title: Increasing levels of the endocannabinoid 2-AG is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.
abstract: Parkinson's disease (PD) is a common chronic neurodegenerative disorder, usually of idiopathic origin. Symptoms including tremor, bradykinesia, rigidity and postural instability are caused by the progressive loss of dopaminergic neurons in the nigrostriatal region of the brain. Symptomatic therapies are available but no treatment slows or prevents the loss of neurons. Neuroinflammation has been implicated in its pathogenesis. To this end, the present study utilises the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to reproduce the pattern of cell death evident in PD patients. Herein, the role of a potential regulator of an immune response, the endocannabinoid system (ECS), is investigated. The most prevalent endocannabinoid, 2-arachidonoylglycerol (2-AG) (3 and 5mg/kg), was added exogenously and its enzymatic degradation inhibited to provide protection against MPTP-induced cell death. Furthermore, the addition of DFU (25mg/kg), a selective inhibitor of inflammatory mediator cyclooxygenase-2 (COX-2), potentiated these effects. Levels of 2-AG were shown to be upregulated in a time- and region-specific manner following MPTP administration, indicating that the ECS represents a natural defence mechanism against inflammation, potentiation of which could provide therapeutic benefits. The results expand the current understanding of the role that this signalling system has and its potential influence in PD.
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD Scotland, UK.
authors.forename: Ross B
authors.initials: RB
authors.lastname: Mounsey
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD Scotland, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Mustafa
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD Scotland, UK; Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY Scotland, UK.
authors.forename: Lianne
authors.initials: L
authors.lastname: Robinson
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario M5S 1A, Canada.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Ross
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD Scotland, UK.
authors.forename: Gernot
authors.initials: G
authors.lastname: Riedel
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD Scotland, UK.
authors.forename: Roger G
authors.initials: RG
authors.lastname: Pertwee
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD Scotland, UK. Electronic address: p.teismann@abdn.ac.uk.
authors.forename: Peter
authors.initials: P
authors.lastname: Teismann
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000627:therapeutic use*; D052117:Benzodioxoles / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005663:Furans / Q000627:therapeutic use; D020233:Gait Disorders, Neurologic / Q000188:drug therapy / Q000209:etiology; D005989:Glycerides / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009498:Neurotoxins / Q000633:toxicity*; D010300:Parkinson Disease / Q000150:complications / Q000178:diet therapy* / Q000209:etiology* / Q000473:pathology; D010880:Piperidines / Q000627:therapeutic use; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C106876:5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; D001095:Arachidonic Acids; D052117:Benzodioxoles; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005663:Furans; D005989:Glycerides; C534333:JZL 184; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010880:Piperidines; C094503:glyceryl 2-arachidonate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D051546:Cyclooxygenase 2
keywords: Endocannabinoids; MPTP; Neuroprotection; Parkinson's disease