Inhibition of monoacylglycerol lipase terminates diazepam-resistant status epilepticus in mice and its effects are potentiated by a ketogenic diet
| Autor: | Christopher Ryan Butler, Justin R. Piro, Alberto Pauletti, Mark J Sheehan, Tarek A. Samad, Massimo Rizzi, Annamaria Vezzani, Gaetano Terrone, Luca Porcu, Bianca R. Villa, Alessia Salamone, Edward Guilmette |
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| Přispěvatelé: | Terrone, Gaetano, Pauletti, Alberto, Salamone, Alessia, Rizzi, Massimo, Villa, Bianca R., Porcu, Luca, Sheehan, Mark J., Guilmette, Edward, Butler, Christopher R., Piro, Justin R., Samad, Tarek A., Vezzani, Annamaria |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Drug Resistant Epilepsy Time Factors Cannabinoid receptor medicine.medical_treatment 2-Arachidonoylglycerol Pharmacology cognitive deficit neuroinflammation Mice Random Allocation chemistry.chemical_compound Epilepsy Status Epilepticus 0302 clinical medicine monoacylglycerol lipase Piperidines Receptor Cannabinoid CB1 Cannabinoid receptor type 1 Excitatory Amino Acid Agonists Mice Knockout Neurons Sulfonamides Kainic Acid Brain Electroencephalography Fluoresceins Endocannabinoid system 2-arachidonoylglycerol Neurology ketogenic diet medicine.symptom Status epilepticus 03 medical and health sciences medicine arachidonic acid Animals Diazepam Dose-Response Relationship Drug business.industry Recognition Psychology endocannabinoid medicine.disease Brain Waves Monoacylglycerol Lipases Mice Inbred C57BL Monoacylglycerol lipase Disease Models Animal 030104 developmental biology chemistry Carbamates Neurology (clinical) Cognition Disorders business 030217 neurology & neurosurgery Ketogenic diet de novo refractory status epilepticu |
| Popis: | SummaryObjective Status epilepticus (SE) is a life-threatening and commonly drug-refractory condition. Novel therapies are needed to rapidly terminate seizures to prevent mortality and morbidity. Monoacylglycerol lipase (MAGL) is the key enzyme responsible for the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) and a major contributor to the brain pool of arachidonic acid (AA). Inhibiting of monoacylglycerol lipase modulates synaptic activity and neuroinflammation, 2 mediators of excessive neuronal activation underlying seizures. We studied the effect of a potent and selective irreversible MAGL inhibitor, CPD-4645, on SE that was refractory to diazepam, its neuropathologic sequelae, and the mechanism underlying the drug's effects. Methods Diazepam-resistant SE was induced in adult mice fed with standard or ketogenic diet or in cannabinoid receptor type 1 (CB1) receptor knock-out mice. CPD-4645 (10 mg/kg, subcutaneously) or vehicle was dosed 1 and 7 h after status epilepticus onset in video–electroencephalography (EEG) recorded mice. At the end of SE, mice were examined in the novel object recognition test followed by neuronal cellloss analysis. Results CPD-4645 maximal plasma and brain concentrations were attained 0.5 h postinjection (half-life = 3.7 h) and elevated brain 2-AG levels by approximately 4-fold. CPD-4645 administered to standard diet–fed mice progressively reduced spike frequency during 3 h postinjection, thereby shortening SE duration by 47%. The drug immediately abrogated SE in ketogenic diet–fed mice. CPD-4645 rescued neuronal cell loss and cognitive deficit and reduced interleukin (IL)-1β and cyclooxygenase 2 (COX-2) brain expression resulting from SE. The CPD-4645 effect on SE was similar in mice lacking CB1 receptors. Significance MAGL represents a novel therapeutic target for treating status epilepticus and improving its sequelae. CPD-4645 therapeutic effects appear to be predominantly mediated by modulation of neuroinflammation. |
| Databáze: | OpenAIRE |
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