The overall goal of this project is to develop a novel, broad-spectrum neurosteroid therapy that will mitigate the morbidity and mortality caused by acute exposure to nerve agents and organophosphate (OP) pesticides, which are credible threat agents for military and civilian populations. Exposure to nerve agents or OP poisoning can result in persistent seizures, status epilepticus (SE), and permanent brain injury. Current anticonvulsant countermeasures (benzodiazepines) for nerve intoxication do not sufficiently protect the brain from SE, a prolonged seizure activity lasting 30 min or longer with significant neuronal injury and mortality. We propose that neurosteroids and selective drugs that enhance phasic and extrasynaptic tonic inhibition produce more effective protection against persistent SE than benzodiazepines, prevent irreversible brain injury, and extend the therapeutic window. This novel therapeutic strategy is based on the emerging molecular mechanisms of neurosteroids and also cellular changes involved in SE, a common neurotoxicity by nerve agents. Neurosteroids are the most powerful anticonvulsants against seizures induced by cholinergic agents. Since OP nerve agents cause persistent seizures and brain damage through cholinergic hyperactivation, it is proposed that neurosteroids are more effective anticonvulsants for OP nerve intoxication than benzodiazepines. We have pilot evidence that late post-exposure neurosteroid therapy can rapidly control SE and be neuroprotective after SE in pilocarpine and DFP models, suggesting the promising efficacy of neurosteroid therapy. The objective of this project is to investigate the efficacy and safety of the synthetic neurosteroid ganaxolone and its analogs as 'broad-spectrum'medical countermeasures for nerve agent and OP pesticide intoxication. This is a logical extension of our R21s for further efficacy validation, lead optimization, and IND application. The primary emphasis is to generate requisite data on the efficacy and safety of the lead candidate and submit an IND application within a 5 year period. To develop neurosteroids as superior countermeasures than diazepam, we will address three specific aims:
(Aim 1) : Determine the efficacy of ganaxolone against DFP- and soman-induced SE and brain damage;
(Aim 2) : Develop ganaxolone analogs with improved formulation pharmacokinetics and efficacy against DFP- and soman-induced SE and brain damage;
and (Aim 3) : Determine the preclinical safety and toxicity of ganaxolone or its lead analog and submit an IND for clinical development under the FDA Animal Rule Pathway. The project will be implemented as per the progressive """"""""go/no-go"""""""" milestones plan, which includes quantitative criteria for the success of key studies focusing on three primary outcome measures: (i) anticonvulsant efficacy;(ii) neuroprotectant efficacy;and (iii) prevention of neurodegeneration. The outcome from this project will identify an effective antidote for OP intoxication and enhance readiness for emergencies.

Public Health Relevance

Nerve agents and organophosphate pesticides are high priority chemical threat agents. Current medical countermeasures for acute nerve agent intoxication do not sufficiently protect the brain from seizures and status epilepticus. This projet is designed to develop synthetic neurosteroids as broad-spectrum countermeasures for nerve agent intoxication, persistent seizures, and brain damage via direct administration during emergency.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS083460-02
Application #
8723912
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Yeung, David
Project Start
2013-09-01
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Texas A&M University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
College Station
State
TX
Country
United States
Zip Code
77845
Chuang, Shu-Hui; Reddy, Doodipala Samba (2018) Genetic and Molecular Regulation of Extrasynaptic GABA-A Receptors in the Brain: Therapeutic Insights for Epilepsy. J Pharmacol Exp Ther 364:180-197
Wu, Xin; Kuruba, Ramkumar; Reddy, Doodipala Samba (2018) Midazolam-Resistant Seizures and Brain Injury after Acute Intoxication of Diisopropylfluorophosphate, an Organophosphate Pesticide and Surrogate for Nerve Agents. J Pharmacol Exp Ther 367:302-321
Reddy, Doodipala Samba (2018) GABA-A Receptors Mediate Tonic Inhibition and Neurosteroid Sensitivity in the Brain. Vitam Horm 107:177-191
Kuruba, Ramkumar; Wu, Xin; Reddy, Doodipala Samba (2018) Benzodiazepine-refractory status epilepticus, neuroinflammation, and interneuron neurodegeneration after acute organophosphate intoxication. Biochim Biophys Acta Mol Basis Dis 1864:2845-2858
Chuang, Shu-Hui; Reddy, Doodipala Samba (2018) 3?-Methyl-Neurosteroid Analogs Are Preferential Positive Allosteric Modulators and Direct Activators of Extrasynaptic ?-Subunit ?-Aminobutyric Acid Type A Receptors in the Hippocampus Dentate Gyrus Subfield. J Pharmacol Exp Ther 365:583-601
Reddy, Doodipala Samba; Chuang, Shu-Hui; Hunn, Dayton et al. (2018) Neuroendocrine aspects of improving sleep in epilepsy. Epilepsy Res 147:32-41
Clossen, Bryan L; Reddy, Doodipala Samba (2017) Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy. Biochim Biophys Acta Mol Basis Dis 1863:1519-1538
Reddy, D S; Colman, E (2017) A Comparative Toxidrome Analysis of Human Organophosphate and Nerve Agent Poisonings Using Social Media. Clin Transl Sci 10:225-230
Clossen, Bryan L; Reddy, Doodipala Samba (2017) Catamenial-like seizure exacerbation in mice with targeted ablation of extrasynaptic ?GABA-a receptors in the brain. J Neurosci Res 95:1906-1916
Samba Reddy, Doodipala (2017) Sex differences in the anticonvulsant activity of neurosteroids. J Neurosci Res 95:661-670

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