Effects of a novel orally administered calpain inhibitor SNJ-1945 on immunomodulation and neurodegeneration in a murine model of multiple sclerosis.
Effects of a novel orally administered calpain inhibitor SNJ-1945 on immunomodulation and neurodegeneration in a murine model of multiple sclerosis.
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DOI：
10.1111/jnc.12659
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发表时间：
2014-07
影响因子：
4.7
通讯作者：
Banik NL
中科院分区：
文献类型：
--
作者：
Trager N;Smith A;Wallace Iv G;Azuma M;Inoue J;Beeson C;Haque A;Banik NL
多发性硬化（MS）病理学的特征是髓鞘特异性T细胞大量浸润到中枢神经系统（CNS）中。在活动性疾病期间T辅助（Th）细胞的标志是促炎性Th 1/Th 17细胞，其在免疫调节性Th 2/Treg细胞上占优势。神经退行性变是进展性MS的一个主要因素，在考虑药物处方时经常被忽视。在这里，我们表明，口服SNJ-1945，一种新的水溶性钙蛋白酶抑制剂，降低实验性自身免疫性脑脊髓炎（EAE）的临床评分在体内，并通过抗炎和保护神经变性具有双管齐下的效果。我们还表明，SNJ-1945治疗下调Th 1/Th 17炎症反应，并促进体内调节性T细胞（T细胞）和髓源性抑制细胞（MDSC），这是已知的有能力抑制辅助以及细胞毒性T细胞功能。通过对脊髓样本的分析，我们发现钙蛋白酶表达减少，炎性细胞浸润减少，神经退行性变的抑制迹象。我们还显示了脊髓（SC）切片中神经元细胞死亡的显著减少。这些结果表明，钙蛋白酶抑制通过减少炎症和神经变性来减弱EAE病理，并且可以在临床环境中用于增强用于治疗MS的标准免疫调节剂的功效。
Multiple Sclerosis (MS) pathology is marked by the massive infiltration of myelin-specific T cells into the central nervous system (CNS). Hallmarks of T helper (Th) cells during active disease are pro-inflammatory Th1/Th17 cells that predominate over immunoregulatory Th2/Treg cells. Neurodegeneration, a major factor in progressive MS, is often overlooked when considering drug prescription. Here, we show that oral dosing with SNJ-1945, a novel water soluble calpain inhibitor, reduces experimental autoimmune encephalomyelitis (EAE) clinical scores in vivo and has a two pronged effect via anti-inflammation and protection against neurodegeneration. We also show that SNJ-1945 treatment downregulates Th1/Th17 inflammatory responses, and promotes regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in vivo, which are known to have the capacity to suppress helper as well as cytotoxic T cell functions. Through analysis of spinal cord samples, we show a reduction of calpain expression, decreased infiltration of inflammatory cells and signs of inhibition of neurodegeneration. We also show a marked reduction of neuronal cell death in spinal cord (SC) sections. These results suggest that calpain inhibition attenuates EAE pathology by reducing both inflammation and neurodegeneration, and could be used in clinical settings to augment the efficacy of standard immunomodulatory agents used to treat MS.
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