Project 3: Novel Mechanisms for Seizure Mitigation and Neuroprotection

The disruption of electrical and Ca2+ signaling events is known to contribute to the induction and severity of seizures as well as promote brain damage. One of the main objectives of this project is to develop in vitro / ex vivo models, or models of isolated tissue, by using high-content, rapid throughput technology to detect these disruptions. Using rapid throughput technology allows for many samples to be processed at once, increasing efficiency. The second goal is to apply these methods to investigate new and existing therapeutic strategies for mitigating the induction, progression and severity of seizures induced by TETS and DFP-intoxication. This project will screen leading therapies already in existence and, along with Cores A and B, discover new therapeutic targets that delay or mitigate seizure activity and neurological damage produced by the chemical threat agents.

Further validation and optimization of the therapeutic strategies, including timing of administration, dosages and drug combinations will be assessed in projects 1 (Prevention and Termination of Seizures) and 2 (Mitigation of Neurological Damage). The rapid throughput methods proposed in project 3 will enable more efficient development of therapeutic strategies by Cores A and B. Understanding the molecular and cellular mechanisms by which TETS and DFP disrupt electrical and Ca2+ events will help researchers comprehend how the threat agents promote seizures and cause neurological damage, providing insight into new drug targets. 

Related Publications

Atefeh Mousavi Nik, Brandon Pressly, Vikrant Singh, Shane Antrobus, Susan Hulsizer, Michael A. Rogawski, Heike Wulff and Isaac N. Pessah
Molecular Pharmacology April 20, 2017, mol.117.108563; DOI: https://doi.org/10.1124/mol.117.108563
Coleman N1, Nguyen HM, Cao Z, Brown BM, Jenkins DP, Zolkowska D, Chen YJ, Tanaka BS, Goldin AL, Rogawski MA, Pessah IN, Wulff H
Neurotherapeutics. 2014 Sep 26. [Epub ahead of print]
PubMed PMID: 
Cao Z, Hammock BD, McCoy M, Rogawski MA, Lein PJ, Pessah IN
Toxicol Sci. 2012 Dec;130(2):362-72.
PubMed PMID: 
PubMed PMCID: 
Cao Z, Cui Y, Nguyen HM, Jenkins DP, Wulff H, Pessah IN.
Mol Pharmacol. 2014 Apr;85(4):630-9.
PubMed PMID: 
PubMed PMCID: