Partial adenosine A(1) receptor agonists inhibit sarin-induced epileptiform activity in the hippocampal slice

Organophosphate poisoning can result in seizures and subsequent neuropathology. One possible therapeutic approach would be to employ adenosine A(1) receptor agonists, which have already been shown to have protective effects against organophosphate poisoning. Using an in vitro model of organophosphate-induced seizures, we have investigated the ability of several adenosine A(1) receptor agonists to inhibit epileptiform activity induced by the organophosphate sarin, in the CA1 stratum pyramidale of the guinea pig hippocampal slice. Application of the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA) or the partial adenosine A(1) receptor agonists 2-deoxy-N(6)-cyclopentyladenosine (2-deoxy-CPA) and 8-butylamino-N(6)-cyclopentyladenosine (8-butylamino-CPA) abolished epileptiform activity in a concentration-related manner. The rank order of potency was CPA (IC(50) 4-5 nM) >2-deoxy-CPA (IC(50) 113-119 nM)=8-butylamino-CPA (IC(50) 90-115 nM). These data suggest that partial adenosine A(1) receptor agonists, which have fewer cardiovascular effects, should be further evaluated in vivo as potential treatments for organophosphate poisoning.