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

Previous work from our laboratory showed prevention of 1-methyl-4-phenyl-1, 2,3,6 tetrahydropyridine (MPTP) induced dopamine depletion in striatum of C 57Bl/6 mice by 17 beta -estradiol, progesterone, and raloxifene, whereas 17 alpha -estradiol had no effect. The present study investigated the mechani sm by which these compounds exert their neuroprotective activity. The hormo nal effect on the dopamine transporter (DAT) was examined to probe the inte grity of dopamine neurons and glutamate receptors in order to find a possib le excitotoxic mechanism. Drugs were injected daily for 5 days before MPTP (four injections, 15 mg/kg ip at 2-h intervals) and drug treatment continue d 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), su ggesting that loss of neuronal nerve terminals was more extensive than cell bodies. This MPTP-induced decrease of striatal [I-125]RTI-121 specific bin ding was prevented by 17 beta -estradiol (2 mug/day), progesterone (2 mug/d ay), or raloxifene (5 mg/kg/day) but not by 17 alpha -estradiol (2 mug/day) or raloxifene (1 mg/kg/day). No treatment completely reversed the decrease d levels of DAT mRNA in the substantia nigra. Striatal [I-125]RTI-121 speci fic binding was positively correlated with dopamine concentrations in intac t, saline, or hormone-treated MPTP mice. Striatal NMDA-sensitive [H-3]gluta mate or [H-3]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 st ereospecific neuroprotection by 17 beta -estradiol of MPTP neurotoxicity, w hich is also observed with progesterone or raloxifene treatment. The presen t paradigm modeled early DA nerve cell damage and was responsive to hormone s. (C) 2001 Wiley-Liss, Inc.