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Neurobiol Aging. 2014 May 28. pii: S0197-4580(14)00384-4. doi: 10.1016/j.neurobiolaging.2014.05.021. [Epub ahead of print]

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

Author information

  • 1Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
  • 2Division of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
  • 3Small Molecule Discovery Platform, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
  • 4Laboratory of Neuroimmunology, Fundación Ciencia y Vida, Santiago, Chile; Programa de Biomedicina, Universidad San Sebastián, Santiago, Chile.
  • 5Laboratory of Neuroimmunology, Fundación Ciencia y Vida, Santiago, Chile.
  • 6Neuroscience Research Center, Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
  • 7Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.
  • 8Division 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.

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.

Copyright © 2014 Elsevier Inc. All rights reserved.

KEYWORDS:

Astroglia; Endocannabinoid system; JZL184; Microglia; Monoacylglycerol lipase; Neuroprotection; Parkinson's disease

PMID:
24973119
[PubMed - as supplied by publisher]
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