Pharmacological modulation of the endocannabinoid system in a viral model of multiple sclerosis.
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-1beta) 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.
Mestre
Leyre
L
Neuroimmunology Group, Neural Plasticity Department, Cajal Institute, CSIC, 28002 Madrid, Spain.
Correa
Fernando
F
Arévalo-Martín
Angel
A
Molina-Holgado
Eduardo
E
Valenti
Marta
M
Ortar
Giorgio
G
Di Marzo
Vincenzo
V
Guaza
Carmen
C
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D001593:Benzyl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D063385:Cannabinoid Receptor Modulators / Q000819:agonists* / Q000378:metabolism; D018188:Cardiovirus Infections / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D063388:Endocannabinoids; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D051379:Mice; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D053284:Polyunsaturated Alkamides; D017945:Theilovirus / Q000472:pathogenicity; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D001095:Arachidonic Acids; D001593:Benzyl Compounds; D063385:Cannabinoid Receptor Modulators; D002352:Carrier Proteins; D016207:Cytokines; D063388:Endocannabinoids; D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; C474344:OMDM-1 cpd; C474343:OMDM-2 cpd; D053284:Polyunsaturated Alkamides; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C078814:anandamide