Type

Other / n/a

Authors

David C Henshall
Tobias Engel
Anindya Bhattacharya
Donncha F O'Brien
Michael A Farrell
Norman Delanty
Ronán M Conroy
M Teresa Miras-Portugal
Michael Letavic
Mariana Alves
and 6 others

Subjects

Psychiatry

Topics
purinergic receptor microglia status epilepticus hippocampal sclerosis physics inflammatory cytokine anticonvulsant physiology

Transient P2X7 Receptor Antagonism Produces Lasting Reductions in Spontaneous Seizures and Gliosis in Experimental Temporal Lobe Epilepsy. (2016)

Abstract Neuroinflammation is thought to contribute to the pathogenesis and maintenance of temporal lobe epilepsy, but the underlying cell and molecular mechanisms are not fully understood. The P2X7 receptor is an ionotropic receptor predominantly expressed on the surface of microglia, although neuronal expression has also been reported. The receptor is activated by the release of ATP from intracellular sources that occurs during neurodegeneration, leading to microglial activation and inflammasome-mediated interleukin 1β release that contributes to neuroinflammation. Using a reporter mouse in which green fluorescent protein is induced in response to the transcription of P2rx7, we show that expression of the receptor is selectively increased in CA1 pyramidal and dentate granule neurons, as well as in microglia in mice that developed epilepsy after intra-amygdala kainic acid-induced status epilepticus. P2X7 receptor levels were increased in hippocampal subfields in the mice and in resected hippocampus from patients with pharmacoresistant temporal lobe epilepsy. Cells transcribing P2rx7 in hippocampal slices from epileptic mice displayed enhanced agonist-evoked P2X7 receptor currents, and synaptosomes from these animals showed increased P2X7 receptor levels and altered calcium responses. A 5 d treatment of epileptic mice with systemic injections of the centrally available, potent, and specific P2X7 receptor antagonist JNJ-47965567 (30 mg/kg) significantly reduced spontaneous seizures during continuous video-EEG monitoring that persisted beyond the time of drug presence in the brain. Hippocampal sections from JNJ-47965567-treated animals obtained >5 d after treatment ceased displayed strongly reduced microgliosis and astrogliosis. The present study suggests that targeting the P2X7 receptor has anticonvulsant and possibly disease-modifying effects in experimental epilepsy.SIGNIFICANCE STATEMENT: Temporal lobe epilepsy is the most common and drug-resistant form of epilepsy in adults. Neuroinflammation is implicated as a pathomechanism, but the upstream mechanisms driving gliosis and how important this is for seizures remain unclear. In our study, we show that the ATP-gated P2X7 receptor is upregulated in experimental epilepsy and resected hippocampus from epilepsy patients. Targeting the receptor with a new centrally available antagonist, JNJ-47965567, suppressed epileptic seizures well beyond the time of treatment and reduced underlying gliosis in the hippocampus. The findings suggest a potential disease-modifying treatment for epilepsy based on targeting the P2X7 receptor.
Collections Ireland -> Royal College of Surgeons in Ireland -> Physiology and Medical Physics Articles
Ireland -> Royal College of Surgeons in Ireland -> Department of Physiology and Medical Physics

Full list of authors on original publication

David C Henshall, Tobias Engel, Anindya Bhattacharya, Donncha F O'Brien, Michael A Farrell, Norman Delanty, Ronán M Conroy, M Teresa Miras-Portugal, Michael Letavic, Mariana Alves and 6 others

Experts in our system

1
David C Henshall
Royal College of Surgeons in Ireland
Total Publications: 127
 
2
Tobias Engel
Royal College of Surgeons in Ireland
Total Publications: 66
 
3
Anindya Bhattacharya
Royal College of Surgeons in Ireland
Total Publications: 4
 
4
Donncha F O'Brien
Royal College of Surgeons in Ireland
Total Publications: 19
 
5
Michael A Farrell
Royal College of Surgeons in Ireland
Total Publications: 43
 
6
Norman Delanty
Royal College of Surgeons in Ireland
Total Publications: 49
 
7
Ronán Conroy
Royal College of Surgeons in Ireland
Total Publications: 150
 
8
M Teresa Miras-Portugal
Royal College of Surgeons in Ireland
Total Publications: 12
 
9
Mariana Alves
Royal College of Surgeons in Ireland
Total Publications: 9