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

Abstract

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.

Neuropsychopharmacological profiling of scoparone in mice

“…Endocannabinoid levels were measured in the brain tissue as described recently 48 in an attempt to explain the scoparone-induced anxiogenic behavior in mice. Tested in FST and EPM mice were euthanized by decapitation, and the brain was collected immediately, hemispheres were separated and rinsed in cold PBS and snap frozen in liquid N 2 .…”

Neurological Benefits, Clinical Challenges, and Neuropathologic Promise of Medical Marijuana: A Systematic Review of Cannabinoid Effects in Multiple Sclerosis and Experimental Models of Demyelination

“…In EAE, increased endocannabinoid levels in the brain, cerebellum, and plasma of C57BL/6 mice treated with a selective endocannabinoid reuptake inhibitor, WOBE437, correlated with significant muscle relaxation, decreased neuroinflammatory infiltration, and lower microglial proliferation [187]. Dynamic transcriptional deregulation in the endocannabinoid system during EAE results in an early shift toward enhanced 2-AGmediated CB1 receptor activation in astrocytes that is followed by deficits at later stages of the disease [188].…”

Phytocannabinoids and Cannabis-Based Products as Alternative Pharmacotherapy in Neurodegenerative Diseases: From Hypothesis to Clinical Practice

“…Additionally, the CB1-mediated signaling is essential for tremor and spasticity control in animal model of chronic relapsing experimental autoimmune encephalomyelitis (CREAE) and EAE in CB1 knockout mice ( Baker et al, 2000 ; Pryce and Baker, 2007 ). Besides, the dual activation of CB1 and CB2 by WIN 55,212-2, a cannabinoid agonist, improves the clinical score shown by animals, reduces inflammation and restores tolerance to self-myelin antigen ( Arevalo-Martin et al, 2012 ), while WOBE437, an inhibitor of eCB reuptake, reduces MS severity and infiltration of immune cells into the CNS ( Reynoso-Moreno et al, 2021 ).…”

“…Several preclinical and clinical studies have described an unbalance in ECS components in animal models and patients diagnosed with AD, PD, and MS ( Cristino et al, 2020 ). Also, more recent studies focusing on animal models of neurodegenerative diseases showed that modulation of ECS is a valid alternative to improve animal’s conditions ( Ramírez et al, 2005 ; García-Arencibia et al, 2007 ; Zhao et al, 2020 ; Reynoso-Moreno et al, 2021 ).…”