The P2X7 Receptor as a Mechanistic Biomarker for Epilepsy

Abstract

Epilepsy, characterized by recurrent spontaneous seizures, is a heterogeneous group of brain diseases affecting over 70 million people worldwide. Major challenges in the management of epilepsy include its diagnosis and treatment. To date, video electroencephalogram (EEG) monitoring is the gold-standard diagnostic method, with no molecular biomarker in routine clinical use. Moreover, treatment based on anti-seizure medications (ASMs) remains ineffective in 30% of patients, and, even if seizure-suppressive, lacks disease-modifying potential. Current epilepsy research is, therefore, mainly focussed on the identification of new drugs with a different mechanism of action effective in patients not responding to current ASMs. The vast heterogeneity of epilepsy syndromes, including differences in underlying pathology, comorbidities and disease progression, represents, however, a particular challenge in drug discovery. Optimal treatment most likely requires the identification of new drug targets combined with diagnostic methods to identify patients in need of a specific treatment. Purinergic signalling via extracellularly released ATP is increasingly recognized to contribute to brain hyperexcitability and, consequently, drugs targeting this signalling system have been proposed as a new therapeutic strategy for epilepsy. Among the purinergic ATP receptors, the P2X7 receptor (P2X7R) has attracted particular attention as a novel target for epilepsy treatment, with P2X7Rs contributing to unresponsiveness to ASMs and drugs targeting the P2X7R modulating acute seizure severity and suppressing seizures during epilepsy. In addition, P2X7R expression has been reported to be altered in the brain and circulation in experimental models of epilepsy and patients, making it both a potential therapeutic and diagnostic target. The present review provides an update on the newest findings regarding P2X7R-based treatments for epilepsy and discusses the potential of P2X7R as a mechanistic biomarker.

Age-Dependent Activation of Pannexin1 Function Contributes to the Development of Epileptogenesis in Autosomal Dominant Sleep-related Hypermotor Epilepsy Model Rats

“…Adenosine metabolized from released ATP in the extracellular space activates both anticonvulsive A1 and proconvulsive A2A receptors [76][77][78]. Therefore, purinergic transmission functions are a double-edged sword in terms of the epileptogenesis/ictogenesis regulation of the excitatory/inhibitory balance of tripartite synaptic transmission [6,7,79,80]. To explore the functional abnormalities of purinergic transmission in S286L-TG, age-dependent extracellular levels of ATP and adenosine in the ADSHE focus region of S286L-TG should be determined using microdialysis.…”

“…Recently, functional abnormalities in tripartite synaptic transmission or astroglial excitatory transmission have been considered to play important roles in the development of epileptogenesis and/or ictogenesis [1][2][3][4][5][6][7][8]. Functional abnormalities of astroglial hemichannels containing connexin43 [9][10][11][12][13] have been demonstrated in a validated genetic rat model of autosomal dominant sleep-related hypermotor epilepsy (ADSHE), named "S286L-TG"; it bears the missense S286L-mutant rat Chrna4, which corresponds to the S284L-mutant human CHRNA4 of patients with ADSHE [8,14].…”

Beneficial effects of gentiopicrin inhibiting experimental epilepsy in young rats through the P2X7R/NLRP3/Caspase-1 inflammatory pathway.

“…The P2X7R (purinergic ligand-gated ion channel 7 receptor), an ATP-gated cation non-selective channel receptor, is a crucial contributor to the formation and release of IL-1β and has been widely considered an essential target in brain tissue inflammatory responses 5 . P2X7R is upregulated at different stages of seizure In various models of epilepsy, including the hippocampus, amygdala, piriform cortex, and neocortex, and its activation can induce and worsen inflammatory reactions 6 . Multiple studies 7,8 have demonstrated that in innate myeloid cells such as monocytes, macrophages, and dendritic cells, the P2X7R is the most effective activator of the NLRP3 inflammasome during the inflammatory process.…”

The Purinergic P2X7 Receptor as a Target for Adjunctive Treatment for Drug-Refractory Epilepsy

“…Research over recent decades has provided compelling proof that purinergic signalling via the adenosine 5'-triphosphate (ATP)-gated cationic P2X7 receptor (P2X7R) is implicated not only in the generation of seizures (ictogenesis), but also epilepsy [8,22]. While several reviews published over recent years have provided a detailed summary of the data demonstrating a role for P2X7Rs during seizures and epilepsy (e.g., [8,[22][23][24][25][26][27][28]), we here will focus on how drugs targeting the P2X7R may be used in a clinically relevant setting.…”