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Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinson’s disease
- Source :
- Recercat. Dipósit de la Recerca de Catalunya, instname
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
Abstract
- Elements of the endocannabinoid system are strongly expressed in the basal ganglia where they suffer profound rearrangements after dopamine depletion. Modulation of the levels of the endocannabinoid 2-arachidonoyl-glycerol by inhibiting monoacylglycerol lipase alters glial phenotypes and provides neuroprotection in a mouse model of Parkinson's disease. In this study, we assessed whether inhibiting fatty acid amide hydrolase could also provide beneficial effects on the time course of this disease. The fatty acid amide hydrolase inhibitor, URB597, was administered chronically to mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp) over 5weeks. URB597 (1mg/kg) prevented MPTPp induced motor impairment but it did not preserve the dopamine levels in the nigrostriatal pathway or regulate glial cell activation. The symptomatic relief of URB597 was confirmed in haloperidol-induced catalepsy assays, where its anti-cataleptic effects were both blocked by antagonists of the two cannabinoid receptors (CB1 and CB2), and abolished in animals deficient in these receptors. Other fatty acid amide hydrolase inhibitors, JNJ1661010 and TCF2, also had anti-cataleptic properties. Together, these results demonstrate an effect of fatty acid amide hydrolase inhibition on the motor symptoms of Parkinson's disease in two distinct experimental models that is mediated by cannabinoid receptors. This work was supported by the projects PI14/02070 and SAF2012-39875-C02-01 from the Spanish Government (Plan estatal I+D+I 2013–2016 and ISCIII-FEDER), Fundación Gangoiti and the UTE-project/Foundation for Applied Medical Research (FIMA). Estefanía Rojo is supported by a predoctoral fellowship from Colfuturo. Partial support was also provided by the Research and Education Program of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin
- Subjects :
- Male
0301 basic medicine
Cannabinoid receptor
Polyunsaturated Alkamides
Immunology
Nigrostriatal pathway
Arachidonic Acids
Pharmacology
Biology
Amidohydrolases
Receptor, Cannabinoid, CB2
Mice
03 medical and health sciences
Behavioral Neuroscience
chemistry.chemical_compound
0302 clinical medicine
Parkinsonian Disorders
Receptor, Cannabinoid, CB1
Fatty acid amide hydrolase
Dopamine
medicine
Animals
Parkinson, Malaltia de
Cannabinoid Receptor Agonists
Endocrine and Autonomic Systems
URB597
Endocannabinoid system
Symptomatic relief
Mice, Inbred C57BL
Monoacylglycerol lipase
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
Biochemistry
chemistry
Benzamides
Carbamates
030217 neurology & neurosurgery
Endocannabinoids
medicine.drug
Subjects
Details
- ISSN :
- 08891591
- Volume :
- 57
- Database :
- OpenAIRE
- Journal :
- Brain, Behavior, and Immunity
- Accession number :
- edsair.doi.dedup.....5731ce6b54dfe1e8d5b7ce77c8a0c6e7