Seizure suppression and neuroprotection in soman-exposed rats following delayed intramuscular treatment of adenosine A 1 receptor agonist as an adjunct to standard medical treatment.

Publisher: Academic Press Country of Publication: United States NLM ID: 0416575 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-0333 (Electronic) Linking ISSN: 0041008X NLM ISO Abbreviation: Toxicol Appl Pharmacol Subsets: MEDLINE

Publication: New York, NY : Academic Press
Original Publication: New York.

Soman*/toxicity ; Adenosine A1 Receptor Agonists*/pharmacology ; Rats, Sprague-Dawley* ; Seizures*/chemically induced ; Seizures*/drug therapy ; Seizures*/prevention & control; Animals ; Male ; Rats ; Injections, Intramuscular ; Neuroprotective Agents/pharmacology ; Neuroprotective Agents/administration & dosage ; Neuroprotective Agents/therapeutic use ; Anticonvulsants/administration & dosage ; Electroencephalography/drug effects ; Adenosine/analogs & derivatives ; Adenosine/administration & dosage ; Adenosine/pharmacology ; Atropine/pharmacology ; Atropine/administration & dosage ; Status Epilepticus/chemically induced ; Status Epilepticus/drug therapy ; Midazolam/pharmacology ; Midazolam/therapeutic use

Soman produces excitotoxic effects by inhibiting acetylcholinesterase in the cholinergic synapses and neuromuscular junctions, resulting in soman-induced sustained status epilepticus (SSE). Our previous work showed delayed intramuscular (i.m.) treatment with A 1 adenosine receptor agonist N-bicyclo-[2.2.1]-hept-2-yl-5'-chloro-5'-deoxyadenosine (ENBA) alone suppressed soman-induced SSE and prevented neuropathology. Using this same rat soman seizure model, we tested if delayed therapy with ENBA (60 mg/kg, i.m.) would terminate seizure, protect neuropathology, and aid in survival when given in conjunction with current standard medical countermeasures (MCMs): atropine sulfate, 2-PAM, and midazolam (MDZ). Either 15- or 30-min following soman-induced SSE onset, male rats received atropine and 2-PAM plus either MDZ or MDZ + ENBA. Electroencephalographic (EEG) activity, physiologic parameters, and motor function were recorded. Either 2- or 14-days following exposure surviving rats were euthanized and perfused for histology. All animals treated with MDZ + ENBA at both time points had 100% EEG seizure termination and reduced total neuropathology compared to animals treated with MDZ (2-day, p = 0.015 for 15-min, p = 0.002 for 30-min; 14-day, p < 0.001 for 15-min, p = 0.006 for 30-min), showing ENBA enhanced MDZ's anticonvulsant and neuroprotectant efficacy. However, combined MDZ + ENBA treatment, when compared to MDZ treatment groups, had a reduction in the 14-day survival rate regardless of treatment time, indicating possible enhancement of MDZ's neuronal inhibitory effects by ENBA. Based on our findings, ENBA shows promise as an anticonvulsant and neuroprotectant in a combined treatment regimen following soman exposure; when given as an adjunct to standard MCMs, the dose of ENBA needs to be adjusted.
Competing Interests: Declaration of competing interest The authors have no conflicts of interest or competing financial interests to declare that are relevant to the content of this article. None of the authors has during the last five years appeared in any legal or regulatory proceedings related to the contents of the paper. The authors alone are responsible for the content and writing of the paper.
(Copyright © 2024. Published by Elsevier Inc.)

Keywords: A(1) adenosine receptor agonist; Anticonvulsant; Delayed therapy; Neuroprotection; Organophosphorus compound; Soman

96-64-0 (Soman)
0 (Adenosine A1 Receptor Agonists)
0 (Neuroprotective Agents)
0 (Anticonvulsants)
K72T3FS567 (Adenosine)
7C0697DR9I (Atropine)
R60L0SM5BC (Midazolam)

Date Created: 20240522 Date Completed: 20240616 Latest Revision: 20240701

20240701

10.1016/j.taap.2024.116970

38777098