Monoacylglycerol lipase inhibitor JZL184 is neuroprotective and alters glial cell phenotype in the chronic MPTP mouse model. Neurobiol Aging 2014 Nov;35(11):2603-2616
Date
06/29/2014Pubmed ID
24973119DOI
10.1016/j.neurobiolaging.2014.05.021Scopus ID
2-s2.0-84922880383 (requires institutional sign-in at Scopus site) 74 CitationsAbstract
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.
Author List
Fernández-Suárez D, Celorrio M, Riezu-Boj JI, Ugarte A, Pacheco R, González H, Oyarzabal J, Hillard CJ, Franco R, Aymerich MSAuthor
Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAnti-Inflammatory Agents
Arachidonic Acids
Benzodioxoles
Corpus Striatum
Disease Models, Animal
Endocannabinoids
Glial Fibrillary Acidic Protein
Glycerides
Male
Mice, Inbred C57BL
Monoacylglycerol Lipases
Nerve Tissue Proteins
Neural Pathways
Neuroglia
Neuroprotective Agents
Parkinsonian Disorders
Piperidines
Probenecid
Substantia Nigra
