The monoacylglycerol lipase inhibitor JZL184 is neuroprotective and alters glial cell phenotype in the chronic MPTP mouse model

Fernández-Suárez, Diana; Celorrio, Marta; Riezu-Boj, José I.; Pacheco, Rodrigo; González, Hugo; Oyarzabal, Julen; Hillard, Cecilia J.; Franco, Rafael; Aymerich, María S.

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 TGF beta messenger RNA expression and in glial cell-derived neurotrophic factor messenger RNA and protein levels. JZL184 induced an increase in beta-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. (C) 2014 Elsevier Inc. All rights reserved.

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Título según WOS: The monoacylglycerol lipase inhibitor JZL184 is neuroprotective and alters glial cell phenotype in the chronic MPTP mouse model
Título según SCOPUS: The monoacylglycerol lipase inhibitor JZL184 is neuroprotective and alters glial cell phenotype in the chronic MPTP mouse model
Título de la Revista: NEUROBIOLOGY OF AGING
Volumen: 35
Número: 11
Editorial: Elsevier Science Inc.
Fecha de publicación: 2014
Página de inicio: 2603
Página final: 2616
Idioma: English
DOI:

10.1016/j.neurobiolaging.2014.05.021

Notas: ISI, SCOPUS - ISI