Sistema cannabinoide y regulación neuroinmune en un modelo viral de esclerosis múltipleEstudio de las citoquinas heterodiméricas il-12/il-23

Resumen

There is a growing amount of evidence suggesting that cannabinoids may be neuroprotective in central nervous system inflammatory conditions. Advances in the understanding of the physiology and pharmacology of the endocannabinoid system have potentiated the interest in the cannabinoids as potential therapeutic drugs. The aim of the present work has been to study the actions of the endocannabinoid anandamide (AEA) on macrophages and microglial cells and their implications on multiple sclerosis (MS). AEA negatively regulates the production by microglial cells of the most important heterodimeric cytokines, IL-12 and IL-23, in the spinal cord of TMEV-infected mice, a viral model of MS (as well as their respective subunits: p35, p40 and p19), by both CB2 receptor dependent and independent mechanisms. CB2 receptor dependent signalling on IL-12/IL-23 regulation includes the activation of ERK1/2 and JNK MAPKs and the inhibition of the PI3k/Akt pathway, as well as the synthesis of the anti-inflammatory cytokine IL-10. CB2 independent mechanisms include the participation of COX-2, oxygenating AEA into prostamide E2, activation of EP2 receptors and the subsequent activation of IL-12p40 promoter repressor, GA-12.The pharmacological manipulation of the endocannabinoid system by targeting the AEA transporter or the inhibition of the main degradative enzyme, FAAH, is associated with a down-regulation of inflammatory responses in the spinal cord of TMEV-infected mice. In addition, AEA down-regulates the mRNA of p19, p35 and p40 in the viral model of MS. The effects of endocannabinoids on the brain cytokine network and on the regulation of neuroinflammatory processes may affect chronic inflammatory demyelinating diseases such as multiple sclerosis.