In Vivo Evaluation of A1 Adenosine Agonists as Novel Anticonvulsant Medical Countermeasures to Nerve Agent Intoxication in a Rat Soman Seizure Model
Technical Report,01 Oct 2017,31 Mar 2018
US Army Medical Research Institute of Chemical Defense Aberdeen Proving Ground United States
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Organophosphorus nerve agents NAs irreversibly inhibit acetylcholinesterase, which results in the accumulation of acetylcholine and widespread excitotoxic seizure activity. Because current medical countermeasures lack sufficient anti-seizure efficacy, those intoxicated are at risk for severe brain damage or death. Toward developing a more effective anti-seizure treatment for NA intoxication, this study evaluated the efficacy of A1 adenosine ADO receptor A1AR agonists in a rat soman seizure model. One minute after exposure to soman 1.6 x LD50, subcutaneous, rats were treated intraperitoneally with one of the following agonists at increasing dose levels until anti-seizure efficacy was achieved N6-cyclopentaladenosine CPA, 2-Chloro-N6-cyclopentyladenosine CCPA, and -5-Chloro-5-deoxy-ENBA ENBA. All A1AR agonists were efficacious in preventing seizure and promoting survival. The effective doses for the A1AR agonists were 60 mgkg CPA, 36 mgkg CCPA, and 62 mgkg ENBA. Whereas vehicle-treated rats experienced 100 seizure and 21 survival N28, ADO treatments reduced seizure occurrence and improved survival rates 8 seizure and 83 survival with CPA 60 mgkg, N12, 17 seizure and 75 survival with CCPA 36 mgkg, N12, and 8 seizure, 83 survival with ENBA 62 mgkg, N12. The brains of ADO-treated rats were also protected from neuropathology. While all ADO agonists provided neuroprotection, rats receiving CCPA and ENBA experienced less severe ADO-induced side effects e.g., sedation, hypothermia, bradycardia than with CPA. The data from this study suggest that the ADO signaling pathway is a promising mechanism for countering seizure activity induced by NAs.
- Chemical, Biological and Radiological Warfare