Screening for Efficacious Anticonvulsants and Neuroprotectants in Delayed Treatment Models of Organophosphate-induced Status Epilepticus. (15th January 2020)

• Record Type: Journal Article
• Authors: Barker, Bryan S.; Spampanato, Jay; McCarren, Hilary S.; Smolik, Melissa; Jackson, Cecelia E.; Hornung, Eden N.; Yeung, David T.; Dudek, F. Edward; McDonough, John H.
• Is Part Of: Neuroscience. Volume 425(2020)
• Page Start: 280
• Page End: 300
• Publication Date: 2020-01-15
• Subjects: Ach Acetylcholine -- AchE Acetylcholinesterase -- AMN Atropine methyl nitrate -- CNS (Program)- CounterACT Neurotherapeutic Screening -- dCA1 Dorsal CA1 -- dCA3 Dorsal CA3 -- DFP Diisopropylfluorophosphate -- EEG Electroencephalogram -- FJB Fluoro-Jade B -- GD Soman -- HPBCD 2-hydroxypropyl-β-cyclodextrin -- IM Intramuscular -- IP Intraperitoneal -- IV Intravenous -- MDZ Midazolam -- OP Organophosphorus -- OPCW Organization for the Prohibition of Chemical Weapons -- PEG Polyethylene glycol -- PTZ Pentylenetetrazol -- ROI Region of interest -- SE Status epilepticus -- TETS Tetramethylenedisulfotetramine -- vCA1 Ventral CA1 -- vCA3 Ventral CA3 -- WHO World Health Organization; organophosphorus -- nerve agent -- diisopropylfluorophosphate -- status epilepticus -- anticonvulsant -- neuroprotectant; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2019.11.020
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: The CNS program screens for novel adjunct therapies in two delayed treatment models of OP-induced status epilepticus. Neurosteroids appear to be the most promising anticonvulsant therapy for OP-induced status epilepticus. Significant neuroprotection against OP-induced status epilepticus seems to require some degree of anticonvulsant efficacy. Abstract: Organophosphorus (OP) compounds are deadly chemicals that exert their intoxicating effects through the irreversible inhibition of acetylcholinesterase (AChE). In addition to an excess of peripheral ailments, OP intoxication induces status epilepticus (SE) which if left untreated may lead to permanent brain damage or death. Benzodiazepines are typically the primary therapies for OP-induced SE, but these drugs lose efficacy as treatment time is delayed. The CounterACT Neurotherapeutic Screening (CNS) Program was therefore established by the National Institutes of Health (NIH) to discover novel treatments that may be administered adjunctively with the currently approved medical countermeasures for OP-induced SE in a delayed treatment scenario. The CNS program utilizes in vivo EEG recordings and Fluoro-Jade B (FJB) histopathology in two established rat models of OP-induced SE, soman (GD) and diisopropylfluorophosphate (DFP), to evaluate the anticonvulsant and neuroprotectant efficacy of novel adjunct therapies when administered at 20 or 60 min after the induction of OP-induced SE. Here we report the results of multiple compounds that have previously shown anticonvulsant or neuroprotectant efficacy in other models of epilepsy or trauma. Drugs tested were ganaxolone, diazoxide, bumetanide, propylparaben, citicoline, MDL-28170, and chloroquine. EEG analysis revealed that ganaxolone demonstrated the most robust anticonvulsant activity, whereas all other drugs failed to attenuate ictal activity in both models of OP-induced SE. FJB staining demonstrated that none of the tested drugs had widespread neuroprotective abilities. Overall these data suggest that neurosteroids may represent the most promising anticonvulsant option for OP-induced SE out of the seven unique mechanisms tested here. Additionally, these results suggest that drugs that provide significant neuroprotection from OP-induced SE without some degree of anticonvulsant activity are elusive, which further highlights the necessity to continue screening novel adjunct treatments through the CNS program.