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

• Published in: Neurotoxicology (Park Forest South) Vol. 68; pp. 167 - 176
• Main Authors: Meerhoff, Gideon F., Vester, Stefanie M., Hesseling, Peter, Klaassen, Steven D., Cornelissen, Alex S., Lucassen, Paul J., Joosen, Marloes J.A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-09-2018; Elsevier BV
• Subjects: Amygdala; Animals; Anticholinergics; Anticonvulsants; Anticonvulsants - administration & dosage; Antidotes; Astrocytes - drug effects; Atropine; Atropine - administration & dosage; Benzodiazepines; Brain - drug effects; Brain - physiopathology; Chemical compounds; Cholinesterase Reactivators - administration & dosage; Cholinesterases - metabolism; Convulsions & seizures; Cortex (entorhinal); Cortex (piriform); Diazepam; Diazepam - administration & dosage; EEG; Effectiveness; Exposure; Gliosis; Glycoproteins; Hazardous materials; HI-6; Male; Microglia; Microglia - drug effects; Nerve agents; Neurons - drug effects; Neuroprotection; Neuroprotective Agents - administration & dosage; Optimization; Organophosphates; Oxime; Oximes; Oximes - administration & dosage; P-Glycoprotein; Potentiation; Pyridinium Compounds - administration & dosage; Quinolines - administration & dosage; Rats; Rats, Wistar; Reagents; Seizing; Seizures; Seizures - chemically induced; Seizures - prevention & control; Soman; Soman - toxicity; Substrates; Sulfates; Tariquidar; Tariquidar; p-Glycoprotein; Atropine; Oxime; Soman; Diazepam; Seizures
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2018.08.005

•Addition of tariquidar to HI-6 and atropine mitigated soman induced seizures.•In combination with diazepam, tariquidar further enhanced efficacy.•A combination of delayed tariquidar and diazepam was also effective.•Lower duration of seizures was associated with less soman-induced neuropathology.•Tariquidar-enhanced brain atropine levels likely decisive for enhanced efficacy.
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.