Potentiation of antiseizure and neuroprotective efficacy of standard nerve agent treatment by addition of tariquidar.

Abstract

Organophosphate (OP) induced seizures are commonly treated with anticholinergics, oximes and anticonvulsants. Inhibition of P-glycoprotein (PgP) has been shown to enhance the efficacy of nerve agent treatment in soman exposed rats. In the present study, the promising effects of the PgP inhibitor tariquidar were investigated in more detail in rats s.c. exposed to 150 μg/kg soman. Treatment with HI-6 and atropine sulfate (125 and 3 mg/kg i.m respectively) was administered 1 min after exposure. Diazepam (0.5 mg/kg i.m.) and/or tariquidar (7.5 mg/kg i.v.) were included either at 1 min or 40 min following onset of seizures. Animals that received tariquidar, in addition to HI-6 and atropine, at 1 min, displayed a rapid normalization of EEG activity and cessation of seizure-associated behaviour. This improvement by addition of tariquidar was even more substantial in animals that also received diazepam, either immediately or delayed. Animals exhibiting lower intensity seizures displayed less severe neuropathology (neuronal loss, microglia activation and astrogliosis), primarily in the piriform cortex, and to a lesser extent amygdala and entorhinal cortex. The present findings suggest that the interaction of tariquidar with atropine may be the decisive factor for enhanced treatment efficacy, given that atropine was previously found to be a PgP substrate. A more thorough understanding of the interactions of nerve agent antidotes, in particular the actions of central anticholinergics with benzodiazepines, could contribute to a future optimization of treatment combinations, particularly those aimed at later stage medical interventions.

• Authors: Gideon F Meerhoff, Stefanie M Vester, Peter Hesseling, Steven D Klaassen, Alex S Cornelissen, Paul J Lucassen, Marloes J A Joosen
• Journal: Neurotoxicology (Neurotoxicology) Vol. 68 Pg. 167-176 (09 2018) ISSN: 1872-9711 [Electronic] Netherlands
• PMID: 30130561 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Anticonvulsants
• Cholinesterase Reactivators
• Neuroprotective Agents
• Oximes
• Pyridinium Compounds
• Quinolines
• Atropine
• Soman
• Cholinesterases
• asoxime chloride
• tariquidar
• Diazepam

Topics

• Animals
• Anticonvulsants (administration & dosage)
• Astrocytes (drug effects)
• Atropine (administration & dosage)
• Brain (drug effects, physiopathology)
• Cholinesterase Reactivators (administration & dosage)
• Cholinesterases (metabolism)
• Diazepam (administration & dosage)
• Male
• Microglia (drug effects)
• Neurons (drug effects)
• Neuroprotective Agents (administration & dosage)
• Oximes (administration & dosage)
• Pyridinium Compounds (administration & dosage)
• Quinolines (administration & dosage)
• Rats, Wistar
• Seizures (chemically induced, prevention & control)
• Soman (toxicity)