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Neuropharmacology. 2019 May 15;150:134-144. doi: 10.1016/j.neuropharm.2019.03.027. Epub 2019 Mar 23.

Astroglial monoacylglycerol lipase controls mutant huntingtin-induced damage of striatal neurons.

Author information

1
Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Universitario de Investigación Neuroquímica (IUIN), Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University, 28040 Madrid, Spain.
2
Department of Organic Chemistry, School of Chemistry, Complutense University, 28040 Madrid, Spain.
3
Institute of Molecular Bioscience, University of Graz, 8010 Graz, Austria.
4
INSERM and University of Bordeaux, NeuroCentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, 33077 Bordeaux, France.
5
Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Universitario de Investigación Neuroquímica (IUIN), Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University, 28040 Madrid, Spain. Electronic address: mguzman@quim.ucm.es.

Abstract

Cannabinoids 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.

KEYWORDS:

Astrocyte; Cannabinoid receptor; Endocannabinoid; Medium spiny neuron; Monoacylglycerol lipase; Neuroprotection

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