Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinson's disease.
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.
Program of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain.
Marta
M
Celorrio
Program of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain.
Diana
D
Fernández-Suárez
Program of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain; Department of Biochemistry and Genetics, School of Science, University of Navarra, Pamplona 31008, Spain.
Estefanía
E
Rojo-Bustamante
Neuroscience Research Center, Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Víctor
V
Echeverry-Alzate
Department of Pharmacology and Toxicology, School of Pharmacy, University of Navarra, Pamplona 31008, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain.
María J
MJ
Ramírez
Neuroscience Research Center, Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Cecilia J
CJ
Hillard
Department of Psychobiology, School of Psychology, Complutense University of Madrid, Madrid, Spain.
José A
JA
López-Moreno
Neuropharmacology Laboratory, University Pompeu Fabra, Barcelona, Spain.
Rafael
R
Maldonado
Small Molecule Discovery Platform, Program of Molecular Therapeutics, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain.
Julen
J
Oyarzábal
Program of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain; Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
Rafael
R
Franco
Program of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain; Department of Biochemistry and Genetics, School of Science, University of Navarra, Pamplona 31008, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain. Electronic address: maymerich@unav.es.
María S
MS
Aymerich
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000378:metabolism*; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D063386:Cannabinoid Receptor Agonists; D002219:Carbamates; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C078814:anandamide
CB(1) receptor; CB(2) receptor; Endocannabinoid system; FAAH; Parkinson’s disease; URB597