Neuroprotective properties of 17beta-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 C57Bl/6 mice by 17beta-estradiol, progesterone, and raloxifene, whereas 17alpha-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 [(125)I]RTI-121 specific binding was prevented by 17beta-estradiol (2 microg/day), progesterone (2 microg/day), or raloxifene (5 mg/kg/day) but not by 17alpha-estradiol (2 microg/day) or raloxifene (1 mg/kg/day). No treatment completely reversed the decreased levels of DAT mRNA in the substantia nigra. Striatal [(125)I]RTI-121 specific binding was positively correlated with dopamine concentrations in intact, saline, or hormone-treated MPTP mice. Striatal NMDA-sensitive [(3)H]glutamate or [(3)H]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 17beta-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.
Callier
S
S
Oncology and Molecular Endocrinology Research Center, and Faculty of Pharmacy, Laval University, Québec, Qc, G1K 7P4, Canada.
Morissette
M
M
Grandbois
M
M
Pélaprat
D
D
Di Paolo
T
T
D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004298:Dopamine / Q000096:biosynthesis / Q000172:deficiency; D050483:Dopamine Plasma Membrane Transport Proteins; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009419:Nerve Tissue Proteins; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011374:Progesterone / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D018091:Receptors, AMPA / Q000819:agonists / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D020845:Selective Estrogen Receptor Modulators; C493215:Slc6a3 protein, mouse; D020849:Raloxifene Hydrochloride; D011374:Progesterone; D004958:Estradiol; D004298:Dopamine