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 #
1U01NS074926-01
Application #
8144604
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
2011-09-15
Budget End
2012-08-31
Support Year
1
Fiscal Year
2011
Total Cost
$605,545
Indirect Cost
Name
Brentwood Biomedical Research Institute
Department
Type
DUNS #
197170756
City
Los Angeles
State
CA
Country
United States
Zip Code
90073
Torolira, Daniel; Suchomelova, Lucie; Wasterlain, Claude G et al. (2017) Phenobarbital and midazolam increase neonatal seizure-associated neuronal injury. Ann Neurol 82:115-120
Niquet, Jerome; Suchomelova, Lucie; Thompson, Kerry et al. (2017) Acute and long-term effects of brivaracetam and brivaracetam-diazepam combinations in an experimental model of status epilepticus. Epilepsia 58:1199-1207
Niquet, Jerome; Baldwin, Roger; Suchomelova, Lucie et al. (2017) Treatment of experimental status epilepticus with synergistic drug combinations. Epilepsia 58:e49-e53
Niquet, Jerome; Baldwin, Roger; Norman, Keith et al. (2017) Simultaneous triple therapy for the treatment of status epilepticus. Neurobiol Dis 104:41-49
Dingledine, Raymond; Coulter, Douglas A; Fritsch, Brita et al. (2017) Transcriptional profile of hippocampal dentate granule cells in four rat epilepsy models. Sci Data 4:170061
Niquet, Jerome; Baldwin, Roger; Suchomelova, Lucie et al. (2016) Benzodiazepine-refractory status epilepticus: pathophysiology and principles of treatment. Ann N Y Acad Sci 1378:166-173
Torolira, Daniel; Suchomelova, Lucie; Wasterlain, Claude G et al. (2016) Widespread neuronal injury in a model of cholinergic status epilepticus in postnatal day 7 rat pups. Epilepsy Res 120:47-54
Niquet, Jerome; Baldwin, Roger; Norman, Keith et al. (2016) Midazolam-ketamine dual therapy stops cholinergic status epilepticus and reduces Morris water maze deficits. Epilepsia 57:1406-15
Niquet, Jerome; Gezalian, Michael; Baldwin, Roger et al. (2015) Neuroprotective effects of deep hypothermia in refractory status epilepticus. Ann Clin Transl Neurol 2:1105-15
Niquet, Jerome; Baldwin, Roger; Gezalian, Michael et al. (2015) Deep hypothermia for the treatment of refractory status epilepticus. Epilepsy Behav 49:313-7

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