Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinson's disease. Brain Behav Immun 2016 Oct;57:94-105
Date
06/19/2016Pubmed ID
27318096DOI
10.1016/j.bbi.2016.06.010Scopus ID
2-s2.0-84977659397 (requires institutional sign-in at Scopus site) 51 CitationsAbstract
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.
Author List
Celorrio M, Fernández-Suárez D, Rojo-Bustamante E, Echeverry-Alzate V, Ramírez MJ, Hillard CJ, López-Moreno JA, Maldonado R, Oyarzábal J, 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
AmidohydrolasesAnimals
Arachidonic Acids
Benzamides
Cannabinoid Receptor Agonists
Carbamates
Disease Models, Animal
Endocannabinoids
Male
Mice
Mice, Inbred C57BL
Parkinsonian Disorders
Polyunsaturated Alkamides
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2
