Division of Biomedical Sciences, UCR School of Medicine, Riverside, CA, 92521, USA.
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
Sci Rep. 2019 Jan 24;9(1):503. doi: 10.1038/s41598-018-37420-x.
Pharmaceutical agents currently approved for the treatment of multiple sclerosis reduce relapse rates, but do not reverse or prevent neurodegeneration nor initiate myelin repair. The highly selective estrogen receptor (ER) β ligand chloroindazole (IndCl) shows particular promise promoting both remyelination while reducing inflammatory cytokines in the central nervous system of mice with experimental autoimmune encephalomyelitis. To optimize these benefits, we developed and screened seven novel IndCl analogues for their efficacy in promoting primary oligodendrocyte (OL) progenitor cell survival, proliferation, and differentiation in vitro by immunohistochemistry. Two analogues, IndCl-o-chloro and IndCl-o-methyl, induced proliferation and differentiation equivalent to IndCl and were selected for subsequent in vivo evaluation for their impact on clinical disease course, white matter pathology, and inflammation. Both compounds ameliorated disease severity, increased mature OLs, and improved overall myelination in the corpus callosum and white matter tracts of the spinal cord. These effects were accompanied by reduced production of the OL toxic molecules interferon-γ and chemokine (C-X-C motif) ligand, CXCL10 by splenocytes with no discernable effect on central nervous system-infiltrating leukocyte numbers, while IndCl-o-methyl also reduced peripheral interleukin (IL)-17. In addition, expression of the chemokine CXCL1, which is associated with developmental oligodendrogenesis, was upregulated by IndCl and both analogues. Furthermore, callosal compound action potential recordings from analogue-treated mice demonstrated a larger N1 component amplitude compared to vehicle, suggesting more functionally myelinated fibers. Thus, the o-Methyl and o-Chloro IndCl analogues represent a class of ERβ ligands that offer significant remyelination and neuroprotection as well as modulation of the immune system; hence, they appear appropriate to consider further for therapeutic development in multiple sclerosis and other demyelinating diseases.
目前批准用于治疗多发性硬化症的药物可降低复发率，但不能逆转或预防神经退行性变，也不能启动髓鞘修复。高度选择性雌激素受体 (ER)β配体氯吲哚（IndCl）在促进实验性自身免疫性脑脊髓炎小鼠的髓鞘再生的同时降低中枢神经系统中的炎症细胞因子方面显示出特别的前景。为了优化这些益处，我们通过免疫组织化学开发并筛选了七种新型 IndCl 类似物，以评估它们促进原代少突胶质细胞（OL）祖细胞在体外存活、增殖和分化的功效。两种类似物 IndCl-o-氯和 IndCl-o-甲基诱导增殖和分化与 IndCl 相当，被选为随后在体内评估它们对临床疾病过程、白质病理学和炎症的影响。这两种化合物均改善了疾病严重程度，增加了成熟的 OL，并改善了胼胝体和脊髓白质束中的整体髓鞘形成。这些作用伴随着 OL 毒性分子干扰素-γ和趋化因子（C-X-C 基序）配体 CXCL10 的产生减少，脾细胞中没有明显影响中枢神经系统浸润白细胞的数量，而 IndCl-o-甲基也减少了外周白细胞介素（IL）-17。此外，与发育性少突胶质细胞形成相关的趋化因子 CXCL1 的表达被 IndCl 和两种类似物上调。此外，与载体相比，来自类似物处理的小鼠的胼胝体复合动作电位记录显示 N1 成分幅度更大，表明有更多功能髓鞘化纤维。因此，o-甲基和 o-氯 IndCl 类似物代表了一类 ERβ 配体，它们具有显著的髓鞘再生和神经保护作用，以及免疫系统的调节作用；因此，它们似乎适合进一步考虑用于多发性硬化症和其他脱髓鞘疾病的治疗开发。
