A Viable Neuroprotection Strategy Following Soman-induced Status Epilepticus

Abstract

Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information The present study examined the neuroprotective effectiveness of dantrolene in the prevention of soman-induced SRBD. (Dantrolene is FDA approved for the treatment of malignant hyperthermia.) The decision to consider this compound is based on its well-known mode of action in preventing the release of calcium from intracellular stores. In addition, we assessed possible synergistic overlap in the neuroprotective effectiveness of combined dantrolene and diazepam co-treatment. The combined neuroprotective effectiveness of diazepam+dantrolene is compared with that of diazepam+HU-2 I1 (dexanabinol). The present results provide strong evidence that, by blocking the release of calcium from intracellular stores, dantrolene synergistically augmented the neuroprotection produced by diazepam alone. ACKNOWLEDGMENTSThe authors wish to express their sincere gratitude to Joe Jaworski, Blair Hontz, Denise Fath, Mark Walters and Roy Railer for their expert technical assistance and efforts above and beyond the call of duty. In addition, the authors wish to extend special thanks to Dr. Harpal Mangat for greatly influencing the decision to administer dantrolene by i.v. injection. The authors are also grateful to MAJ Stephen Dalal for his expert instructions in rodent i.v. injection techniques. Considering that science does not progress in a vacuum, sincere appreciation is extended to Dr. Harpal Mangat and Dr. Robert Kan for stimulating and productive intellectual exchanges regarding various aspects of this study.111,o ABSTRACT It is well known that termination of seizures using anticonvulsant drug therapy is the most effective means of preventing soman-induced seizure-related brain damage (SRBD), i.e., neuronal necrosis resulting from glutamate-induced excitotoxicity. Somaninduced seizures, however, become refractive to anticonvulsant therapy within 40 minutes after onset and development of status epilepticus. Even in cases where seizure termination is successful, excitotoxicity that has already been initiated by seizures of sufficient duration (i.e., 15 minutes or longer) will continue to develop over the ensuing several hours in accordance with well-defined pathways leading to neuronal necrosis or apoptosis. Our laboratory has previously demonstrated proof of concept that a classical neuroprotective approach (i.e., the prevention of delayed calcium overload [Randall and Thayer, 1992]) can interrupt the excitotoxic sequence initiated by seizures and block the development of soman-induced SRBD; this has been accomplished...

Treatment of cholinergic‐induced status epilepticus with polytherapy targeting GABA and glutamate receptors

“…Since delayed treatment of SE is refractory to benzodiazepine treatment, improved ASMs and neuroprotectants are needed to reduce or prevent the long‐term effects of OPNA‐induced SE. Preclinical studies in our laboratory and others, reviewed in details in Sections 2‐4 of this article, show benefit of early polytherapy with ketamine in combination with a benzodiazepine (diazepam or midazolam) in reducing cholinergic‐induced seizure, functional impairment, and neurodegeneration 21–24,53–57 . In contrast, early treatment with a nonsedating dose (15 mg/kg, IP) of ketamine was not effective at terminating seizure in rats when administered early 5 minutes after soman‐induced seizure; this was without a benzodiazepine 15 .…”

“…Preclinical studies in our laboratory and others, reviewed in details in Sections 2-4 of this article, show benefit of early polytherapy with ketamine in combination with a benzodiazepine (diazepam or midazolam) in reducing cholinergic-induced seizure, functional impairment, and neurodegeneration. [21][22][23][24][53][54][55][56][57] In contrast, early treatment with a nonsedating dose (15 mg/ kg, IP) of ketamine was not effective at terminating seizure in rats when administered early 5 minutes after somaninduced seizure; this was without a benzodiazepine. 15 A higher acute dose or repeated lower doses of ketamine administered to guinea pigs in combination with atropine sulfate protected against the soman-induced lethality and neuropathology.…”

Efficacy of 2-APB (2-Aminoethyldiphenylborate) in Rescuing Neurons After Soman-Induced Brain Injury

“…Additional evidence indicates that a sizable portion of the intracellular free calcium that contributes to neuronal pathogenesis comes from intracellular stores (i.e., the endoplasmic reticulum, ER) (Randal and Thayer, 1992;Mody and MacDonald, 1995;Yoon et al, 1996;Wei and Perry, 1996;Neibauer and Gruenthal, 1999;Pelletier et al, 1999;Yu et al, 1999;Nakayama et al, 2002;Verkhratsky and Toescu, 2003). The ryanodine receptor antagonist dantrolene has been shown to diminish soman-induced SRBD by blocking calcium release from the ER (Ballough and Filbert, 2003).…”