Beyond Seizure Control: Treating Comorbidities in Epilepsy via Targeting of the P2X7 Receptor

Abstract

Epilepsy is one of the most common chronic diseases of the central nervous system (CNS). Treatment of epilepsy remains, however, a clinical challenge with over 30% of patients not responding to current pharmacological interventions. Complicating management of treatment, epilepsy comes with multiple comorbidities, thereby further reducing the quality of life of patients. Increasing evidence suggests purinergic signalling via extracellularly released ATP as shared pathological mechanisms across numerous brain diseases. Once released, ATP activates specific purinergic receptors, including the ionotropic P2X7 receptor (P2X7R). Among brain diseases, the P2X7R has attracted particular attention as a therapeutic target. The P2X7R is an important driver of inflammation, and its activation requires high levels of extracellular ATP to be reached under pathological conditions. Suggesting the therapeutic potential of drugs targeting the P2X7R for epilepsy, P2X7R expression increases following status epilepticus and during epilepsy, and P2X7R antagonism modulates seizure severity and epilepsy development. P2X7R antagonism has, however, also been shown to be effective in treating conditions most commonly associated with epilepsy such as psychiatric disorders and cognitive deficits, which suggests that P2X7R antagonisms may provide benefits beyond seizure control. This review summarizes the evidence suggesting drugs targeting the P2X7R as a novel treatment strategy for epilepsy with a particular focus of its potential impact on epilepsy-associated comorbidities.

Longitudinal Positron Emission Tomography Imaging with P2X7 Receptor-Specific Radioligand 18F-FTTM in a Kainic Acid Rat Model of Temporal Lobe Epilepsy

“…7 Emerging evidence supports the role of P2X7R in psychiatric disorders such as depression, anxiety, and schizophrenia that stems from both human data and research conducted on animal disease models. 24 Clinical studies on P2X7R antagonists (NCT04116606) in psychiatric disorders are also underway. Patients with epilepsy (approximately 25−50%), especially with drug-resistant epilepsy, have psychiatric comorbidities due to seizures or drug side-effects.…”

“…P2X7R as a gatekeeper of inflammation is most clearly understood; however, it also plays a number of other important roles pertinent to ictogenesis and epileptogenesis: depolarization of the cell membrane, the release of macromolecules, and the induction of apoptosis and synaptic reorganization . Emerging evidence supports the role of P2X7R in psychiatric disorders such as depression, anxiety, and schizophrenia that stems from both human data and research conducted on animal disease models . Clinical studies on P2X7R antagonists (NCT04116606) in psychiatric disorders are also underway.…”

Characterization of the Novel P2X7 Receptor Radioligand [3H]JNJ-64413739 in Human Brain Tissue

“…The P2X7R expression has been shown to be increased in several brain regions including the neocortex in animal models of prolonged seizure activity including status epilepticus, such as systemic kainic acid and intra-amygdala injections of kainic acid, ,, or systemic pilocarpine. , Extracellular ATP is increased after seizures and P2X7R antagonists have been reported to produce antiepileptic effects, ,, which further has attracted interest for P2X7R being a tentative drug target for epilepsy. ,− …”

“…Under normal physiological conditions, extracellular ATP concentrations are below the threshold required for P2X7R activation, but under some pathological conditions, ATP levels can reach sufficiently high levels to activate the receptor . Accordingly, mounting evidence point to the important role of P2X7R in multiple diseases in the CNS, particularly those involving neuronal cell death and regeneration. − …”

Hypoxia‐inducible factor 1 alpha (HIF‐1α) stimulated and P2X7 receptor activated by COVID-19, as a potential therapeutic target and risk factor for epilepsy

“…ADP receptors are subtypes of P2Y receptors. Adenosine can activate P1 (G protein-coupled) receptors [ 35 ] …”