positively correlated with dopamine concentrations in intact, saline, or hormone-treated MPTP mice. Striatal NMDA-sensitive [3H]glutamate or [3H]AMPA specific binding remained unchanged in intact, saline, or hormone-treated MPTP mice, suggesting the unlikely implication of changes of glutamate receptors in an excitotoxic mechanism. These results show a stereospecific neuroprotection by 17β-estradiol of MPTP neurotoxicity, which is also observed with progesterone or raloxifene treatment. The present paradigm modeled early DA nerve cell damage and was responsive to hormones. Synapse 41:131–138, 2001. © 2001 Wiley-Liss, Inc.

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