Selective Endocannabinoid Reuptake Inhibitor WOBE437 Reduces Disease Progression in a Mouse Model of Multiple Sclerosis

[Image: see text] The modulation of the endocannabinoid system (ECS) has shown positive results in animal models of multiple sclerosis (MS) and immune and inflammatory disorders. However, chronic administration of CB1 receptor agonists and degrading enzyme inhibitors can lead to CB1 receptor desensitization and sedation. WOBE437 is the prototype of a new class of ECS modulators named selective endocannabinoid reuptake inhibitors (SERIs), which mildly and selectively increase central endocannabinoid levels with a self-limiting mode of action. In previous studies, WOBE437 demonstrated analgesic, anxiolytic, and anti-inflammatory effects. Here, we tested the therapeutic potential of WOBE437 in a clinically relevant mouse model of MS (experimental autoimmune encephalomyelitis). C57BL/6 mice were administered WOBE437 (10 mg/kg, 20 days) or vehicle using two therapeutic options: (1) starting the treatment at the disease onset or (2) before reaching the peak of the disease. In both strategies, WOBE437 significantly reduced disease severity and accelerated recovery through CB1 and CB2 receptor-dependent mechanisms. At the peak of the disease, WOBE437 increased endocannabinoid levels in the cerebellum, concurring with a reduction of central nervous system (CNS)-infiltrating immune cells and lower microglial proliferation. At the end of treatment, endocannabinoid levels were mildly increased in brain, cerebellum, and plasma of WOBE437-treated mice, without desensitization of CB1 receptor in the brain and cerebellum. In a mouse model of spasticity (Straub test), WOBE437 (10 mg/kg) induced significant muscle relaxation without eliciting the typical sedative effects associated with muscle relaxants or CB1 receptor agonists. Collectively, our results show that WOBE437 (and SERIs) may represent a novel therapeutic strategy for slowing MS progression and control major symptoms.