Martínez-Torres, SaraCutando Ruiz, Laura, 1985-Pastor, AntonioKato, AkoSakimura, KenjiTorre Fornell, Rafael de laValjent, EmmanuelMaldonado, Rafael, 1961-Kano, MasanobuOzaita Mintegui, Andrés, 1969-2019-06-282019Martínez-Torres S, Cutando L, Pastor A, Kato A, Sakimura K, de la Torre R et al. Monoacylglycerol lipase blockade impairs fine motor coordination and triggers cerebellar neuroinflammation through cyclooxygenase-2. Brain Behav Immun. 2019;81:399-409. DOI: 10.1016/j.bbi.2019.06.0360889-1591http://hdl.handle.net/10230/41890Monoacylglycerol lipase (MAGL) is the main enzyme implicated in the degradation of the most abundant endocannabinoid in the brain, 2-arachidonoylglycerol (2-AG), producing arachidonic acid (AA) and glycerol. MAGL pharmacological inhibition with JZL184 or genetic deletion results in an exacerbated 2-AG signaling and reduced synthesis of prostaglandins (PGs), due to the reduced AA precursor levels. We found that acute JZL184 administration, previously described to exert anti-inflammatory effects, and MAGL knockout (KO) mice display cerebellar, but not hippocampal, microglial reactivity, accompanied with increased expression of the mRNA levels of neuroinflammatory markers, such as cyclooxygenase-2 (COX-2). Notably, this neuroinflammatory phenotype correlated with relevant motor coordination impairment in the beam-walking and the footprint tests. Treatment with the COX-2 inhibitor NS398 during 5 days prevented the deficits in cerebellar function and the cerebellar microglia reactivity in MAGL KO, without affecting hippocampal reactivity. Altogether, this study reveals the brain region-specific response to MAGL inhibition, with an important role of COX-2 in the cerebellar deficits associated, which should be taken into account for the use of MAGL inhibitors as anti-inflammatory drugs.application/pdfeng© Elsevier http://dx.doi.org/10.1016/j.bbi.2019.06.036info:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.bbi.2019.06.036Monoacylglycerol lipase2-arachidonoylglycerolMicrogliaCyclooxygenase-2CerebellumMotor coordinationNeuroinflammationProstaglandinsHippocampusinfo:eu-repo/semantics/openAccess