Moore S, Khalaj AJ, Yoon J, Patel R, Hannsun G, Yoo T, Sasidhar M, Martinez-Torres L, Hayardeny L, Tiwari-Woodruff SK. Therapeutic laquinimod treatment decreases inflammation, initiates axon remyelination, and improves motor deficit in a mouse model of multiple sclerosis. Brain Behav. 2013;3(6):664-82. doi: 10.1002/brb3.174
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.
Lacquinimod is not a very good DMT based on the doses used in MS and was worse than the interferons at stopping relapses in MS, yet in EAE it could stop CNS autoimmunity and not surprisingly this was associated with inhibition in the development of autoimmunity in the CNS and so this will inhibit the downstream consequences of this like CNS infiltration and the damage that this causes like axonal damage and myelin damage.
In this study it is claimed that there is neurorestorative function which sounds promising. However, was this “improvement” and “recovery” in nerve function or more likely “slowing of the loss of function” so if the drug has a peripheral immunosuppressive action the downstream consequences will not occur. This is very different from having function shown to be lost and then actually recovering the lost function. In one scenario there is recovery from something in the other the something never happens. Based on the data it can be largely explained by immunosuppression.
Have a read it is open access.
CoI. It was supported by Teva