The goal of this project is to develop safe and effective treatments against the damage to the brain caused by organophosphate (OP) induced status epilepticus (SE). Exposure to organophosphates has been identified as a major chemical threat for terrorist attacks against civilians or for exposure by an accident or natural disaster. Advances have been made to stop SE, but at present there are no therapies available to prevent the long term morbidity associated with SE. Our research laboratory has made a major advance in understanding how SE causes neuronal damage and the development of acquired epilepsy. We discovered that following OP SE there is a prolonged elevation in hippocampal neuronal calcium (Ca2+) that lasts for over a week. Furthermore, the Ca2+ plateau plays a major role in causing SE induced neuronal damage and the development of acquired epilepsy. We made a breakthrough in our preliminary research and discovered that hypothermia treatment following OP SE can prevent the Ca2+ plateau following SE. This study will develop this novel finding and test the Central Hypothesis that hypothermia applied after SE can rapidly reverse the long lasting Ca2+ plateau and thus decrease or prevent the SE induced neuronal loss and development of acquired epilepsy. This study will use the organophosphate, diisopropylfluorophosphate (DFP) to induce OP SE in rats. Our laboratory is ideally suited to conduct these studies and has developed the necessary skills to carry out the following specific aims:
Aim 1 : Determine whether hypothermia can prevent the development of the Ca2+ plateau after SE when administered after DFP SE. Hypothesis: The Ca2+ plateau from SE can be prevented or reversed by treatment after DFP SE with hypothermia.
Aim 2 : Determine whether hypothermia prevents neuronal loss and the development of AE when administered after DFP SE. Hypothesis: Hypothermia can decrease or prevent neuronal loss and AE from SE when administered after DFP SE. Hypothermia is widely used in hospitals and ambulances to treat cardiac arrest and anoxic brain injury. The preliminary results demonstrate the feasibility of these studies and underscore the potential significance of conducting this exploratory study. If these preliminary findings are documented, this study may provide the first insight for the use of hypothermia as an effective CounterACT measure to protect the brain against organophosphate toxicity.

Public Health Relevance

Status epilepticus (SE) caused by organophosphate chemical agents form terrorist attacks or accidental exposures cause significant morbidity, including brain damage and the development of epilepsy. There are currently no treatments to prevent these devastating disabilities induced by organophosphate SE. We have made the discovery that cooling the body after SE may prevent these severe disabilities. The proposed studies provide insights into preventing neuronal loss and epilepsy after organophosphate toxicity and may lead to a clinical breakthrough for preventing these major consequences following organophosphate exposure. This offers new hope for preventing some of the long disabilities that are associated with the use of these chemical agents and may go from the bench to the bed side in treating organophosphate toxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS072061-02
Application #
8337698
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (55))
Program Officer
Yeung, David
Project Start
2011-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$373,750
Indirect Cost
$123,750
Name
Virginia Commonwealth University
Department
Neurology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Deshpande, Laxmikant S; Carter, Dawn S; Phillips, Kristin F et al. (2014) Development of status epilepticus, sustained calcium elevations and neuronal injury in a rat survival model of lethal paraoxon intoxication. Neurotoxicology 44:17-26
Deshpande, Laxmikant S; Phillips, Kristin; Huang, Beverly et al. (2014) Chronic behavioral and cognitive deficits in a rat survival model of paraoxon toxicity. Neurotoxicology 44:352-7
Phillips, Kristin F; Deshpande, Laxmikant S; DeLorenzo, Robert J (2013) Hypothermia reduces calcium entry via the N-methyl-D-aspartate and ryanodine receptors in cultured hippocampal neurons. Eur J Pharmacol 698:186-92