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.
Highlights
Mounting evidence demonstrates that purinergic signalling via extracellularly released adenosine triphosphate (ATP) plays an important role during several shared pathological conditions among brain diseases and, constitutes a possible common pathological mechanism underlying primary diseases of the brain and their associated comorbidities [20,21]
Comorbidities can arise due to seizures themselves, adverse effects of Anti-seizure drugs (ASD) or other treatments, or shared underlying pathologies and aetiologies, with the latter suggesting that drugs acting on shared pathological processes may provide the opportunity to target both primary disease and associated comorbidities
P2X7 receptor (P2X7R) antagonism has been suggested as a potential novel treatment strategy for an array of different central nervous system (CNS) conditions, including the most common comorbidities associated with epilepsy, as briefly discussed within this section
Summary
Current Treatments and Shortcomings The term epilepsy comprises a heterogeneous group of brain disorders that all share in common an enduring predisposition to generate spontaneous, recurrent seizures. Epilepsy is one of the most common chronic diseases of the central nervous system (CNS), with an incidence of 1–2% within the general population. This amounts to over 70 million people diagnosed with epilepsy worldwide, disproportionally affecting the young and the elderly [1–3]. While in the majority of cases the exact causes of epilepsy remain unknown, epilepsy can result from genetic abnormalities (e.g., Dravet syndrome) or can be acquired following a precipitating injury. Temporal lobe epilepsy (TLE), which can be acquired following an injury to the brain and includes structural, physiological, biochemical, and epigenetic alterations within the limbic system, is the most common form of epilepsy in adults and is prone to drug-refractoriness [16,18]. We will provide an up-to-date summary of the evidence suggesting a contribution of the ATP-P2X7R axis to seizures and epilepsy with a particular focus on epilepsy-associated comorbidities
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