Brief isoflurane administration as an adjunct treatment to control organophosphate-induced convulsions and neuropathology

Narayanan Puthillathu; John R Moffett; Alexandru Korotcov; Asamoah Bosomtwi; Ranjini Vengilote; Jishnu K S Krishnan; Erik A Johnson; Peethambaran Arun; Aryan M Namboodiri

doi:10.3389/fphar.2023.1293280

Brief isoflurane administration as an adjunct treatment to control organophosphate-induced convulsions and neuropathology

Front Pharmacol. 2023 Dec 5:14:1293280. doi: 10.3389/fphar.2023.1293280. eCollection 2023.

Authors

Narayanan Puthillathu¹, John R Moffett¹, Alexandru Korotcov^{2

3}, Asamoah Bosomtwi³, Ranjini Vengilote¹, Jishnu K S Krishnan¹, Erik A Johnson⁴, Peethambaran Arun¹, Aryan M Namboodiri¹

Affiliations

¹ Department of Anatomy, Physiology, and Genetics, Neuroscience Program and Molecular and Cell Biology Program, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.
² Department of Radiology and Radiological Sciences, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.
³ The Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF), Bethesda, MD, United States.
⁴ Department of Neuroscience, United States Army Medical Research Institute of Chemical Defense, Gunpowder, MD, United States.

Abstract

Organophosphate-based chemical agents (OP), including nerve agents and certain pesticides such as paraoxon, are potent acetylcholinesterase inhibitors that cause severe convulsions and seizures, leading to permanent central nervous system (CNS) damage if not treated promptly. The current treatment regimen for OP poisoning is intramuscular injection of atropine sulfate with an oxime such as pralidoxime (2-PAM) to mitigate cholinergic over-activation of the somatic musculature and autonomic nervous system. This treatment does not provide protection against CNS cholinergic overactivation and therefore convulsions require additional medication. Benzodiazepines are the currently accepted treatment for OP-induced convulsions, but the convulsions become refractory to these GABA_A agonists and repeated dosing has diminishing effectiveness. As such, adjunct anticonvulsant treatments are needed to provide improved protection against recurrent and prolonged convulsions and the associated excitotoxic CNS damage that results from them. Previously we have shown that brief, 4-min administration of 3%-5% isoflurane in 100% oxygen has profound anticonvulsant and CNS protective effects when administered 30 min after a lethal dose of paraoxon. In this report we provide an extended time course of the effectiveness of 5% isoflurane delivered for 5 min, ranging from 60 to 180 min after a lethal dose of paraoxon in rats. We observed substantial effectiveness in preventing neuronal loss as shown by Fluoro-Jade B staining when isoflurane was administered 1 h after paraoxon, with diminishing effectiveness at 90, 120 and 180 min. In vivo magnetic resonance imaging (MRI) derived T2 and mean diffusivity (MD) values showed that 5-min isoflurane administration at a concentration of 5% prevents brain edema and tissue damage when administered 1 h after a lethal dose of paraoxon. We also observed reduced astrogliosis as shown by GFAP immunohistochemistry. Studies with continuous EEG monitoring are ongoing to demonstrate effectiveness in animal models of soman poisoning.

Keywords: acetylcholinesterase; brain edema; convulsant antidote for nerve agents; magnetic resonance imaging; mean diffusivity; paraoxon.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work supported by USUHS grant # HU0001-22-2-00662.