Nudging oligodendrocyte intrinsic signaling to remyelinate and repair: Estrogen receptor ligand effects.
Nudging oligodendrocyte intrinsic signaling to remyelinate and repair: Estrogen receptor ligand effects.
复制标题
DOI：
10.1016/j.jsbmb.2016.01.006
复制
发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Tiwari-Woodruff SK
中科院分区：
文献类型：
--
作者：
Khalaj AJ;Hasselmann J;Augello C;Moore S;Tiwari-Woodruff SK
多发性硬化症（MS）的脱髓鞘导致显著的、进行性的轴突和神经元变性。目前存在的免疫抑制和免疫调节疗法缓解MS症状并减缓但不能预防或逆转疾病进展。通过补充成熟的少突胶质细胞（OLs）来恢复受损的髓鞘不仅可以恢复跳跃式轴突传导，而且还可以大大促进轴突存活。我们以前的工作已经表明，适度选择性通用雌激素受体（ER）β激动剂二芳基丙腈（DPN）治疗性治疗通过刺激内源性髓鞘形成在MS的慢性实验性自身免疫性脑脊髓炎（EAE）小鼠模型中赋予功能性神经保护作用。最近，我们发现更有效的选择性ERβ激动剂吲唑氯化物（Ind-Cl）改善临床疾病和运动表现。重要的是，电生理测量显示胼胝体传导改善，轴突不应性降低。这种Ind-Cl处理诱导的功能性髓鞘再生可归因于OL祖细胞（OPC）和成熟OL数量的增加。在细胞内信号传导水平，早期OPCs向晚期OPCs的转变需要Erk 1/2信号传导，未成熟OLs向成熟OLs的转变需要mTOR信号传导;因此，PI 3 K/Akt/mTOR通路在OL分化和髓鞘形成的晚期阶段起主要作用。事实上，用各种ERβ激动剂治疗EAE小鼠导致脑源性神经营养因子（BDNF）和磷酸化（p）Akt和p-mTOR水平增加。值得注意的是，虽然DPN的神经保护作用发生在外周和中枢炎症的存在下，但Ind-Cl是直接的神经保护作用，如通过铜腙诱导的脱髓鞘模型中的髓鞘再生作用以及抗炎作用所证明的。阐明ER激动剂和其他直接髓鞘再生剂调节内源性OPC和OL调节信号的机制对于开发有效的髓鞘再生药物至关重要。发现诱导功能性髓鞘再生的信号传导靶点将有价值地有助于治疗脱髓鞘神经系统疾病，包括MS、中风和创伤性脑和脊髓损伤。
Demyelination in multiple sclerosis (MS) leads to significant, progressive axonal and neuronal degeneration. Currently existing immunosuppressive and immunomodulatory therapies alleviate MS symptoms and slow, but fail to prevent or reverse, disease progression. Restoration of damaged myelin sheath by replenishment of mature oligodendrocytes (OLs) should not only restore saltatory axon conduction, but also provide a major boost to axon survival. Our previous work has shown that therapeutic treatment with the modestly selective generic estrogen receptor (ER) β agonist diarylpropionitrile (DPN) confers functional neuroprotection in a chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS by stimulating endogenous myelination. Recently, we found that the more potent, selective ERβ agonist indazole-chloride (Ind-Cl) improves clinical disease and motor performance. Importantly, electrophysiological measures revealed improved corpus callosal conduction and reduced axon refractoriness. This Ind-Cl treatment-induced functional remyelination was attributable to increased OL progenitor cell (OPC) and mature OL numbers. At the intracellular signaling level, transition of early to late OPCs requires Erk1/2 signaling, and transition of immature to mature OLs requires mTOR signaling; thus, the PI3K/Akt/mTOR pathway plays a major role in the late stages of OL differentiation and myelination. Indeed, therapeutic treatment of EAE mice with various ERβ agonists results in increased brain-derived neurotrophic factor (BDNF) and phosphorylated (p) Akt and p-mTOR levels. It is notable that while DPN’s neuroprotective effects occur in the presence of peripheral and central inflammation, Ind-Cl is directly neuroprotective, as demonstrated by remyelination effects in the cuprizone-induced demyelination model, as well as anti-inflammatory. Elucidating the mechanisms by which ER agonists and other directly remyelinating agents modulate endogenous OPC and OL regulatory signaling is critical to the development of effective remyelinating drugs. The discovery of signaling targets to induce functional remyelination will valuably contribute to the treatment of demyelinating neurological diseases, including MS, stroke, and traumatic brain and spinal cord injury.
影响因子：
3.3
作者：
Bonetti A;Koivisto K;Pirttilä T;Elovaara I;Reunanen M;Laaksonen M;Ruutiainen J;Peltonen L;Rantamäki T;Tienari PJ
通讯作者：
Tienari PJ