Stimulation of central A1 adenosine receptors suppresses seizure and neuropathology in a soman nerve agent seizure rat model

Abstract

The current regimen for treating nerve agent poisoning does not sufficiently suppress the excitotoxic activity that causes severe brain damage, especially in cases where treatment is delayed and nerve agent-induced status epilepticus develops. New therapeutic targets are required to improve survivability and minimize neuropathology after irreversible acetylcholinesterase inactivation. Earlier studies have shown that systemic delivery of adenosine agonists decreases nerve agent lethality; however, the mechanism of protection remains to be understood. The primary aim of this study was to investigate the role of central adenosine receptor (AR) stimulation in neuroprotection by directly injecting (6)-cyclopentyladenosine (CPA), an adenosine agonist specific to the A1 receptor subtype (A1R), into the brain intracerebroventricularly (ICV) in a soman seizure rat model. In addition to general A1R stimulation, we hypothesized that bilateral micro-injection of CPA into the cholinergic basal forebrain (BF) could also suppress excitotoxic activity. The results from these studies demonstrated that centrally administered adenosine agonists are anti-seizure and neuroprotective. CPA-delivered ICV prevented seizure and convulsion in 100% of the animals. Moreover, neuropathological evaluation indicated that adenosine treatments reduced brain damage from severe to minimal. Inhibition of the BF via CPA had varied results. Some animals were protected by treatment; however, others displayed similar pathology to the control. Overall, these data suggest that stimulating central ARs could be an effective target for the next generation countermeasures for nerve agent intoxication.