title: P2X purinoceptors as a link between hyperexcitability and neuroinflammation in status epilepticus.
abstract: There remains a need for more efficacious treatments for status epilepticus. Prolonged seizures result in the release of ATP from cells which activates the P2 class of ionotropic and metabotropic purinoceptors. The P2X receptors gate depolarizing sodium and calcium entry and are expressed by both neurons and glia throughout the brain, and a number of subtypes are upregulated after status epilepticus. Recent studies have explored the in vivo effects of targeting ATP-gated P2X receptors in preclinical models of status epilepticus, with particular focus on the P2X7 receptor (P2X7R). The P2X7R mediates microglial activation and the release of the proepileptogenic inflammatory cytokine interleukin 1β. The receptor may also directly modulate neurotransmission and gliotransmission and promote the recruitment of immune cells into brain parenchyma. Data from our group and collaborators show that status epilepticus produced by intraamygdala microinjection of kainic acid increases P2X7R expression in the hippocampus and neocortex of mice. Antagonism of the P2X7R in the model reduced seizure severity, microglial activation and interleukin 1β release, and neuronal injury. Coadministration of a P2X7R antagonist with a benzodiazepine also provided seizure suppression in a model of drug-refractory status epilepticus when either treatment alone was minimally effective. More recently, we showed that status epilepticus in immature rats is also reduced by P2X7R antagonism. Together, these findings suggest that P2X receptors may be novel targets for seizure control and interruption of neuroinflammation after status epilepticus. This article is part of a Special Issue entitled "Status Epilepticus".
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Ireland. Electronic address: dhenshall@rcsi.ie.
authors.forename: David C
authors.initials: DC
authors.lastname: Henshall
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Ireland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Engel
mesh_terms: D000818:Animals; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D058469:Receptors, Purinergic P2X / Q000378:metabolism*; D013226:Status Epilepticus / Q000188:drug therapy / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D058920:Purinergic P2X Receptor Antagonists; D058469:Receptors, Purinergic P2X
keywords: Adenosine; Epileptogenesis; Hippocampal sclerosis; Purinoceptor; Super-refractory status epilepticus