title: Evaluation of monoacylglycerol lipase as a therapeutic target in a transgenic mouse model of ALS.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor neuron system with limited therapeutic options. While an increasing number of ALS patients can be linked to a small number of autosomal-dominantly inherited cases, most cases are termed sporadic. Both forms are clinically and histopathologically indistinguishable, raising the prospect that they share key pathogenic steps, including potential therapeutic intervention points. The endocannabinoid system is emerging as a versatile, druggable therapeutic target in the CNS and its dysregulation is an early hallmark of neurodegeneration. Whether this is a defense mechanism or part of the pathogenesis remains to be determined. The neuroprotective and anti-inflammatory endocannabinoid 2-arachidonoylglycerol (2-AG), which is degraded by monoacylglycerol lipase (MAGL), accumulates in the spinal cords of transgenic models of ALS. We tested the hypothesis that this 2-AG increase is a protective response in the low-copy SOD1G93Amouse model of ALS. We show that oral application of the MAGL inhibitor KML29 delays disease onset, progression and survival. Furthermore, we could demonstrate that KML29 reduced proinflammatory cytokines and increased brain-derived neurotrophic factor (BDNF) expression levels in the spinal cord, the major site of neurodegeneration in ALS. Moreover, treatment of primary mouse neurons and primary mousecroglia with 2-AG confirmed the neuroprotective and anti-inflammatory action by increasing BDNF and arginase-1 and decreasing proinflammatory cytokines in vitro. In summary, we show that elevating 2-AG levels by MAGL inhibition is a therapeutic target in ALS and demonstrate that the endocannabinoid defense mechanisms can be exploited therapeutically in neurodegenerative diseases. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology".
authors.affiliation: Department of Experimental Neurology, Ulm University, Helmholtzstraße 8/1, D-89081 Ulm, Germany; CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, D-88400 Biberach an der Riß, Germany.
authors.forename: Noemi
authors.initials: N
authors.lastname: Pasquarelli
authors.affiliation: Department of Experimental Neurology, Ulm University, Helmholtzstraße 8/1, D-89081 Ulm, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Engelskirchen
authors.affiliation: Department of Experimental Neurology, Ulm University, Helmholtzstraße 8/1, D-89081 Ulm, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Hanselmann
authors.affiliation: Department of Experimental Neurology, Ulm University, Helmholtzstraße 8/1, D-89081 Ulm, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Endres
authors.affiliation: Department of Experimental Neurology, Ulm University, Helmholtzstraße 8/1, D-89081 Ulm, Germany; CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, D-88400 Biberach an der Riß, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Porazik
authors.affiliation: Department of Experimental Neurology, Ulm University, Helmholtzstraße 8/1, D-89081 Ulm, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Bayer
authors.affiliation: Department of Experimental Neurology, Ulm University, Helmholtzstraße 8/1, D-89081 Ulm, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Buck
authors.affiliation: Institute of Pharmacology and Toxicology, Ulm University, Albert-Einstein-Allee 11, D-89081 Ulm, Germany; Neuronal and Cellular Signal Transduction, Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Martinistr. 52, D-20246 Hamburg, Germany.
authors.forename: Meliha
authors.initials: M
authors.lastname: Karsak
authors.affiliation: Department of Experimental Neurology, Ulm University, Helmholtzstraße 8/1, D-89081 Ulm, Germany; Department of Neurology, Ulm University, Oberer Eselsberg 45, D-89081 Ulm, Germany; Department of Neurodegenerative Diseases and Gerontopsychiatry/Neurology, Bonn University, Sigmund-Freud-Str. 25, D-53127 Bonn, Germany. Electronic address: patrick.weydt@ukbonn.de.
authors.forename: Patrick
authors.initials: P
authors.lastname: Weydt
authors.affiliation: CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, D-88400 Biberach an der Riß, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Ferger
authors.affiliation: Department of Experimental Neurology, Ulm University, Helmholtzstraße 8/1, D-89081 Ulm, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Witting
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001119:Arginase / Q000378:metabolism; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000494:pharmacology; D005260:Female; D005989:Glycerides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy / Q000379:methods*; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D061251:Primary Cell Culture; D013116:Spinal Cord / Q000378:metabolism*
chemical_list: C000601471:1,1,1,3,3,3-hexafluoropropan-2-yl 4-(bis(benzo(d)(1,3)dioxol-5-yl)(hydroxy)methyl)piperidine-1-carboxylate; D001095:Arachidonic Acids; D052117:Benzodioxoles; D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D063388:Endocannabinoids; D005989:Glycerides; D010880:Piperidines; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases; C544448:Arg1 protein, mouse; D001119:Arginase
keywords: 2-Arachidonoylglycerol; Amyotrophic lateral sclerosis; Brain-derived neurotrophic factor; Cannabinoid receptor 1; Endocannabinoid system; KML29; Monoacylglycerol lipase