Effects of A1 receptor agonist/antagonist on spontaneous seizures in pilocarpine-induced epileptic rats

Adenosine is an endogenous anticonvulsant that activates pre- and postsynaptic adenosine A(1) receptors. A(1) receptor agonists increase the latency for the development of seizures and status epilepticus following pilocarpine administration. Although hippocampal adenosine is increased in the chronic phase of the pilocarpine model, it is not known whether the modulation of A(1) receptors may influence the frequency of spontaneous recurrent seizures (SRS). Here, we tested the hypothesis that the A(1) receptor agonist RPia ([R]-N-phenylisopropyladenosine) and the A(1) antagonist DPCPX (8-Cyclopentyl-1,3-dipropylxanthine) administered to chronic pilocarpine epileptic rats would respectively decrease and increase the frequency of SRS and hippocampal excitability. Four months after Pilo-induced SE, chronic epileptic rats were video-monitored for the recording of SRS before (basal) and after a 2-week treatment with RPia (25 mu g/kg) or DPCPX (50 mu g/kg). Following sacrifice, brain slices were studied with electrophysiology. We found that rats given RPia had a 93% nonsignificant reduction in the frequency of seizures compared with their own pretreatment baseline. In contrast, the administration of DPCPX resulted in an 87% significant increase in seizure rate. Nontreated epileptic rats had a similar frequency of seizures along the study. Corroborating our behavioral data, in vitro recordings showed that slices from animals previously given DPCPX had a shorter latency to develop epileptiform activity, longer and higher DC shifts, and higher spike amplitude compared with slices from nontreated Pilo controls. In contrast, smaller spike amplitude was recorded in slices from animals given RPia. In summary, the administration of A(1) agonists reduced hippocampal excitability but not the frequency of spontaneous recurrent seizures in chronic epileptic rats, whereas A(1) receptor antagonists increased both. (C) 2016 Elsevier Inc. All rights reserved.FAPESPFAPEMIGCNPqFinep ((CT-SAUDE E FNS)Univ Fed Sao Paulo, Disciplina Neurofisiol, Sao Paulo, BrazilCtr Addict & Mental Hlth, Behav Neurobiol Lab, Toronto, ON, CanadaUniv Toronto, Toronto Western Hosp, Div Neurosurg, Toronto, ON, CanadaUniv Fed Sao Joao del Rei, Lab Neurociencia Expt & Computac, Sao Joao Del Rei, BrazilUniv Fed Sao Paulo, Disciplina Neurol Expt, Sao Paulo, BrazilUniv Fed Sao Paulo, Disciplina Neurofisiol, Sao Paulo, BrazilUniv Fed Sao Paulo, Disciplina Neurol Expt, Sao Paulo, BrazilFAPESP: 2011/50680-2FAPESP: 2012/50950-2FAPESP: 2012/10764-5FAPEMIG: PPM 00283/14CNPq: 310649/2011-0Finep ((CT-SAUDE E FNS): 1264/13Web of Scienc