The Use of Adenosine Agonists to Treat Nerve Agent-Induced Seizure and Neuropathology
Technical Report,17 Sep 2012,05 Aug 2015
U.S. Army Medical Research Institute of Chemical Defense Aberdeen Proving Ground United States
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Nerve agents NAs induce a cholinergic crisis by inhibiting acetylcholinesterase AChE 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 A1adenosine receptorsA1ARs has been hypothesized to be an effective therapeutic strategy against NAs. The Netherlands Organization for Applied Scientific Research TNO was the first to test that hypothesis in 1998 and demonstrated some success. However, TNO discontinued ADO research in the early 2000s because of ADOs cardiovascular side effects. We rekindled ADO-NA research in 2012 and tested novel treatment strategies using the A1AR 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 preventedterminated seizure via pre- and post synaptic neuronal mechanisms. Data also suggested that immediate CPA treatment may have protected AChE from soman inhibition. Future research aims to better understand ADOs promising neuroprotective mechanisms and therapeutic potential.