title: Inhibition of monoacylglycerol lipase mediates a cannabinoid 1-receptor dependent delay of kindling progression in mice.
abstract: Endocannabinoids, including 2-arachidonoylglycerol (2-AG), activate presynaptic cannabinoid type 1 receptors (CB1R) on inhibitory and excitatory neurons, resulting in a decreased release of neurotransmitters. The event-specific activation of the endocannabinoid system by inhibition of the endocannabinoid degrading enzymes may offer a promising strategy to selectively activate CB1Rs at the site of excessive neuronal activation with the overall goal to prevent the development epilepsy. The aim of this study was to investigate the impact of monoacylglycerol lipase (MAGL) inhibition on the development and progression of epileptic seizures in the kindling model of temporal lobe epilepsy. Therefore, we selectively blocked MAGL by JZL184 (8mg/kg, i.p.) in mice to analyze the effects of increased 2-AG levels on kindling acquisition and to exclude an anticonvulsive potential. Our results showed that JZL184 treatment significantly delayed the development of generalized seizures (p=0.0066) and decreased seizure (p<0.0001) and afterdischarge duration (p<0.001) in the kindling model of temporal lobe epilepsy, but caused only modest effects in fully kindled mice. Moreover, we proved that JZL184 treatment had no effects in conditional CB1R knockout mice lacking expression of the receptor in principle neurons of the forebrain. In conclusion, the data demonstrate that indirect CB1R agonism delays the development of generalized epileptic seizures but has no relevant acute anticonvulsive effects. Furthermore, we confirmed that the effects of JZL184 on kindling progression are CB1R mediated. Thus, the data indicate that the endocannabinoid 2-AG might be a promising target for an anti-epileptogenic approach.
authors: Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians-University, Munich, Germany; Graduate School of Systemic Neurosciences, Munich, Germany.
authors: E L
authors: EL
authors: von Rüden
authors: Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians-University, Munich, Germany; Graduate School of Systemic Neurosciences, Munich, Germany.
authors: R M
authors: RM
authors: Bogdanovic
authors: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors: C T
authors: CT
authors: Wotjak
authors: Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians-University, Munich, Germany. Electronic address: potschka@pharmtox.vetmed.uni-muenchen.de.
authors: H
authors: H
authors: Potschka
mesh_terms: D000679:Amygdala / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D052117:Benzodioxoles / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004827:Epilepsy / Q000209:etiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007696:Kindling, Neurologic / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008994:Monoacylglycerol Lipases / Q000378:metabolism*; D010880:Piperidines / Q000627:therapeutic use*; D011930:Reaction Time / Q000187:drug effects; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D052117:Benzodioxoles; D004791:Enzyme Inhibitors; C534333:JZL 184; D010880:Piperidines; D043884:Receptor, Cannabinoid, CB1; D049452:Green Fluorescent Proteins; D008994:Monoacylglycerol Lipases
keywords: Anandamide; Endocannabinoid system; Epileptogenesis; FAAH; Fatty acid amide hydrolase