Estrogen receptors modulate striatal metabotropic receptor type 5 in intact and MPTP male mice model of Parkinson's disease.

Glutamate is the most important brain excitatory neurotransmitter and glutamate overactivity is well documented in Parkinson's disease (PD). Metabotropic glutamate (mGlu) receptors are reported to interact with membrane estrogen receptors (ERs) and more specifically the mGlu5 receptor subtype. 17ß-estradiol and mGlu5 antagonists have neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We previously reported that ERα and ERß are involved in neuroprotection following MPTP toxicity. The present study investigated the implication of ERs on the mGlu5 receptor adaptive response to MPTP toxicity in the brain of wild type (WT), ER knockout (ERKO)α and ERKOß male mice. Autoradiography of [(3)H]ABP688 specific binding to striatal mGlu5 receptors showed a dorsal/ventral gradient similar for WT, ERKOα and ERKOß mice with higher values ventrally. The lateral septum had highest [(3)H]ABP688 specific binding that remained unchanged in all experimental groups. ERKOα and ERKOß mice had similarly lower striatal [(3)H]ABP688 specific binding than WT mice as measured also by Western blots. MPTP dose-dependently decreased striatal [(3)H]ABP688 specific binding in WT but not in ERKOα and ERKOß mice; this correlated positively with striatal dopamine concentrations. A 17ß-estradiol treatment for 10 days left unchanged striatal [(3)H]ABP688 specific binding of unlesioned mice of the three genotypes. 17ß-estradiol treatment for 5 days before MPTP and for 5 days after partially prevented the mGlu5 receptor decrease only in WT MPTP mice and this was associated with higher BDNF striatal contents. These results thus show that in male mice ERs affect striatal mGlu5 receptor levels and their response to MPTP.

Estrogen receptors and lesion-induced response of striatal dopamine receptors.

Neuroprotection by 17ß-estradiol and an estrogen receptor (ER) agonist against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion were shown to implicate protein kinase B (Akt) signaling in mice. In order to evaluate the associated mechanisms, this study compared estrogen receptor alpha (ERα) and estrogen receptor beta (ERß) intact or knockout (KO) and wild-type (WT) C57Bl/6 male mice following MPTP treatment of 7, 9, 11mg/kg and/or 17ß-estradiol. Striatal D1 and D2 dopamine (DA) receptors were measured by autoradiography with the specific ligands [(3)H]-SCH 23390 and [(3)H]-raclopride, respectively and signaling by Western blot for Akt, glycogen synthase kinase 3ß (GSK3ß) and extracellular-regulated signal kinases (ERK1 and ERK2). Control ERKOß mice had lower striatal [(3)H]-SCH 23390 specific binding than WT and ERKOα mice; both KO mice had lower [(3)H]-raclopride specific binding. Striatal D1 receptors decreased with increasing doses of MPTP in correlation with striatal DA concentrations in ERKOα mice and remained unchanged in WT and ERKOß mice. Striatal D2 receptors decreased with increasing doses of MPTP in correlation with striatal DA concentrations in WT and ERKOα mice and increased in ERKOß mice. In MPTP-lesioned mice, 17ß-estradiol treatment increased D1 receptors in ERKOα and ERKOß mice and D2 receptors in WT and ERKOß mice. MPTP did not affect striatal pAkt/Akt and pGSK3ß/GSK3ß levels in WT and ERKOα mice, while in vehicle-treated ERKOß mice these levels were higher and increased with MPTP lesioning. Striatal pERK1/ERK1 and pERK2/ERK2 levels showed to a lesser extent a similar pattern. In conclusion, ERs affected the response of striatal DA receptors to a MPTP lesion and post receptor signaling.

Effect of oestrogen receptors on brain NMDA receptors of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice.

Parkinson's disease (PD) is characterised by the loss of nigrostriatal dopamine (DA) neurones and glutamate overactivity. There is substantial evidence to suggest that oestrogens prevent or delay the disease. 17ß-oestradiol has neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and modulates brain NMDA receptors. In MPTP-lesioned mice, oestrogen receptor (ER)α and ERß are important in 17ß-oestradiol-induced neuroprotection. To evaluate the role of ERs in the response of NMDA receptors to lesion, we compared wild-type (WT) with ER knockout (KO) C57Bl/6 male mice that received 7, 9 or 11 mg/kg of MPTP. These mice were also treated with MPTP (9 mg/kg) and 17ß-oestradiol. [(3) H]Ro 25-6981 specific binding autoradiography was used to label NMDA receptors containing NR2B subunits. In the frontal and cingulate cortex and striatum, vehicle-treated WT mice had higher [(3) H]Ro 25-6981 specific binding compared to ERKO mice. Cortical [(3) H]Ro 25-6981 specific binding decreased with increasing doses of MPTP in WT and ERKOα but not ERKOß mice, whereas a dose-related decrease was only observed in the striatum of WT mice remaining low in ERKOα and ERKOß mice. No effect of 17ß-oestradiol treatment in intact or MPTP-lesioned mice of all three genotypes was observed in the cortex, whereas it increased striatal specific binding of intact ERKOß and MPTP-lesioned WT mice. Striatal [(3) H]Ro 25-6981 specific binding positively correlated with striatal DA concentrations only in WT mice. MPTP and 17ß-oestradiol treatments had more limited effects in the hippocampus. Only in the CA3 and dentate gyrus did vehicle and 17ß-oestradiol-treated ERKOα mice have higher [(3) H]Ro 25-6981 specific binding than WT and ERKOß mice, whereas MPTP decreased this specific binding only in the CA1, CA2 and CA3 of ERKOα mice. Hence, brain NMDA receptors were affected by the deletion of ERs, which affect the response to MPTP and 17ß-oestradiol treatments with brain region specificity.

Oestrogen receptors and signalling pathways: implications for neuroprotective effects of sex steroids in Parkinson's disease.

Parkinson's disease (PD) is an age-related neurodegenerative disorder with a higher incidence in the male population. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, 17ß-oestradiol but not androgens were shown to protect dopamine (DA) neurones. We report that oestrogen receptors (ER)α and ß distinctly contribute to neuroprotection against MPTP toxicity, as revealed by examining the membrane DA transporter (DAT), the vesicular monoamine transporter 2 (VMAT2) and tyrosine hyroxylase in ER wild-type (WT) and knockout (ERKO) C57Bl/6 male mice. Intact ERKOß mice had lower levels of striatal DAT and VMAT2, whereas ERKOα mice were the most sensitive to MPTP toxicity compared to WT and ERKOß mice and had the highest levels of plasma androgens. In both ERKO mice groups, treatment with 17ß-oestradiol did not provide neuroprotection against MPTP, despite elevated plasma 17ß-oestradiol levels. Next, the recently described membrane G protein-coupled oestrogen receptor (GPER1) was examined in female Macaca fascicularis monkeys and mice. GPER1 levels were increased in the caudate nucleus and the putamen of MPTP-monkeys and in the male mouse striatum lesioned with methamphetamine or MPTP. Moreover, neuroprotective mechanisms in response to oestrogens transmit via Akt/glycogen synthase kinase-3 (GSK3) signalling. The intact and lesioned striata of 17ß-oestradiol treated monkeys, similar to that of mice, had increased levels of pAkt (Ser 473)/ßIII-tubulin, pGSK3 (Ser 9)/ßIII-tubulin and Akt/ßIII-tubulin. Hence, ERα, ERß and GPER1 activation by oestrogens is imperative in the modulation of ER signalling and serves as a basis for evaluating nigrostriatal neuroprotection.

Contribution of estrogen receptors alpha and beta to the effects of estradiol in the brain.

Clinical and experimental studies show a modulatory role of estrogens in the brain and suggest their beneficial action in mental and neurodegenerative diseases. The estrogen receptors ERalpha and ERbeta are present in the brain and their targeting could bring selectivity and reduced risk of cancer. Implication of ERs in the effect of estradiol on dopamine, opiate and glutamate neurotransmission is reviewed. The ERalpha agonist, PPT, is shown as estradiol to modulate hippocampal NMDA receptors and AMPA receptors in cortex and striatum of ovariectomized rats whereas the ERbeta agonist DPN is inactive. Striatal DPN activity suggests implication of ERbeta in estradiol modulation of D2 receptors and transporters in ovariectomized rats and is supported by the lack of effect of estradiol in ERbeta knockout (ERKObeta) mice. Both ERalpha and ERbeta agonists modulate striatal preproenkephalin (PPE) gene expression in ovariectomized rats. In male mice PPT protects against MPTP toxicity to striatal dopamine; this implicates Akt/GSK3beta signaling and the apoptotic regulators Bcl2 and Bad. This suggests a role for ERalpha in striatal dopamine neuroprotection. ERKOalpha mice are more susceptible to MPTP toxicity and not protected by estradiol; differences in ERKObeta mice are subtler. These results suggest therapeutic potential for the brain of ER specific agonists.