Ruiz Calvo, AndreaBajo Grañeras, RaquelMaroto Martínez, Irene BereniceZian, DeboraGrabner, Gernot F.García-Taboada, ElenaResel, EvaZechner, RudolfZimmermann, RobertOrtega Gutiérrez, SilviaGalve Roperh, IsmaelBellocchio, LuigiGuzmán, Manuel2023-06-172023-06-172019-05-150028-3908https://doi-org.bucm.idm.oclc.org/10.1016/j.neuropharm.2019.03.027https://hdl.handle.net/20.500.14352/12334Cannabinoids exert neuroprotection in a wide array of preclinical models. A number of these studies has focused on cannabinoid CB1 receptors in striatal medium spiny neurons (MSNs) and the most characteristic MSN-degenerative disease, Huntington's disease (HD). Accruing evidence supports that astrocytes contribute to drive HD progression, and that they express CB1 receptors, degrade endocannabinoids, and modulate endocannabinergic transmission. However, the possible role of the astroglial endocannabinoid system in controlling MSN integrity remains unknown. Here, we show that JZL-184, a selective inhibitor of monoacylglycerol lipase (MGL), the key enzyme that deactivates the endocannabinoid 2-arachidonoylglycerol, prevented the mutant huntingtin-induced up-regulation of the pro-inflammatory cytokine tumor necrosis factor-α in primary mouse striatal astrocytes via CB1 receptors. To study the role of astroglial MGL in vivo, we injected stereotactically into the mouse dorsal striatum viral vectors that encode mutant or normal huntingtin under the control of the glial fibrillary acidic protein promoter. We observed that, in wild-type mice, pharmacological blockade of MGL with JZL-184 (8 mg/kg/day, i.p.) conferred neuroprotection against mutant huntingtin-induced striatal damage, as evidenced by the prevention of MSN loss, astrogliosis, and motor coordination impairment. We next found that conditional mutant mice bearing a genetic deletion of MGL selectively in astroglial cells (MGLfloxed/floxed;GFAP-Cre/+ mice) were resistant to mutant huntingtin-induced MSN loss, astrogliosis, and motor coordination impairment. Taken together, these data support that astroglial MGL controls the availability of a 2-arachidonoylglycerol pool that ensues protection of MSNs in the mouse striatum in vivo, thus providing a potential druggable target for reducing striatal neurodegeneration.engjournal articlehttps://www-sciencedirect-com.bucm.idm.oclc.org/science/article/pii/S0028390819301066#!restricted access577.1577.2612.8AstrocyteCannabinoid receptorEndocannabinoidMedium spiny neuronMonoacylglycerol lipaseNeuroprotectionBiología molecular (Biología)Bioquímica (Biología)Neurociencias (Biológicas)2415 Biología Molecular2302 Bioquímica2490 Neurociencias