Dopamine transporter as a marker of neuroprotection in methamphetamine-lesioned mice treated acutely with estradiol.
Our laboratories have shown the positive effect of estradiol on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- and methamphetamine (MA)-induced striatal dopamine (DA) depletion. Most studies on E neuroprotection use chronic administration of the steroid to evaluate its beneficial effect. In the present report, we investigated the neuroprotective potential of 17 beta-estradiol-3-benzoate (E) under acute conditions when administered 24, 12 or 0.5 h before MA. The effects of E on striatal DA and dihydroxyphenylacetic acid (DOPAC) contents, and DA transporter (DAT) protein and mRNA were measured using high-performance liquid chromatography, autoradiography and in situ hybridization, respectively. We observed neuroprotection with an acute dose of E, and also that protection presents a different time course for each dopaminergic marker. DAT mRNA responded more quickly to E than its protein (at 0.5 h vs. 24 h). Also, E treatment 12 h prior to MA resulted in 'normal' (equal to control) DA content, while DAT protein was still decreased as compared to control values. These different responses for each marker may represent different mechanisms of action of E (genomic versus nongenomic). Since most experimental studies use DA content as the sole indicator of nigrostriatal toxicity and examine a single time point following chronic E administration, the present results demonstrate the importance of evaluating differences in temporally dependent responses of DA, DAT protein and mRNA, to achieve a more comprehensive indication of the nigrostriatal state and the means by which E can function as a neuroprotectant in this system.
D'Astous
Myreille
M
Molecular Endocrinology and Oncology Research Center, Laval University Medical Center, CHUL, and Faculty of Pharmacy, Laval University, Quebec City, Que. G1V 4G2, Canada.
Gajjar
Tapasdip M
TM
Dluzen
Dean E
DE
Di Paolo
Thérèse
T
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001345:Autoradiography / Q000379:methods; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003042:Cocaine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000037:antagonists & inhibitors / Q000633:toxicity; D004347:Drug Interactions; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D017403:In Situ Hybridization / Q000379:methods; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008694:Methamphetamine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051379:Mice; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009422:Nervous System Diseases / Q000139:chemically induced / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010052:Ovariectomy / Q000379:methods; D011485:Protein Binding / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D007456:Iodine Isotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D012333:RNA, Messenger; C493215:Slc6a3 protein, mouse; D015102:3,4-Dihydroxyphenylacetic Acid; C079213:RTI 121; C074283:estradiol 3-benzoate; D008694:Methamphetamine; D004958:Estradiol; D003042:Cocaine; D004298:Dopamine