Project 2: Mitigation Of Neurological Damage Following Seizures

In the case of accidental or terrorist release of organophosphate (OP) anticholinesterase inhibitors or the GABAA antagonist TETS, it is likely medical support will be unavailable for the first 30 to 60 minutes after people start exhibiting seizures. This means the processes that promote brain damage will have already been set in motion. The objective of project 2 is to identify therapies for treating the delayed neurological effects of intoxication with these chemical threat agents. Another goal is to develop non-invasive in vivo imaging strategies to longitudinally monitor the progression of neurological damage and the effectiveness of treatment.

To date, we have interacted with Project 1 to develop a mouse model of TETS-induced status epilepticus (SE) and we have refine a rat model of DFP-induced SE for use in neuroprotection studies. Using these preclinical models, Projects 1 and 2 showed that allopregnanolone, a positive allosteric modulator of GABAA receptors, was a superior countermeasure for TETS-induced SE in mice, particularly when administered at delayed times. We are currently examining allopregnanolone in combination with midazolam for efficacy in terminating seizures and/or protecting against persistent neuropathology in the rat DFP model. We are also screening candidate neuroprotectants that significantly reduce neuropathology when administered at delayed time post-DFP exposure.

 

Related Publications

Guignet M, Dhakal K, Flannery BM, Hobson BA, Zolkowska D, Dhir A, Bruun DA, Li S, Harvey DJ, Silverman JL, Rogawski MA, Lein PJ
(under review) Arch Toxicol (submitted Jan 31, 2017)
Hobson BA, Siso S, Rowland DJ, Harvey DJ, Bruun DA, Garbow JR, Lein PJ
(under review) Toxicol Sci (submitted Dec 19, 2016)
Siso S, Hobson BA, Harvey DJ, Bruun DA, Lein PJ
(under review) Toxicol Sci (submitted Dec 19, 2016)
Chapman CAR, Chen H, Zhu X, Yankik AA, Lein PJ, Seker E
(under review) Sci Rep (revision submitted Nov 27, 2016)