Activation of the endocannabinoid system as therapeutic approach in a murine model of multiple sclerosis.
Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is a well-characterized murine model of human multiple sclerosis (MS) that closely resembles the chronic and progressive clinical form of the disease. Recent studies have described the involvement of the cannabinoid system in the progression of the disease and the benefits associated with the administration of cannabinoid agonists. With the objective to study whether "indirect" agonists, that is, compounds able to reinforce the physiological endocannabinoid transmission and, therefore, devoid of the psychotropic effects of "direct" agonists, could be suitable agents for the amelioration of MS neurological deficits, we administered the potent and selective anandamide uptake inhibitor UCM707 to TMEV-infected mice. Our results indicate that treatment during established disease significantly improves the motor function of the diseased mice. At the histological level, UCM707 is able to reduce microglial activation, diminish major histocompatibility complex class II antigen expression, and decrease cellular infiltrates in the spinal cord. Additionally, in microglial cells, UCM707 decreases the production of the proinflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6; reduces nitric oxide levels and inducible nitric oxide synthase expression; and is able to potentiate the action of a subeffective dose of the endocannabinoid anandamide. Overall, these results suggest that agents able to activate the endocannabinoid system could constitute a new series of drugs for the treatment of MS.
Ortega-Gutiérrez
Silvia
S
Neuroimmunology Group, Neural Plasticity Department, Cajal Institute, CSIC, Madrid, Spain.
Molina-Holgado
Eduardo
E
Arévalo-Martín
Angel
A
Correa
Fernando
F
Viso
Alma
A
López-Rodríguez
María L
ML
Di Marzo
Vincenzo
V
Guaza
Carmen
C
D000818:Animals; D001095:Arachidonic Acids / Q000627:therapeutic use*; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D002478:Cells, Cultured; D063388:Endocannabinoids; D005260:Female; D005663:Furans / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D017628:Microglia / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009103:Multiple Sclerosis / Q000188:drug therapy*; D009569:Nitric Oxide / Q000096:biosynthesis; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology; D043885:Receptor, Cannabinoid, CB2 / Q000502:physiology; D015398:Signal Transduction; D017945:Theilovirus; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005663:Furans; D007375:Interleukin-1; D015850:Interleukin-6; C443680:N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide