The seizures generated by organophosphates quickly become self-sustaining, independent of their original cholinergic trigger, and refractory to standard treatment (benzodiazepines), and represent an unresolved problem and potentially a very serious military and terrorist threat. This proposal is based on the hypothesis that in the treatment of cholinergic seizures, polypharmacy is superior to monotherapy. Based on our observations that these seizures cause internalization and loss of synaptic GABAA receptors, and increases in synaptic NMDA receptors, we proposed to study triple therapy for those seizures. This would combine 1/ a GABAA receptor agonist, which would partially restore inhibition by stimulating the residual synaptic GABAA receptors;2/ an NMDA antagonist which would reduce excitation by blocking some NMDA receptors;and 3/ an anticonvulsant which would increase inhibition at non-GABA sites. We propose to explore combinations of the following drugs: 1/ Midazolam, a GABAA receptor agonist which is easily delivered intra-muscularly. 2/ a NMDA receptor antagonist which could be non-specific (dizocilpine or ketamine) or NR2B subunit-preferring (R025-6981 or felbamate), and 3/ an anticonvulsant acting at a non-GABA site such as rapidly inactivating sodium channels (valproate);or slowly inactivating sodium channels (lacosamide);or potassium channels (ezogabine);or presynaptic vesicles (levetiracetam). Our preliminary results suggest that such three-drug combinations can, with little depression of consciousness, stop seizures induced by high-dose lithium and pilocarpine and refractory to a profoundly anesthetic dose of benzodiazepine, the best 2- and 3-drug combinations in a lithium-pilocarpine model will be studied in a model of soman-induced seizures. At the end of this project, we will have identified an effective three-drug combination which can stop benzodiazepine-refractory cholinergic seizures at the cost of little or no behavioral toxicity, and is ready to be tested in subhuman primates and then included in our therapeutic kits.

Public Health Relevance

Because of the ease with which they are synthesized, concealed and of their potential for mass casualties, nerve agents are among the most serious terrorist and military threats to day. Seizures are the most treatment-refractory complication of nerve agent intoxication. Finding a treatment for those seizures is clearly an important national goal. We are proposing to do this using new combinations of FDA-approved drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS074926-03
Application #
8526584
Study Section
Special Emphasis Panel (ZRG1-MDCN-J (50))
Program Officer
Jett, David A
Project Start
2011-09-15
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$623,462
Indirect Cost
$64,182
Name
Brentwood Biomedical Research Institute
Department
Type
DUNS #
197170756
City
Los Angeles
State
CA
Country
United States
Zip Code
90073
Wasterlain, Claude G; Naylor, David E; Liu, Hantao et al. (2013) Trafficking of NMDA receptors during status epilepticus: therapeutic implications. Epilepsia 54 Suppl 6:78-80