Repurposing the cardiac glycoside digoxin to stimulate myelin regeneration in chemically-induced and immune-mediated mouse models of multiple sclerosis.
Repurposing the cardiac glycoside digoxin to stimulate myelin regeneration in chemically-induced and immune-mediated mouse models of multiple sclerosis.
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多发性硬化（MS）是一种中枢神经系统（CNS）自身免疫性疾病，其特征在于炎症、脱髓鞘和神经变性。理想的MS治疗将特异性抑制潜在的自身免疫反应并促进髓鞘的修复/再生以及轴突完整性的维持。目前批准的MS疗法包括非特异性免疫抑制分子/抗体，其阻断自身反应性T细胞的活化或CNS归巢，但没有批准用于刺激髓鞘再生或维持轴突完整性的疗法。为了改变FDA批准的髓鞘修复药物的用途，我们选择检查地高辛的有效性，地高辛是一种强心苷（Na+/K+ ATP酶抑制剂），最初在体外筛选中被确定为促髓鞘形成。我们发现，地高辛在体外调节少突胶质细胞祖细胞（OPCs）中对少突胶质细胞（OL）分化至关重要的多个基因，在体外和体内促进雌性幼稚C57 BL/6 J（B6）小鼠的OL分化，并刺激B6小鼠在铜腙诱导的胼胝体脱髓鞘和溶血磷脂酰胆碱（LPC）诱导的脊髓脱髓鞘后有髓轴突的恢复，分别与MS的治疗更相关的是，我们表明，地高辛治疗已建立MOG 35 - 55诱导的Th 1/Th 17介导的慢性EAE的小鼠，结合静脉输注与MOG 35 - 55偶联的可生物降解聚（丙交酯-共-乙交酯）纳米颗粒（PLG-MOG 35 - 55）诱导的耐受性，完全改善了临床疾病症状，并刺激了OL谱系细胞数量的恢复。这些发现提供了关键的临床前证据，支持未来在MS患者中进行髓鞘修复/再生药物（如地高辛）的髓鞘特异性耐受性临床试验。地高辛在体外促进少突胶质细胞谱系细胞的分化，在体内促进髓鞘的更早/更稳健的恢复，并且与免疫耐受相结合改善EAE疾病症状并恢复少突胶质细胞谱系。
Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by inflammation, demyelination, and neurodegeneration. The ideal MS therapy would both specifically inhibit the underlying autoimmune response and promote repair/regeneration of myelin as well as maintenance of axonal integrity. Currently approved MS therapies consist of non‐specific immunosuppressive molecules/antibodies which block activation or CNS homing of autoreactive T cells, but there are no approved therapies for stimulation of remyelination nor maintenance of axonal integrity. In an effort to repurpose an FDA‐approved medication for myelin repair, we chose to examine the effectiveness of digoxin, a cardiac glycoside (Na+/K+ ATPase inhibitor), originally identified as pro‐myelinating in an in vitro screen. We found that digoxin regulated multiple genes in oligodendrocyte progenitor cells (OPCs) essential for oligodendrocyte (OL) differentiation in vitro, promoted OL differentiation both in vitro and in vivo in female naïve C57BL/6J (B6) mice, and stimulated recovery of myelinated axons in B6 mice following demyelination in the corpus callosum induced by cuprizone and spinal cord demyelination induced by lysophosphatidylcholine (LPC), respectively. More relevant to treatment of MS, we show that digoxin treatment of mice with established MOG35‐55‐induced Th1/Th17‐mediated chronic EAE combined with tolerance induced by the i.v. infusion of biodegradable poly(lactide‐co‐glycolide) nanoparticles coupled with MOG35‐55 (PLG‐MOG35‐55) completely ameliorated clinical disease symptoms and stimulated recovery of OL lineage cell numbers. These findings provide critical pre‐clinical evidence supporting future clinical trials of myelin‐specific tolerance with myelin repair/regeneration drugs, such as digoxin, in MS patients. Digoxin promoted differentiation of oligodendrocyte lineage cells in vitro, promoted earlier/more robust recovery of myelin in vivo, and combined with immune tolerance ameliorated EAE disease symptoms and recovered the oligodendrocyte cell lineage.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.1146/annurev-bioeng-110315-020137
发表时间：
2016-07-11
影响因子：
9.7
作者：
Luo X;Miller SD;Shea LD
通讯作者：
Shea LD
影响因子：
14.5
作者：
KAJI, R;SUZUMURA, A;SUMNER, AJ
通讯作者：
SUMNER, AJ
影响因子：
17.1
作者：
Hunter Z;McCarthy DP;Yap WT;Harp CT;Getts DR;Shea LD;Miller SD
通讯作者：
Miller SD
影响因子：
11.2
作者：
KAJI, R;SUMNER, AJ
通讯作者：
SUMNER, AJ