Pharmacological modulation of the endocannabinoid system in a viral model of multiple sclerosis

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Abstract
Theiler's virus infection of the central nervous system (CNS) induces an immune‐mediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis (MS). Cannabinoids have been shown to exert beneficial effects on animal models of MS and evidence suggests that the endocannabinoid system plays a role in the tonic control of spasticity. In this study we show that OMDM1 [(R)‐N‐oleoyl‐(1′‐hydroxybenzyl)‐2′‐ethanolamine] and OMDM2 [(S)‐N‐oleoyl‐(1′‐hydroxybenzyl)‐2′‐ethanolamine], two selective inhibitors of the putative endocannabinoid transporter and hence of endocannabinoid inactivation, provide an effective therapy for Theiler murine encephalomyelitis virus‐induced demyelinating disease (TMEV‐IDD). Treatment of TMEV‐infected mice with OMDM1 and OMDM2 enhanced anandamide levels in the spinal cord and ameliorated motor symptoms. This was associated with a down‐regulation of inflammatory responses in the spinal cord. In addition we show that OMDM1 and OMDM2 down‐regulate macrophage function by (i) decreasing the surface expression of major histocompatibility complex (MHC) class II molecules, (ii) inhibiting nitric oxide synthase‐2 (NOS‐2) expression and (iii) reducing the production of the pro‐inflammatory cytokines interleukin‐1beta (IL‐1β) and interleukin‐12 (IL‐12p40). Taken together, these results point to the manipulation of the endocannabinoid system as a possible strategy to develop future MS therapeutic drugs.