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Models to identify treatments for the acute and persistent effects of seizure‐inducing chemical threat agents
Author(s) -
Pessah Isaac N.,
Rogawski Michael A.,
Tancredi Daniel J.,
Wulff Heike,
Zolkowska Dorota,
Bruun Donald A.,
Hammock Bruce D.,
Lein Pamela J.
Publication year - 2016
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/nyas.13137
Subject(s) - translational research , neuroprotection , epilepsy , neuroscience , medicine , broad spectrum , drug discovery , pharmacology , in vivo , psychology , bioinformatics , biology , chemistry , pathology , combinatorial chemistry , microbiology and biotechnology
Exposures to seizure‐inducing chemical threat agents are a major public health concern. Of particular need is improved treatment to terminate convulsions and to prevent the long‐term neurological sequelae in survivors. We are studying the organophosphorus cholinesterase inhibitor diisopropyl fluorophosphate (DFP) and the GABA receptor inhibitor tetramethylenedisulfotetramine (TETS), which arguably encompass the mechanistic spectrum of seizure‐inducing chemical threats, with the goal of identifying therapeutic approaches with broad‐spectrum efficacy. Research efforts have focused on developing translational models and translational diagnostic approaches, including (1) in vivo models of DFP‐ and TETS‐induced seizures for studying neuropathological mechanisms and identifying treatment approaches; (2) in vivo imaging modalities for noninvasive longitudinal monitoring of neurological damage and response to therapeutic candidates; and (3) higher‐throughput in vitro platforms for rapid screening of compounds to identify potential antiseizure and neuroprotective agents, as well as mechanistically relevant novel drug targets. This review summarizes our progress toward realizing these goals and discusses best practices and mechanistic insights derived from our modeling efforts.