Treatment with an estrogen receptor α ligand is neuroprotective in experimental autoimmune encephalomyelitis
Treatment with an estrogen receptor α ligand is neuroprotective in experimental autoimmune encephalomyelitis
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DOI：
10.1523/jneurosci.0453-06.2006
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发表时间：
2006-06-21
影响因子：
5.3
通讯作者：
Voskuhl, Rhonda R.
中科院分区：
文献类型：
--
作者：
Morales, Laurie Beth J.;Loo, Kyi Kyi;Voskuhl, Rhonda R.
多发性硬化是一种炎症性神经退行性疾病，实验性自身免疫性脑脊髓炎（EAE）是其模型。雌激素治疗已被证明通过抗炎机制降低EAE的严重程度。在这里，我们调查了是否治疗与雌激素受体α（ER α）配体可以概括的雌激素介导的保护临床EAE。然后，我们继续研究抗炎和神经保护机制。在野生型、ER α-或ER β-缺陷小鼠中诱导EAE，并分别用高选择性ER α激动剂丙基吡唑三醇治疗，以确定对临床结果以及炎症和神经退行性变化的影响。ER α配体治疗改善了野生型和ER β敲除小鼠的临床疾病，但在ER α敲除小鼠中没有改善，从而证明ER α配体在疾病期间保持了体内ER α选择性。ER α配体治疗还诱导外周免疫系统中自身抗原特异性细胞因子产生的有利变化[TNF α、干扰素-γ和白细胞介素-6减少，白细胞介素-5增加]和CNS白色物质炎症和脱髓鞘减少。有趣的是，在临床疾病的最早阶段，即临床体征发作后1-2天，在EAE小鼠脊髓灰质中观察到神经元染色[NeuN+（神经元特异性核蛋白）/β-3微管蛋白+/Nissl]减少，伴随着这些异常神经元周围的小胶质细胞/单核细胞（Mac 3+）细胞的免疫标记增加。用雌二醇或ER α配体治疗显著减少了这种灰质病理。总之，ER α配体治疗在体内具有高度选择性，在EAE中介导抗炎和神经保护作用。
Multiple sclerosis is an inflammatory, neurodegenerative disease for which experimental autoimmune encephalomyelitis (EAE) is a model. Treatments with estrogens have been shown to decrease the severity of EAE through anti-inflammatory mechanisms. Here we investigated whether treatment with an estrogen receptor alpha (ER alpha) ligand could recapitulate the estrogen-mediated protection in clinical EAE. We then went on to examine both anti-inflammatory and neuroprotective mechanisms. EAE was induced in wild-type, ER alpha-, or ER beta-deficient mice, and each was treated with the highly selective ER alpha agonist, propyl pyrazole triol, to determine the effect on clinical outcomes, as well as on inflammatory and neurodegenerative changes. ER alpha ligand treatment ameliorated clinical disease in both wild-type and ER beta knock-out mice, but not in ER alpha knock- out mice, thereby demonstrating that the ER alpha ligand maintained ER alpha selectivity in vivo during disease. ER alpha ligand treatment also induced favorable changes in autoantigen-specific cytokine production in the peripheral immune system [decreased TNF alpha, interferon-gamma, and interleukin-6, with increased interleukin-5] and decreased CNS white matter inflammation and demyelination. Interestingly, decreased neuronal staining [NeuN+ (neuronal-specific nuclear protein)/beta-3tubulin+/Nissl], accompanied by increased immunolabeling of microglial/monocyte (Mac 3+) cells surrounding these abnormal neurons, was observed in gray matter of spinal cords of EAE mice at the earliest stage of clinical disease, 1-2 d after the onset of clinical signs. Treatment with either estradiol or the ER alpha ligand significantly reduced this gray matter pathology. In conclusion, treatment with an ER alpha ligand is highly selective in vivo, mediating both anti-inflammatory and neuroprotective effects in EAE.