Pharmacological Evaluation of Candidate Adenosine Agonists as Novel Anticonvulsant Medical Countermeasures to Soman Nerve Agent Intoxication
Abstract
Toward developing a more effective anti-seizure treatment for nerve agent (NA) intoxication, this study evaluated the efficacy of A1adenosine (ADO) receptor (A1AR) agonists in a rat soman (GD) seizure model. One minute after exposure to GD (1.6 x LD50, SC) or control vehicle, 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 60mg/kg CPA, 36 mg/kg CCPA, and 62 mg/kg ENBA. Whereas saline-treated rats experienced 100% seizure and 21% survival (N=28),ADO treatments reduced seizure occurrence and improved survival rates: 8 seizure and 83 survival with CPA (60 mg/kg, N=12), 17% seizure and 75% survival with CCPA (36 mg/kg, N=12), and 8 seizure, 83 survival with ENBA (62 mg/kg, N=12). 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 NA seizure.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 31, 2017
- Accession Number
- AD1056473
Entities
People
- Amy Wegener
- Thaddeus S. Thomas
- Tsung-Ming Shih
Organizations
- United States Army Medical Research Institute of Chemical Defense