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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.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.issn | 0889-1591 |
dc.identifier.uri | http://hdl.handle.net/10230/41890 |
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.language.iso | eng |
dc.publisher | Elsevier |
dc.relation.ispartof | Brain, Behavior, and Immunity. 2019;81:399-409 |
dc.rights | © Elsevier http://dx.doi.org/10.1016/j.bbi.2019.06.036 |
dc.title | Monoacylglycerol lipase blockade impairs fine motor coordination and triggers cerebellar neuroinflammation through cyclooxygenase-2 |
dc.type | info:eu-repo/semantics/article |
dc.identifier.doi | http://dx.doi.org/10.1016/j.bbi.2019.06.036 |
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.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.accessRights | info:eu-repo/semantics/openAccess |
dc.type.version | info:eu-repo/semantics/acceptedVersion |