title: The synthetic neuroactive steroid SGE-516 reduces status epilepticus and neuronal cell death in a rat model of soman intoxication.
abstract: Organophosphorus nerve agents (OPNAs) are irreversible inhibitors of acetylcholinesterase that pose a serious threat to public health because of their use as chemical weapons. Exposure to high doses of OPNAs can dramatically potentiate cholinergic synaptic activity and cause status epilepticus (SE). Current standard of care for OPNA exposure involves treatment with cholinergic antagonists, oxime cholinesterase reactivators, and benzodiazepines. However, data from pre-clinical models suggest that OPNA-induced SE rapidly becomes refractory to benzodiazepines. Neuroactive steroids (NAS), such as allopregnanolone, retain anticonvulsant activity in rodent models of benzodiazepine-resistant SE, perhaps because they modulate a broader variety of GABAAreceptor subtypes. SGE-516 is a novel, next generation NAS and a potent and selective GABAAreceptor positive allosteric modulator (PAM). The present study first established that SGE-516 reduced electrographic seizures in the rat lithium-pilocarpine model of pharmacoresistant SE. Then the anticonvulsant activity of SGE-516 was investigated in the soman-intoxication model of OPNA-induced SE. SGE-516 (5.6, 7.5, and 10mg/kg, IP) significantly reduced electrographic seizure activity compared to control when administered 20min after SE onset. When 10mg/kg SGE-516 was administered 40min after SE onset, seizure activity was still significantly reduced compared to control. In addition, all cohorts of rats treated with SGE-516 exhibited significantly reduced neuronal cell death as measured by FluoroJade B immunohistochemistry. These data suggest synthetic NASs that positively modulate both synaptic and extrasynaptic GABAAreceptors may be candidates for further study in the treatment of OPNA-induced SE.
authors.affiliation: Drug Discovery, Sage Therapeutics, Inc., Cambridge, MA, USA. Electronic address: alison.althaus@sagerx.com.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Althaus
authors.affiliation: United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD, USA.
authors.forename: Hilary S
authors.initials: HS
authors.lastname: McCarren
authors.affiliation: United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD, USA.
authors.forename: Aymen
authors.initials: A
authors.lastname: Alqazzaz
authors.affiliation: United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD, USA.
authors.forename: Cecelia
authors.initials: C
authors.lastname: Jackson
authors.affiliation: United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: McDonough
authors.affiliation: United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD, USA.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Smith
authors.affiliation: Drug Discovery, Sage Therapeutics, Inc., Cambridge, MA, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Hoffman
authors.affiliation: Drug Discovery, Sage Therapeutics, Inc., Cambridge, MA, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Hammond
authors.affiliation: Drug Discovery, Sage Therapeutics, Inc., Cambridge, MA, USA.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Robichaud
authors.affiliation: Drug Discovery, Sage Therapeutics, Inc., Cambridge, MA, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Doherty
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects*; D003292:Convulsants; D018757:GABA Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009474:Neurons / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010862:Pilocarpine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D012999:Soman; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; D018757:GABA Modulators; D018377:Neurotransmitter Agents; D010862:Pilocarpine; D012999:Soman