Monoacylglycerol lipase blockade impairs fine motor coordination and triggers cerebellar neuroinflammation through cyclooxygenase-2

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• dc.contributor.author Martínez-Torres, Sara
• dc.contributor.author Cutando Ruiz, Laura, 1985-
• dc.contributor.author Pastor, Antonio
• dc.contributor.author Kato, Ako
• dc.contributor.author Sakimura, Kenji
• dc.contributor.author Torre Fornell, Rafael de la
• dc.contributor.author Valjent, Emmanuel
• dc.contributor.author Maldonado, Rafael, 1961-
• dc.contributor.author Kano, Masanobu
• dc.contributor.author Ozaita Mintegui, Andrés, 1969-
• dc.date.accessioned 2019-06-28T07:36:21Z
• dc.date.issued 2019
• dc.description.abstract Monoacylglycerol 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.
• dc.description.sponsorship This work was supported by the Ministerio de Economía, Innovación y Competitividad (MINECO) [#BFU2015-68568-P to A.O., #SAF2017-84060-R to R.M.]; the Instituto de Salud Carlos III [#RD16/0017/0020 to R.M.]; the Generalitat de Catalunya [2017SGR-669 to R.M.]; the ICREA (Institució Catalana de Recerca i Estudis Avançats) Academia to A.O. and R.M.; Grant “Unidad de Excelencia María de Maeztu”, funded by the MINECO [#MDM-2014-0370]; PLAN E (Plan Español para el Estímulo de la Economía y el Empleo); Fondation pour la Recherche Médicale to E.V and FEDER funding is also acknowledged.
• dc.format.mimetype application/pdf
• dc.identifier.citation Martínez-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.2019.06.036
• dc.identifier.doi http://dx.doi.org/10.1016/j.bbi.2019.06.036
• dc.identifier.issn 0889-1591
• dc.identifier.uri http://hdl.handle.net/10230/41890
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Brain, Behavior, and Immunity. 2019;81:399-409
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2015-68568-P
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-84060-R
• dc.rights © Elsevier http://dx.doi.org/10.1016/j.bbi.2019.06.036
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword Monoacylglycerol lipase
• dc.subject.keyword 2-arachidonoylglycerol
• dc.subject.keyword Microglia
• dc.subject.keyword Cyclooxygenase-2
• dc.subject.keyword Cerebellum
• dc.subject.keyword Motor coordination
• dc.subject.keyword Neuroinflammation
• dc.subject.keyword Prostaglandins
• dc.subject.keyword Hippocampus
• dc.title Monoacylglycerol lipase blockade impairs fine motor coordination and triggers cerebellar neuroinflammation through cyclooxygenase-2
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion