Re-examining the potential of targeting ABHD6 in multiple sclerosis: Efficacy of systemic and peripherally restricted inhibitors in experimental autoimmune encephalomyelitis

Neuropharmacology
Andrea ManterolaSusana Mato

Abstract

α/β-Hydrolase domain-containing 6 (ABHD6) contributes to the hydrolysis of the major endocannabinoid 2-arachidonoylglycerol (2-AG) in the central nervous system (CNS) and in the periphery. ABHD6 blockade has been proposed as novel strategy to treat multiple sclerosis (MS), based on the observation that the inhibitor WWL70 exerts protective anti-inflammatory effects in experimental autoimmune encephalomyelitis (EAE). According to recent data, WWL70 exhibits off-target anti-inflammatory activity in microglial cells and the potential of ABHD6 as drug target in MS remains controversial. Here we further investigated the role of ABHD6 during autoimmune demyelination by comparing the efficacy of two novel inhibitors with different CNS permeability in vivo. Preventive treatment with the systemically active inhibitor KT182 ameliorated the neurological signs of EAE during the time-course of disease. By contrast, administration of the peripherally restricted compound KT203 was ineffective in attenuating EAE symptomatology. Both inhibitors failed to improve corticospinal tract conduction latency and to attenuate inflammation at EAE recovery phase, despite being equally active at targeting brain ABHD6. Chronic administration of KT182 was as...Continue Reading

Citations

Aug 8, 2020·ChemMedChem·Samuele Maramai, Margherita Brindisi
Dec 19, 2019·Frontiers in Molecular Neuroscience·Annelot C M van EsbroeckMario van der Stelt
Jan 15, 2021·British Journal of Pharmacology·Cristina MiralpeixRosalía Rodríguez-Rodríguez
Mar 12, 2019·Trends in Pharmacological Sciences·Jessica K CaoNephi Stella
Jul 3, 2021·Journal of Medicinal Chemistry·Giulia BononiCarlotta Granchi

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