Screening for Efficacious Anticonvulsants and Neuroprotectants in Delayed Treatment Models of Organophosphate-induced Status Epilepticus.

Autor: Barker BS; Medical Toxicology Research Division, Neuroscience Department, U.S. Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Rd, Aberdeen Proving Ground, MD 21010, USA. Electronic address: bryan.s.barker2.ctr@mail.mil., Spampanato J; Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT 84108, USA., McCarren HS; Medical Toxicology Research Division, Neuroscience Department, U.S. Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Rd, Aberdeen Proving Ground, MD 21010, USA., Smolik M; Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT 84108, USA., Jackson CE; Medical Toxicology Research Division, Neuroscience Department, U.S. Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Rd, Aberdeen Proving Ground, MD 21010, USA., Hornung EN; Medical Toxicology Research Division, Neuroscience Department, U.S. Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Rd, Aberdeen Proving Ground, MD 21010, USA., Yeung DT; Chemical Countermeasures Research Program, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892, USA., Dudek FE; Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT 84108, USA., McDonough JH; Medical Toxicology Research Division, Neuroscience Department, U.S. Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Rd, Aberdeen Proving Ground, MD 21010, USA.
Jazyk: angličtina
Zdroj: Neuroscience [Neuroscience] 2020 Jan 15; Vol. 425, pp. 280-300. Date of Electronic Publication: 2019 Nov 26.
DOI: 10.1016/j.neuroscience.2019.11.020
Abstrakt: 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-JadeB (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.
(Copyright © 2019 IBRO. All rights reserved.)
Databáze: MEDLINE
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