sar127303 and Disease-Models--Animal

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.. 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.. 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.. 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.

Topics: Animals; Brain; Brain Waves; Carbamates; Cognition Disorders; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistant Epilepsy; Electroencephalography; Excitatory Amino Acid Agonists; Fluoresceins; Kainic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Monoacylglycerol Lipases; Neurons; Piperidines; Random Allocation; Receptor, Cannabinoid, CB1; Recognition, Psychology; Status Epilepticus; Sulfonamides; Time Factors

Monoacylglycerol lipase (MAGL) represents a primary degradation enzyme of the endogenous cannabinoid (eCB), 2-arachidonoyglycerol (2-AG). This study reports a potent covalent MAGL inhibitor, SAR127303. The compound behaves as a selective and competitive inhibitor of mouse and human MAGL, which potently elevates hippocampal levels of 2-AG in mice. In vivo, SAR127303 produces antinociceptive effects in assays of inflammatory and visceral pain. In addition, the drug alters learning performance in several assays related to episodic, working and spatial memory. Moreover, long term potentiation (LTP) of CA1 synaptic transmission and acetylcholine release in the hippocampus, two hallmarks of memory function, are both decreased by SAR127303. Although inactive in acute seizure tests, repeated administration of SAR127303 delays the acquisition and decreases kindled seizures in mice, indicating that the drug slows down epileptogenesis, a finding deserving further investigation to evaluate the potential of MAGL inhibitors as antiepileptics. However, the observation that 2-AG hydrolysis blockade alters learning and memory performance, suggests that such drugs may have limited value as therapeutic agents.

Topics: Acetylcholine; Administration, Oral; Analgesics; Animals; Arachidonic Acids; Binding Sites; Brain; Cannabinoid Receptor Antagonists; Carbamates; Chromatography, High Pressure Liquid; Crystallography, X-Ray; Disease Models, Animal; Electric Stimulation; Endocannabinoids; Enzyme Inhibitors; Glycerides; Hippocampus; Humans; Hydrolysis; In Vitro Techniques; Learning; Long-Term Potentiation; Mass Spectrometry; Memory, Short-Term; Mice; Mice, Inbred C57BL; Mice, SCID; Monoacylglycerol Lipases; Pain; Piperidines; Protein Structure, Tertiary; Pyrazoles; Rimonabant; Seizures; Sulfonamides