No abstract

SUMMARYPurpose: Status epilepticus (SE) remains a potentially devastating condition that quickly becomes refractory to antiepileptic drug treatment and arises as a result of a failure of the brain's endogenous antiepileptic mechanisms. Understanding these mechanisms and how they are disrupted in SE is necessary in order to identify novel therapeutic approaches. Adenosine is considered an endogenous anticonvulsant. Extracellular concentrations increase coinciding with seizure termination; activation of A 1 receptors (A 1 Rs) reduces seizure-induced damage and epileptiform activity. The present study examines the effectiveness of focal drug delivery in a model of limbic SE that closely resembles the human condition and describes, for the first time, alterations in A 1 R signaling during prolonged seizures that may contribute to the progression from self-terminating seizures to self-sustaining SE (SSSE). Methods: We developed a rat perforant path stimulation model in which 50% of rats develop SSSE and tested whether modulation of A 1 Rs influenced SSSE development when drugs were infused to the dentate gyrus. We further determined the ability of A 1 Rs to modulate perforant path to granule cell transmission in hippocampal slices taken from sham-operated control and post-SE animals. Key Findings: Adenosine (3 lM) and the A 1 R-selective agonist 2-chloro-N 6 -cyclopentyladenosine (CCPA; 10 lM) reduced the severity of SSSE as measured by spike count, electroencephalography power and behavioral seizure score. In addition, CCPA suppressed the progression to SSSE. Surprisingly, the A 1 R-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 1 lM) had no effect on the severity of or progression to SSSE, suggesting a lack of intrinsic A 1 R activation. Immunohistochemistry revealed no alterations in total A 1 R expression. However, we observed a marked down-regulation of A 1 R modulation of neurotransmission in vitro, indicating acute A 1 R desensitization. Significance: These findings indicate that A 1 R activation can prevent the progression to SE and suggest that reduced A 1 R signaling promotes the transition of seizures to SSSE.