Stereospecific prevention by 17beta-estradiol of MPTP-induced dopamine depletion in mice.

Neuroprotective activity of estrogens is reported in Alzheimer disease and recently has also been suggested for Parkinson disease, a disease affecting more men than women. To characterize this estrogenic activity, we studied the effects of 17beta- and 17alpha-estradiol treatment (1 microg twice daily 5 days before, during the day of four MPTP (15 mg/kg) injections, and for the following 5 days) on dopamine striatal toxicity induced by the neurotoxin MPTP in retired breeder male C57BL/6 mice. Striatal dopamine concentrations and its metabolites dihydroxyphenylacetic acid and homovanillic acid measured by HPLC in MPTP mice that received 17beta-estradiol were comparable to control animals, whereas MPTP mice treated with saline or 17alpha-estradiol showed important decreases of dopamine and its metabolites. Striatal serotonin and its metabolite 5-hydroxyindoleacetic acid concentrations remained unchanged after MPTP and treatments with steroids. Striatal [(3)H]GBR 12935 binding autoradiography to the dopamine transporter was as extensively decreased and correlated with dopamine depletion in MPTP mice, whereas this transporter mRNA decrease in the substantia nigra pars compacta was less pronounced. Treatment with steroids did not significantly change [(3)H]GBR 12935 binding, whereas dopamine transporter mRNA levels were not significantly different from controls. Under the present paradigm in retired breeder male mice, our results show dopaminergic and stereospecificity of estradiol to augment dopamine levels in MPTP-lesioned mice without protecting against the extensive loss of dopamine terminals and moderate cell body loss.

Callier S ，Morissette M ，Grandbois M ，Di Paolo T ... -  《SYNAPSE》

Dehydroepiandrosterone (DHEA) such as 17beta-estradiol prevents MPTP-induced dopamine depletion in mice.

Previous work from our laboratory has shown prevention of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced striatal dopamine (DA) depletion in mice by 17beta-estradiol, progesterone, and raloxifene. Dehydroepiandrosterone (DHEA), a neurosteroid, was shown to have neuroprotective activities in various paradigms of neuronal death but its effect in vivo in mice on MPTP toxicity has not been reported. We investigated the effects of 17beta-estradiol (2 microg/day) and DHEA (3 mg/day) for 5 days before and after an acute treatment of four MPTP (10 mg/kg) injections in male C57Bl/6 mice. Striatal DA concentrations and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured by HPLC. MPTP mice that received 17beta-estradiol or DHEA had striatal DA, DOPAC, and HVA concentrations comparable to intact animals and higher than striatal DA, DOPAC, and HVA levels in saline-MPTP-treated mice. MPTP treatment led to an increase of striatal DA turnover (assessed with the HVA/DA ratio); DHEA and 17beta-estradiol prevented this increase. 17beta-Estradiol did not affect striatal DA and metabolites concentrations in intact mice in this paradigm. Furthermore, in the substantia nigra DHEA and 17beta-estradiol prevented the MPTP-induced dopamine transporter and tyrosine hydroxylase mRNA decreases measured by in situ hybridization. Therefore, DHEA such as 17beta-estradiol is active in preventing the catecholamine-depleting effect of MPTP and our results suggest that this involves neuroprotection of DA neurons.

D'Astous M ，Morissette M ，Tanguay B ，Callier S ，Di Paolo T ... -  《SYNAPSE》

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

Callier S ，Morissette M ，Grandbois M ，Pélaprat D ，Di Paolo T ... -  《SYNAPSE》

Lack of effect of testosterone and dihydrotestosterone compared to 17beta-oestradiol in 1-methyl-4-phenyl-1,2,3,6, tetrahydropyridine-mice.

Ekue A ，Boulanger JF ，Morissette M ，Di Paolo T ... -  《JOURNAL OF NEUROENDOCRINOLOGY》

Regulation of striatal preproenkephalin mRNA levels in MPTP-lesioned mice treated with estradiol.

We reported previously the protective effect of 17beta-estradiol (17beta-E(2)) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine (DA) depletion. This protection was stereospecific, because 17beta-E(2) showed activity but 17alpha-estradiol (17alpha-E(2)) did not. The mechanisms by which estradiol exerts its beneficial effects, however, remain unknown. We investigated a possible implication of enkephalins (ENK) in neuroprotective activity of 17beta-E(2). Protection against MPTP-induced DA depletion was obtained with 17beta-E(2) but not 17alpha-E(2). MPTP lesion increased striatal preproenkephalin (PPE) mRNA levels and they remained elevated in 17alpha-E(2)-treated MPTP mice whereas 17beta-E(2) treatment decreased these levels to control values. This is the first report of estradiol modulation of striatal PPE mRNA in mice. Negative and significant correlations between DA levels, vesicular monoamine transporter (VMAT(2)) density, and PPE mRNA were observed in the striatum of lesioned animals. This effect of 17beta-E(2) on PPE mRNA after a lesion could be one of many mechanisms by which this steroid exerts its neuroprotective activity.

D'Astous M ，Morissette M ，Callier S ，Di Paolo T ... -  《JOURNAL OF NEUROSCIENCE RESEARCH》