Differential protective properties of estradiol and tamoxifen against methamphetamine-induced nigrostriatal dopaminergic toxicity in mice.
Mechanisms implicated in protective potential of estrogens are poorly understood. Tamoxifen, a selective estrogen receptor modulator (SERM), presents a neuroprotective effect against methamphetamine (MA)- and methoxy-phenyltetrahydropyridine (MPTP)-induced toxicity when used alone but abolishes estrogen's positive effects when combined with this hormone. In order to understand tamoxifen's protective properties, the present study compared it to estradiol on several markers of dopaminergic neurons to achieve a relatively comprehensive comparison between these two agents. Estradiol benzoate (E) or tamoxifen were used at different concentrations (E: 1, 10 or 40 microg; tamoxifen: 12.5, 125 or 500 microg) 24 h prior to a MA injection in ovariectomized CD-1 mice. The effects of the lesion and treatments were studied on striatal dopamine (DA) concentrations, dopamine and monoamine vesicular transporters (DAT and VMAT2), and preproenkephalin (PPE) mRNA levels. Both treatments, at all concentrations, prevented the MA-induced decrease of striatal DA concentrations and VMAT2 binding. Only E was able to prevent loss of DAT binding in the lateral striatum and to attenuate the MA-induced increase in striatal PPE mRNA levels (at 1 or 40 microg). Therefore, in this paradigm, E and tamoxifen differentially modulated MA-induced neuronal damages. While both treatments prevented the DA decrease, E protected more efficiently other dopaminergic parameters suggesting that overall E is more effective than tamoxifen as a neuroprotectant of the nigrostriatal dopaminergic system.
D'Astous
Myreille
M
Molecular Endocrinology and Oncology Research Center, Laval University Medical Center, CHUL, and Faculty of Pharmacy, Laval University, Quebec City, Canada.
Mickley
Katherine R
KR
Dluzen
Dean E
DE
Di Paolo
Thérèse
T
D000818:Animals; D001345:Autoradiography; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004745:Enkephalins / Q000378:metabolism; D004958:Estradiol / Q000627:therapeutic use*; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D017403:In Situ Hybridization; D008694:Methamphetamine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051379:Mice; D020258:Neurotoxicity Syndromes / Q000517:prevention & control*; D011498:Protein Precursors / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D013629:Tamoxifen / Q000627:therapeutic use*; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D004745:Enkephalins; D004965:Estrogen Antagonists; D011498:Protein Precursors; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D013629:Tamoxifen; D008694:Methamphetamine; D004958:Estradiol; C033660:preproenkephalin