Therapeutic laquinimod treatment decreases inflammation, initiates axon remyelination, and improves motor deficit in a mouse model of multiple sclerosis

Brain and Behavior

Spencer Moore²  Anna J. Khalaj²  JaeHee Yoon²  Rhusheet Patel²  Gemmy Hannsun²  Timothy Yoo²  Manda Sasidhar²  Leonardo Martinez-Torres²  Liat Hayardeny¹ 

[1] Pharmacology Unit, Global Innovative R&D, Teva Pharmaceutical Industries, Netanya, Israel;Multiple Sclerosis Program, Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California

关键词: Axon conduction;    demyelination;    experimental autoimmune encephalomyelitis;    laquinimod;    multiple sclerosis;    myelination;    neuroprotective drug;    oligodendrocytes;    peripheral cytokines;    rotorod motor performance;    therapeutic treatment;   

DOI  :  10.1002/brb3.174

来源: Wiley

【 摘 要 】

Abstract

Background

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.

Aims

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.

Materials and methods

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.

Results

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.

Discussion

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.

Conclusions

Our results support a potential neuroprotective, in addition to immunomodulatory, effect of LQ treatment in inhibiting ongoing MS/EAE disease progression.

【 授权许可】

CC BY   
© 2013 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.