title: Therapeutic laquinimod treatment decreases inflammation, initiates axon remyelination, and improves motor deficit in a mouse model of multiple sclerosis.
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.
  
  
  OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Multiple Sclerosis Program, Department of Neurology, David Geffen School of Medicine at UCLA Los Angeles, California.
authors.forename: Spencer
authors.initials: S
authors.lastname: Moore
authors.affiliation: Multiple Sclerosis Program, Department of Neurology, David Geffen School of Medicine at UCLA Los Angeles, California.
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Khalaj
authors.affiliation: Multiple Sclerosis Program, Department of Neurology, David Geffen School of Medicine at UCLA Los Angeles, California.
authors.forename: Jaehee
authors.initials: J
authors.lastname: Yoon
authors.affiliation: Multiple Sclerosis Program, Department of Neurology, David Geffen School of Medicine at UCLA Los Angeles, California.
authors.forename: Rhusheet
authors.initials: R
authors.lastname: Patel
authors.affiliation: Multiple Sclerosis Program, Department of Neurology, David Geffen School of Medicine at UCLA Los Angeles, California.
authors.forename: Gemmy
authors.initials: G
authors.lastname: Hannsun
authors.affiliation: Multiple Sclerosis Program, Department of Neurology, David Geffen School of Medicine at UCLA Los Angeles, California.
authors.forename: Timothy
authors.initials: T
authors.lastname: Yoo
authors.affiliation: Multiple Sclerosis Program, Department of Neurology, David Geffen School of Medicine at UCLA Los Angeles, California.
authors.forename: Manda
authors.initials: M
authors.lastname: Sasidhar
authors.affiliation: Multiple Sclerosis Program, Department of Neurology, David Geffen School of Medicine at UCLA Los Angeles, California.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Martinez-Torres
authors.affiliation: Pharmacology Unit, Global Innovative R&D, Teva Pharmaceutical Industries Netanya, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Hayardeny
authors.affiliation: Multiple Sclerosis Program, Department of Neurology, David Geffen School of Medicine at UCLA Los Angeles, California ; Brain Research Institute, UCLA School of Medicine Los Angeles, California ; Intellectual Development and Disabilities Research Center, UCLA Los Angeles, California.
authors.forename: Seema K
authors.initials: SK
authors.lastname: Tiwari-Woodruff
keywords: Axon conduction; demyelination; experimental autoimmune encephalomyelitis; laquinimod; multiple sclerosis; myelination; neuroprotective drug; oligodendrocytes; peripheral cytokines; rotorod motor performance; therapeutic treatment