Tian Ke-Wei, Zhang Fan, Jiang Hong, Wang Beibei, Han Shu
Institute of Anatomy and Cell Biology, Medical College, Zhejiang University, Hangzhou, China.
Department of Electrophysiology, Sir Run Run Shaw Hospital, Medical College, Zhejiang University, Hangzhou, China.
J Anat. 2017 Jan;230(1):30-46. doi: 10.1111/joa.12541. Epub 2016 Oct 19.
Multiple sclerosis (MS) is a chronic neurological disorder that affects the central nervous system (CNS), and results in CNS inflammation and damage to myelin. In this study, we examined the possible synergistic effects of C16, angiopoietin-1 (Ang-1) and regeneration gene protein 2 (Reg-2) in alleviating inflammation in an acute experimental autoimmune encephalomyelitis (EAE) model. We employed multiple histological, morphological and iconographic assays to examine the effect of those drugs on disease onset, clinical scores and behavioral deficits. Our results demonstrated that triple combination therapy was more efficient than the monotherapy in EAE treatment. The triple therapy significantly delayed the onset of motor symptoms, reduced disease severity, attenuated inflammatory cell infiltration and suppressed the secretion of proinflammatory cytokines. Additionally, treatment increased anti-inflammatory cytokines expression, inhibited reactive astrocytes proliferation, reduced demyelination and axonal loss, and finally reduced the neural death. Specifically, Reg-2 administration rescued oligodendrocytes and neuronal axons mainly by direct neurotrophic effects, while C16+Ang-1 (C+A) mainly improved the inflammatory milieu. In conclusion, our study suggests a possible synergistic effect through targeting a variety of pathways in relieving the clinical symptoms of inflammation in acute EAE model. Therefore, using molecules that target different molecular pathways can be beneficial for exploring novel therapeutic approaches for MS treatment.
多发性硬化症（MS）是一种影响中枢神经系统（CNS）的慢性神经疾病，会导致中枢神经系统炎症和髓鞘损伤。在本研究中，我们检测了C16、血管生成素-1（Ang-1）和再生基因蛋白2（Reg-2）在急性实验性自身免疫性脑脊髓炎（EAE）模型中减轻炎症的可能协同作用。我们采用了多种组织学、形态学和影像学检测方法，来检测这些药物对疾病发作、临床评分和行为缺陷的影响。我们的结果表明，三联疗法在EAE治疗中比单一疗法更有效。三联疗法显著延迟了运动症状的发作，降低了疾病严重程度，减轻了炎性细胞浸润，并抑制了促炎细胞因子的分泌。此外，治疗增加了抗炎细胞因子的表达，抑制了反应性星形胶质细胞的增殖，减少了脱髓鞘和轴突损失，最终减少了神经死亡。具体而言，给予Reg-2主要通过直接的神经营养作用拯救少突胶质细胞和神经元轴突，而C16+Ang-1（C+A）主要改善炎症环境。总之，我们的研究表明，在急性EAE模型中，通过靶向多种途径可能存在协同效应以减轻炎症的临床症状。因此，使用靶向不同分子途径的分子可能有助于探索治疗MS的新方法。
