The Use of Adenosine Agonists to Treat Nerve-Agent Induced Seizure and Neuropathology
Abstract
Organophosphorus nerve agents, such as soman, induce a cholinergic crisis by inhibiting the enzyme acetylcholinesterase throughout the nervous system. While current medical countermeasures effectively mitigate peripheral effects, the brain is vulnerable to severe damage as sustained seizure activity is refractory to treatment. Because adenosine (ADO) has profound inhibitory effects in the brain, stimulation of A1 adenosine receptors has been hypothesized to be an effective therapeutic strategy against nerve agents. The Netherlands Organization for Applied Scientific Research (TNO) was the first to test that hypothesis in 1998 and demonstrated some success. However, TNO discontinued adenosine research in the early 2000s because of adenosines cardiovascular side effects. We rekindled adenosine-nerve agent research in 2012 and tested novel treatment strategies using the A1 adenosine receptor agonist N6-cyclopentyladenosine (CPA). We demonstrated that CPA injected into the brain or periphery at high doses was highly neuroprotective against soman. Results strongly indicated that CPA prevented/terminated seizure via pre- and post-synaptic neuronal mechanisms. Data also suggested that immediate CPA treatment may have protected acetylcholinesterase from soman inhibition. Additionally, the hypothermia that develops after ADO treatment may also enhance neuroprotection and survivability after exposure to nerve agents. Further research is needed to better understand adenosines promising neuroprotective mechanisms and therapeutic potential as novel medical countermeasure for nerve agent intoxication. Here is a review of current research in progress.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 10, 2019
- Accession Number
- AD1100269
Entities
People
- Thaddeus P. Thomas
- Tsung-Ming Shih
Organizations
- United States Army Medical Research Institute of Chemical Defense