{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:37:25Z","timestamp":1788910645679,"version":"build-2803163510"},"reference-count":41,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2017,11,24]],"date-time":"2017-11-24T00:00:00Z","timestamp":1511481600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:title>Summary<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Status epilepticus (SE) is a life\u2010threatening and commonly drug\u2010refractory 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\u2010arachidonoylglycerol (2\u2010AG) 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\u20104645, on SE that was refractory to diazepam, its neuropathologic sequelae, and the mechanism underlying the drug's effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Diazepam\u2010resistant SE was induced in adult mice fed with standard or ketogenic diet or in cannabinoid receptor type 1 (CB1) receptor knock\u2010out mice. CPD\u20104645 (10\u00a0mg\/kg, subcutaneously) or vehicle was dosed 1 and 7\u00a0h after status epilepticus onset in video\u2013electroencephalography (EEG) recorded mice. At the end of SE, mice were examined in the novel object recognition test followed by neuronal cellloss analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>CPD\u20104645 maximal plasma and brain concentrations were attained 0.5\u00a0h postinjection (half\u2010life\u00a0=\u00a03.7\u00a0h) and elevated brain 2\u2010AG levels by approximately 4\u2010fold. CPD\u20104645 administered to standard diet\u2013fed mice progressively reduced spike frequency during 3\u00a0h postinjection, thereby shortening SE duration by 47%. The drug immediately abrogated SE in ketogenic diet\u2013fed mice. CPD\u20104645 rescued neuronal cell loss and cognitive deficit and reduced interleukin (IL)\u20101\u03b2 and cyclooxygenase 2 (COX\u20102) brain expression resulting from SE. The CPD\u20104645 effect on SE was similar in mice lacking CB1 receptors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>MAGL represents a novel therapeutic target for treating status epilepticus and improving its sequelae. CPD\u20104645 therapeutic effects appear to be predominantly mediated by modulation of neuroinflammation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.13950","type":"journal-article","created":{"date-parts":[[2017,11,24]],"date-time":"2017-11-24T00:02:49Z","timestamp":1511481769000},"page":"79-91","source":"Crossref","is-referenced-by-count":54,"title":["Inhibition of monoacylglycerol lipase terminates diazepam\u2010resistant status epilepticus in mice and its effects are potentiated by a ketogenic diet"],"prefix":"10.1111","volume":"59","author":[{"given":"Gaetano","family":"Terrone","sequence":"first","affiliation":[{"name":"Department of Neuroscience IRCCS\u2010Mario Negri Institute for Pharmacological Research Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Pauletti","sequence":"additional","affiliation":[{"name":"Department of Neuroscience IRCCS\u2010Mario Negri Institute for Pharmacological Research Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Salamone","sequence":"additional","affiliation":[{"name":"Department of Neuroscience IRCCS\u2010Mario Negri Institute for Pharmacological Research Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Rizzi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience IRCCS\u2010Mario Negri Institute for Pharmacological Research Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca R.","family":"Villa","sequence":"additional","affiliation":[{"name":"Department of Neuroscience IRCCS\u2010Mario Negri Institute for Pharmacological Research Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Porcu","sequence":"additional","affiliation":[{"name":"Department of Oncology IRCCS\u2010Mario Negri Institute for Pharmacological Research Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J.","family":"Sheehan","sequence":"additional","affiliation":[{"name":"Internal Medicine Research Unit Pfizer Worldwide Research and Development Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Guilmette","sequence":"additional","affiliation":[{"name":"Internal Medicine Research Unit Pfizer Worldwide Research and Development Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher R.","family":"Butler","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Pfizer Worldwide Research &amp; Development Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin R.","family":"Piro","sequence":"additional","affiliation":[{"name":"Internal Medicine Research Unit Pfizer Worldwide Research and Development Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarek A.","family":"Samad","sequence":"additional","affiliation":[{"name":"Internal Medicine Research Unit Pfizer Worldwide Research and Development Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Vezzani","sequence":"additional","affiliation":[{"name":"Department of Neuroscience IRCCS\u2010Mario Negri Institute for Pharmacological Research Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,11,24]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0000000000000307"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.5698\/1535-7597-16.1.48"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(10)70214-3"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.62.9.1428"},{"key":"e_1_2_8_6_1","first-page":"S37","article-title":"Outcome of status epilepticus. 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