Details

Autor(en) / Beteiligte

• Martínez-Torres, Sara
• Cutando, Laura
• Pastor, Antoni
• Kato, Ako
• Sakimura, Kenji
• de la Torre, Rafael
• Valjent, Emmanuel
• Maldonado, Rafael
• Kano, Masanobu
• Ozaita, Andrés

Titel

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

Ist Teil von

• Brain, behavior, and immunity, 2019-10, Vol.81, p.399-409

Ort / Verlag

Netherlands: Elsevier Inc

Erscheinungsjahr

2019

Quelle

ScienceDirect

Beschreibungen/Notizen

• •Monoacylglycerol lipase (MAGL) inactivation increases microglial perimeter in the cerebellum.•Cerebellar microglia activation concurs with COX-2 over-expression and motor deficits.•COX-2 inhibition prevents the cerebellar neuroinflammation caused by MAGL deletion.•MAGL depletion decreased AA and PGs levels in the cerebellum and hippocampus.•Regional differences in MAGL inhibition outcome caution endocannabinoid targeting. 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.