title: Monoacylglycerol lipase inhibitor JZL184 is neuroprotective and alters glial cell phenotype in the chronic MPTP mouse model.
abstract: Changes in cannabinoid receptor expression and concentration of endocannabinoids have been described in Parkinson's disease; however, it remains unclear whether they contribute to, or result from, the disease process. To evaluate whether targeting the endocannabinoid system could provide potential benefits in the treatment of the disease, the effect of a monoacylglycerol lipase inhibitor that prevents degradation of 2-arachidonyl-glycerol was tested in mice treated chronically with probenecid and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTPp). Chronic administration of the compound, JZL184 (8 mg/kg), prevented MPTPp-induced motor impairment and preserved the nigrostriatal pathway. Furthermore, none of the hypokinetic effects associated with cannabinoid receptor agonism were observed. In the striatum and substantia nigra pars compacta, MPTPp animals treated with JZL184 exhibited astroglial and microglial phenotypic changes that were accompanied by increases in TGFβ messenger RNA expression and in glial cell-derived neurotrophic factor messenger RNA and protein levels. JZL184 induced an increase in β-catenin translocation to the nucleus, implicating the Wnt/catenin pathway. Together, these results demonstrate a potent neuroprotective effect of JZL184 on the nigrostriatal pathway of parkinsonian animals, likely involving restorative astroglia and microglia activation and the release of neuroprotective and antiinflammatory molecules.
authors: Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors: Diana
authors: D
authors: Fernández-Suárez
authors: Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors: Marta
authors: M
authors: Celorrio
authors: Division of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors: José Ignacio
authors: JI
authors: Riezu-Boj
authors: Small Molecule Discovery Platform, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors: Ana
authors: A
authors: Ugarte
authors: Laboratory of Neuroimmunology, Fundación Ciencia y Vida, Santiago, Chile; Programa de Biomedicina, Universidad San Sebastián, Santiago, Chile.
authors: Rodrigo
authors: R
authors: Pacheco
authors: Laboratory of Neuroimmunology, Fundación Ciencia y Vida, Santiago, Chile.
authors: Hugo
authors: H
authors: González
authors: Small Molecule Discovery Platform, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors: Julen
authors: J
authors: Oyarzabal
authors: Neuroscience Research Center, Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Cecilia J
authors: CJ
authors: Hillard
authors: Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.
authors: Rafael
authors: R
authors: Franco
authors: Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Department of Biochemistry and Genetics, School of Science, University of Navarra, Pamplona, Spain. Electronic address: maymerich@unav.es.
authors: María S
authors: MS
authors: Aymerich
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism; D001095:Arachidonic Acids / Q000378:metabolism; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein; D005989:Glycerides / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009434:Neural Pathways / Q000473:pathology / Q000503:physiopathology; D009457:Neuroglia / Q000473:pathology*; D018696:Neuroprotective Agents / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D011339:Probenecid; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D000893:Anti-Inflammatory Agents; D001095:Arachidonic Acids; D052117:Benzodioxoles; D063388:Endocannabinoids; D005904:Glial Fibrillary Acidic Protein; D005989:Glycerides; C534333:JZL 184; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010880:Piperidines; C528900:glial fibrillary astrocytic protein, mouse; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases; D011339:Probenecid
keywords: Astroglia; Endocannabinoid system; JZL184; Microglia; Monoacylglycerol lipase; Neuroprotection; Parkinson's disease