Pharmacological blockade of 2-AG degradation ameliorates clinical, neuroinflammatory and synaptic alterations in experimental autoimmune encephalomyelitis

The endocannabinoid system (ECS) is critically involved in the pathophysiology of Multiple Sclerosis (MS), a neuroinflammatory and neurodegenerative disease of the central nervous system (CNS). Over the past decade, the neuroprotective and anti-inflammatory effects of the ECS have been studied, and inhibiting the degradation of the endocannabinoid 2-arachydonoylglycerol (2-AG) is emerging as a promising strategy to counteract brain damage in MS. In this study, a systemic and preventive in vivo treatment with MAGLi 432, the reversible inhibitor of monoacylglycerol lipase (MAGLi), was performed in experimental autoimmune encephalomyelitis (EAE) mice. Clinical, biochemical, electrophysiological and immunofluorescence analyses were carried out to evaluate the impact of the drug on motor disability, neuroinflammation and synaptic damage. MAGLi 432 induced a less severe EAE disease, accompanied by an increase of 2-AG and a reduction of acid arachidonic (AA) and prostaglandins (PGs) brain levels.