Acute down-regulation of adenosine A1 receptor activity in status epilepticus

• Published in: Epilepsia (Copenhagen) Vol. 53; no. 1; pp. 177 - 188
• Main Authors: Hamil, Nicola E., Cock, Hannah R., Walker, Matthew C.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-01-2012; Wiley Subscription Services, Inc
• Subjects: A1 receptor; Adenosine; Adenosine A1 receptors; Anticonvulsants; Antiepileptic agents; Brain slice preparation; Dentate gyrus; Drug delivery; Drug development; EEG; Epilepsy; Granule cells; Immunohistochemistry; Neuromodulation; Neurotransmission; Perforant path stimulation; Perforant paths; Seizures; Status epilepticus
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/j.1528-1167.2011.03340.x

Summary
Purpose:  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 A1 receptors (A1Rs) 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 A1R 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 A1Rs influenced SSSE development when drugs were infused to the dentate gyrus. We further determined the ability of A1Rs to modulate perforant path to granule cell transmission in hippocampal slices taken from sham‐operated control and post‐SE animals.
Key Findings:  Adenosine (3 μm) and the A1R‐selective agonist 2‐chloro‐N6‐cyclopentyladenosine (CCPA; 10 μm) 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 A1R‐selective antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX; 1 μm) had no effect on the severity of or progression to SSSE, suggesting a lack of intrinsic A1R activation. Immunohistochemistry revealed no alterations in total A1R expression. However, we observed a marked down‐regulation of A1R modulation of neurotransmission in vitro, indicating acute A1R desensitization.
Significance:  These findings indicate that A1R activation can prevent the progression to SE and suggest that reduced A1R signaling promotes the transition of seizures to SSSE.