title: Pharmacological blockade of the calcium plateau provides neuroprotection following organophosphate paraoxon induced status epilepticus in rats.
abstract: Organophosphate (OP) compounds which include nerve agents and pesticides are considered chemical threat agents. Currently approved antidotes are crucial in limiting OP mediated acute mortality. However, survivors of lethal OP exposure exhibit delayed neuronal injury and chronic behavioral morbidities. In this study, we investigated neuroprotective capabilities of dantrolene and carisbamate in a rat survival model of paraoxon (POX) induced status epilepticus (SE). Significant elevations in hippocampal calcium levels were observed 48-h post POX SE survival, and treatment with dantrolene (10mg/kg, i.m.) and carisbamate (90mg/kg, i.m.) lowered these protracted calcium elevations. POX SE induced delayed neuronal injury as characterized by Fluoro Jade C labeling was observed in critical brain areas including the dentate gyrus, parietal cortex, amygdala, and thalamus. Dantrolene and carisbamate treatment provided significant neuroprotection against delayed neuronal damage in these brain regions when administered one-hour after POX-SE. These results indicate that dantrolene or carisbamate could be effective adjuvant therapies to the existing countermeasures to reduce neuronal injury and behavioral morbidities post OP SE survival.
authors.affiliation: Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Laxmikant S
authors.initials: LS
authors.lastname: Deshpande
authors.affiliation: Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Blair
authors.affiliation: Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Huang
authors.affiliation: Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Kristin F
authors.initials: KF
authors.lastname: Phillips
authors.affiliation: Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: Robert.DeLorenzo@vcuhealth.org.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: DeLorenzo
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000473:pathology; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D002219:Carbamates / Q000008:administration & dosage*; D003620:Dantrolene / Q000008:administration & dosage*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010261:Paraoxon / Q000633:toxicity*; D010296:Parietal Lobe / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced* / Q000517:prevention & control*; D013788:Thalamus / Q000187:drug effects / Q000473:pathology
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; D018696:Neuroprotective Agents; C518914:S-2-O-carbamoyl-1-o-chlorophenyl-ethanol; D003620:Dantrolene; D010261:Paraoxon; D002118:Calcium
keywords: Calcium; Carisbamate; Cell death; Dantrolene; Paraoxon; Status epilepticus