Bains Mona, Roberts James L
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, United states.
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, United states.
Neurosci Lett. 2016 Jan 1;610:79-85. doi: 10.1016/j.neulet.2015.10.054. Epub 2015 Oct 28.
Astrocytes regulate neuronal homeostasis and have been implicated in affecting the viability and functioning of surrounding neurons under stressed and injured conditions. Previous data from our lab suggests indirect actions of estrogen through ERα in neighboring astroglia to protect dopamine neurons against 1-methyl-4-phenylpyridinium (MPP(+)) toxicity in mouse mesencephalic cultures. We further evaluate estrogen signaling in astrocytes and the mechanism of estrogen's indirect neuroprotective effects on dopamine neurons. Primary mesencephalic cultures pre-treated with 17β-estradiol and the membrane impermeable estrogen, E2-BSA, were both neuroprotective against MPP(+) -induced dopamine neuron toxicity, suggesting membrane-initiated neuroprotection. ERα was found in the plasma membrane of astrocyte cultures and colocalized with the lipid raft marker, flotillin-1. A 17β-estradiol time course revealed a significant increase in Akt, which was inhibited by the PI3 kinase inhibitor, LY294004. Estrogen conditioned media collected from pure astrocyte cultures rescued glial deficient mesencephalic cultures from MPP(+). This indirect estrogen-mediated neuroprotective effect in mesencephalic cultures was significantly reduced when PI3 kinase signaling in astrocytes was blocked prior to collecting estrogen-conditioned media using the irreversible PI3 kinase inhibitor, Wortmannin. Estrogen signaling via astrocytes is rapidly initiated at the membrane level and requires PI3 kinase signaling in order to protect primary mesencephalic dopamine neurons from MPP(+) neurotoxicity.
星形胶质细胞调节神经元的内环境稳定，并在应激和损伤条件下影响周围神经元的活力和功能。我们实验室之前的数据表明，雌激素通过内质网α（ERα）在邻近的星形胶质细胞中发挥间接作用，以保护小鼠中脑培养物中的多巴胺能神经元免受1-甲基-4-苯基吡啶鎓（MPP(+)）的毒性影响。我们进一步评估了星形胶质细胞中的雌激素信号传导以及雌激素对多巴胺能神经元间接神经保护作用的机制。用17β-雌二醇和膜不可渗透的雌激素E2-BSA预处理的原代中脑培养物，对MPP(+)诱导的多巴胺能神经元毒性均具有神经保护作用，提示存在膜起始的神经保护作用。在星形胶质细胞培养物的质膜中发现了ERα，并且它与脂筏标记物flotillin-1共定位。17β-雌二醇的时间进程显示Akt显著增加，这被PI3激酶抑制剂LY294004所抑制。从纯星形胶质细胞培养物中收集的雌激素条件培养基可使胶质细胞缺陷的中脑培养物免受MPP(+)的损伤。当在使用不可逆的PI3激酶抑制剂渥曼青霉素收集雌激素条件培养基之前阻断星形胶质细胞中的PI3激酶信号传导时，中脑培养物中这种间接的雌激素介导的神经保护作用显著降低。通过星形胶质细胞的雌激素信号传导在膜水平迅速启动，并且需要PI3激酶信号传导才能保护原代中脑多巴胺能神经元免受MPP(+)的神经毒性。
