Multiple functional therapeutic effects of the estrogen receptor β agonist indazole-Cl in a mouse model of multiple sclerosis
Multiple functional therapeutic effects of the estrogen receptor β agonist indazole-Cl in a mouse model of multiple sclerosis
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DOI：
10.1073/pnas.1411294111
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发表时间：
2014-12-16
影响因子：
11.1
通讯作者：
Tiwari-Woodruff, Seema Kaushalya
中科院分区：
文献类型：
--
作者：
Moore, Spencer M.;Khalaj, Anna J.;Tiwari-Woodruff, Seema Kaushalya
目前可用的免疫调节疗法并不能阻止多发性硬化症（MS）的发病机制，并且只能部分有效地预防MS患者永久性残疾的发生。确定一种刺激内源性髓鞘再生和/或最小化轴突变性的药物将降低疾病进展的速度和程度。在这里，高选择性雌激素受体(ER) β激动剂茚唑氯（Ind-Cl）对慢性实验性自身免疫性脑脊髓炎（EAE）小鼠的功能性再髓鞘形成的影响，通过评估预防和治疗（EAE峰值）用Ind-Cl治疗的病理、功能和行为后果。测量自身抗原刺激的脾细胞的外周细胞因子，并通过免疫组织化学和电子显微镜评估免疫细胞的中枢神经系统浸润、轴突健康和髓鞘形成。治疗性Ind-Cl改善了EAE小鼠的临床疾病和旋转性能，并降低了周围Th1细胞因子和反应性星形胶质细胞，激活的小胶质细胞和T细胞。胼胝体髓鞘形成和成熟少突胶质细胞的增加与胼胝体传导和耐火性的改善有关。治疗性Ind-Cl诱导的髓鞘再生与其对免疫系统的影响无关，因为Ind-Cl在铜铜酮饮食诱导的脱髓鞘模型中增加了髓鞘再生。我们得出结论，Ind-Cl是一种能够刺激功能相关的内源性髓鞘形成的精制药物，对进展性MS治疗具有重要意义。
Currently available immunomodulatory therapies do not stop the pathogenesis underlying multiple sclerosis (MS) and are only partially effective in preventing the onset of permanent disability in patients with MS. Identifying a drug that stimulates endogenous remyelination and/or minimizes axonal degeneration would reduce the rate and degree of disease progression. Here, the effects of the highly selective estrogen receptor (ER) beta agonist indazole chloride (Ind-Cl) on functional remyelination in chronic experimental autoimmune encephalomyelitis (EAE) mice were investigated by assessing pathologic, functional, and behavioral consequences of both prophylactic and therapeutic (peak EAE) treatment with Ind-Cl. Peripheral cytokines from autoantigen-stimulated splenocytes were measured, and central nervous system infiltration by immune cells, axon health, and myelination were assessed by immunohistochemistry and electron microscopy. Therapeutic Ind-Cl improved clinical disease and rotorod performance and also decreased peripheral Th1 cytokines and reactive astrocytes, activated microglia, and T cells in brains of EAE mice. Increased callosal myelination and mature oligodendrocytes correlated with improved callosal conduction and refractoriness. Therapeutic Ind-Cl-induced remyelination was independent of its effects on the immune system, as Ind-Cl increased remyelination within the cuprizone diet-induced demyelinating model. We conclude that Ind-Cl is a refined pharmacologic agent capable of stimulating functionally relevant endogenous myelination, with important implications for progressive MS treatment.