In Vivo Evaluation of A1 Adenosine Agonists as Novel Anticonvulsant Medical Countermeasures to Nerve Agent Intoxication in a Rat Soman Seizure Model

Autor:	Amy J. Wegener, Tsung-Ming Shih, Thaddeus P. Thomas
Rok vydání:	2019
Předmět:	Male 0301 basic medicine medicine.medical_treatment Soman Pharmacology Toxicology Neuroprotection Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Epilepsy 0302 clinical medicine Seizures Animals Medicine Nerve agent Dose-Response Relationship Drug business.industry General Neuroscience Hypothermia medicine.disease Adenosine Adenosine A1 Receptor Agonists Rats 030104 developmental biology Anticonvulsant chemistry Medical Countermeasures CCPA Anticonvulsants medicine.symptom Nerve Agents business 030217 neurology & neurosurgery medicine.drug
Zdroj:	Neurotoxicity Research. 36:323-333
ISSN:	1476-3524 1029-8428
Popis:	Organophosphorus nerve agents (NAs) irreversibly inhibit acetylcholinesterase, which results in the accumulation of acetylcholine and widespread excitotoxic seizure activity. Because current medical countermeasures (anticholinergics, AChE reactivators, and benzodiazepines) lack sufficient anti-seizure efficacy when treatment is delayed, those intoxicated are at risk for severe brain damage or death if treatment is not immediately available. 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 × 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 mg/kg CPA, 36 mg/kg CCPA, and 62 mg/kg ENBA. Whereas vehicle-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 damage as indicated by neurohistopathological analysis. 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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b32e6c20082b90bc495ea3042e5464c3 https://doi.org/10.1007/s12640-019-00034-w Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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