Estrogen receptor β ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis.
Estrogen receptor β ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis.
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DOI：
10.1016/j.nbd.2013.04.005
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发表时间：
2013-08
影响因子：
6.1
通讯作者：
Tiwari-Woodruff SK
中科院分区：
文献类型：
--
作者：
Kumar S;Patel R;Moore S;Crawford DK;Suwanna N;Mangiardi M;Tiwari-Woodruff SK
鉴定出一种在多发性硬化症 (MS) 过程中刺激内源性髓鞘形成并避免轴突变性的药物可能会降低疾病进展的速度。使用实验性自身免疫性脑脊髓炎（EAE）（MS 小鼠模型），我们之前已经证明，预防性施用雌激素受体（ER）β配体 2,3-双（4-羟基苯基）-丙腈（DPN）可减少临床疾病，具有神经保护作用，刺激内源性髓鞘形成，并在不改变轴突传导的情况下改善轴突传导 外周细胞因子的产生或减少中枢神经系统（CNS）炎症。在这里，我们评估了 EAE 疾病高峰期间 DPN 治疗的效果，这代表了一种更具临床相关性的治疗范例。此外，我们还研究了 EAE 期间 DPN 治疗诱导恢复的作用机制。鉴于 EAE 期间使用 DPN 进行预防性和治疗性治疗可改善髓鞘再生诱导的轴突传导，并且少突胶质细胞谱系细胞上存在 ER（α 和 β）和膜（m）ER，因此治疗可能对少突胶质细胞产生直接影响。 DPN 治疗 EAE 动物会导致 ERβ 磷酸化，并激活磷脂酰肌醇 3 激酶 (PI3K)/丝氨酸-苏氨酸特异性蛋白激酶 (Akt)/哺乳动物雷帕霉素靶蛋白 (mTOR) 信号通路，这是少突胶质细胞存活和轴突髓鞘形成所需的通路。这些结果，加上我们之前对预防性 DPN 治疗的研究，使 DPN 和类似的 ERβ 配体成为脱髓鞘疾病的直接且有利的治疗候选者。
The identification of a drug that stimulates endogenous myelination and spares axon degeneration during multiple sclerosis (MS) could potentially reduce the rate of disease progression. Using experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, we have previously shown that prophylactic administration of the estrogen receptor (ER) β ligand 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) decreases clinical disease, is neuroprotective, stimulates endogenous myelination, and improves axon conduction without altering peripheral cytokine production or reducing central nervous system (CNS) inflammation. Here, we assessed the effects of therapeutic DPN treatment during peak EAE disease, which represents a more clinically relevant treatment paradigm. In addition, we investigated the mechanism of action of DPN treatment-induced recovery during EAE. Given that prophylactic and therapeutic treatment with DPN during EAE improved remyelination-induced axon conduction, and that ER (α and β) and membrane (m)ERs are present on oligodendrocyte lineage cells, a direct effect of treatment on oligodendrocytes is likely. DPN treatment of EAE animals resulted in phosphorylated ERβ and activated the phosphatidylinositol 3-kinase (PI3K)/ serine–threonine-specific protein kinase (Akt)/ mammalian target of rapamycin (mTOR) signaling pathway, a pathway required for oligodendrocyte survival and axon myelination. These results, along with our previous studies of prophylactic DPN treatment, make DPN and similar ERβ ligands immediate and favorable therapeutic candidates for demyelinating disease.