P2X receptors as targets for the treatment of status epilepticus

Abstract

Prolonged seizures are amongst the most common neurological emergencies. Status epilepticus is a state of continuous seizures that is life-threatening and prompt termination of status epilepticus is critical to protect the brain from permanent damage. Frontline treatment comprises parenteral administration of anticonvulsants such as lorazepam that facilitate γ-amino butyric acid (GABA) transmission. Because status epilepticus can become refractory to anticonvulsants in a significant proportion of patients, drugs which act on different neurotransmitter systems may represent potential adjunctive treatments. P2X receptors are a class of ligand-gated ion channel activated by ATP that contributes to neuro- and glio-transmission. P2X receptors are expressed by both neurons and glia in various brain regions, including the hippocampus. Electrophysiology, pharmacology and genetic studies suggest certain P2X receptors are activated during pathologic brain activity. Expression of several members of the family including P2X2, P2X4, and P2X7 receptors has been reported to be altered in the hippocampus following status epilepticus. Recent studies have shown that ligands of the P2X7 receptor can have potent effects on seizure severity during status epilepticus and mice lacking this receptor display altered seizures in response to chemoconvulsants. Antagonists of the P2X7 receptor also modulate neuronal death, microglial responses and neuroinflammatory signaling. Recent work also found altered neuronal injury and inflammation after status epilepticus in mice lacking the P2X4 receptor. In summary, members of the P2X receptor family may serve important roles in the pathophysiology of status epilepticus and represent novel targets for seizure control and neuroprotection.

Keywords: ATP; anticonvulsant; epilepsy; hippocampus; interleukin-1β; microglia; neuroprotection.

Figure 1

Potential sites of action of ATP released during status epilepticus, expressional responses of individual P2X receptors, and consequences of receptor activation. Cartoon depicts the various different cell types reported to express P2X receptors and their presumed cellular locations. ATP is released during sustained neuronal activity and from damaged neurons to act pre- and post-synaptically on neurons, particularly targeting pre-synaptic receptors to modulate neurotransmitter release. ATP may also act on receptors of microglia to promote activation and release of interleukin-1β, and act on astrocytes and oligodendrocytes to trigger cell death. Drugs such as A-438079 and BBG have been reported to reduce seizures and gliosis after status epilepticus. SE, status epilepticus; IL-1β, interleukin-1β.