Therapeutic laquinimod treatment decreases inflammation, initiates axon remyelination, and improves motor deficit in a mouse model of multiple sclerosis.
Therapeutic laquinimod treatment decreases inflammation, initiates axon remyelination, and improves motor deficit in a mouse model of multiple sclerosis.
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DOI：
10.1002/brb3.174
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发表时间：
2013-11
影响因子：
3.1
通讯作者：
Tiwari-Woodruff, Seema K.
中科院分区：
文献类型：
--
作者：
Moore, Spencer;Khalaj, Anna J.;Yoon, JaeHee;Patel, Rhusheet;Hannsun, Gemmy;Yoo, Timothy;Sasidhar, Manda;Martinez-Torres, Leonardo;Hayardeny, Liat;Tiwari-Woodruff, Seema K.
关键词：
诱导有效的神经保护和增强内在修复机制的治疗策略是多发性硬化症（MS）以及其他疾病未来治疗的中心目标。拉喹莫德（LQ）是一种口服给药的中枢神经系统（CNS）活性免疫调节剂，在MS临床试验中证明了疗效，并具有良好的安全性和耐受性。我们的目的是探讨病理，功能和行为后果的预防性和治疗性（临床疾病高峰后）LQ治疗的慢性实验性自身免疫性脑脊髓炎（EAE）小鼠模型MS。主动EAE诱导的8周龄C57 BL/6小鼠通过口服灌胃5或25 mg/kg/天LQ开始EAE免疫后第0，8或21天。在整个病程中评估临床评分和旋转棒运动表现。对自身抗原刺激的脾细胞进行免疫分析，对胼胝体轴突进行电生理传导，对富含白色物质的胼胝体和脊髓进行免疫组织化学分析。LQ的预防性和治疗性治疗显著降低了平均临床疾病评分，抑制了Th 1细胞因子的产生，并降低了CNS炎症反应。在EAE过程中，LQ诱导的轴突髓鞘形成和完整性的改善是功能性的，如胼胝体轴突传导和轴突不应性的显著恢复和旋转棒运动性能的显著改善所证明的。这些改善与LQ诱导的EAE诱导的脱髓鞘和轴突损伤的衰减以及有髓鞘轴突数量的改善相关。即使在疾病高峰期开始，LQ治疗在慢性EAE小鼠模型中也具有有益效果。除了其免疫调节作用之外，LQ治疗对少突胶质细胞数量和髓鞘密度的积极作用表明了显著的功能性神经保护和神经恢复作用。我们的研究结果支持LQ治疗在抑制正在进行的MS/EAE疾病进展中的潜在神经保护作用以及免疫调节作用。
Therapeutic strategies that induce effective neuroprotection and enhance intrinsic repair mechanisms are central goals for future treatment of multiple sclerosis (MS), as well as other diseases. Laquinimod (LQ) is an orally administered, central nervous system (CNS)-active immunomodulator with demonstrated efficacy in MS clinical trials and a favorable safety and tolerability profile. We aimed to explore the pathological, functional, and behavioral consequences of prophylactic and therapeutic (after presentation of peak clinical disease) LQ treatment in the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Active EAE-induced 8-week-old C57BL/6 mice were treated with 5 or 25 mg/kg/day LQ via oral gavage beginning on EAE post-immunization day 0, 8, or 21. Clinical scores and rotorod motor performance were assessed throughout the disease course. Immune analysis of autoantigen-stimulated splenocytes, electrophysiological conduction of callosal axons, and immunohistochemistry of white matter-rich corpus callosum and spinal cord were performed. Prophylactic and therapeutic treatment with LQ significantly decreased mean clinical disease scores, inhibited Th1 cytokine production, and decreased the CNS inflammatory response. LQ-induced improvement in axon myelination and integrity during EAE was functional, as evidenced by significant recovery of callosal axon conduction and axon refractoriness and pronounced improvement in rotorod motor performance. These improvements correlate with LQ-induced attenuation of EAE-induced demyelination and axon damage, and improved myelinated axon numbers. Even when initiated at peak disease, LQ treatment has beneficial effects within the chronic EAE mouse model. In addition to its immunomodulatory effects, the positive effects of LQ treatment on oligodendrocyte numbers and myelin density are indicative of significant, functional neuroprotective and neurorestorative effects. Our results support a potential neuroprotective, in addition to immunomodulatory, effect of LQ treatment in inhibiting ongoing MS/EAE disease progression.
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影响因子：
11.2
作者：
Chang, Ansi;Staugaitis, Susan M.;Dutta, Ranjan;Batt, Courtney E.;Easley, Kathryn E.;Chomyk, Anthony M.;Yong, V. Wee;Fox, Robert J.;Kidd, Grahame J.;Trapp, Bruce D.
通讯作者：
Trapp, Bruce D.
影响因子：
6.1
作者：
Kumar S;Patel R;Moore S;Crawford DK;Suwanna N;Mangiardi M;Tiwari-Woodruff SK
通讯作者：
Tiwari-Woodruff SK
影响因子：
14.5
作者：
Bannerman, PG;Hahn, A;Pleasure, D
通讯作者：
Pleasure, D
影响因子：
3.3
作者：
ENG, LF
通讯作者：
ENG, LF
影响因子：
168.9
作者：
Comi, G.;Pulizzi, A.;Filippi, M.
通讯作者：
Filippi, M.