Abstract
Epilepsy encompasses a heterogeneous group of neurological syndromes which are characterized by recurrent seizures affecting over 60 million people worldwide. Current anti-epileptic drugs (AEDs) are mainly designed to target ion channels and/or GABA or glutamate receptors. Despite recent advances in drug development, however, pharmacoresistance in epilepsy remains as high as 30%, suggesting the need for the development of new AEDs with a non-classical mechanism of action. Neuroinflammation is increasingly recognized as one of the key players in seizure generation and in the maintenance of the epileptic phenotype. Consequently, targeting signaling molecules involved in inflammatory processes may represent new avenues to improve treatment in epilepsy. Nucleotides such as adenosine-5′-triphosphate (ATP) and uridine-5′-triphosphate (UTP) are released in the brain into the extracellular space during pathological conditions such as increased neuronal firing or cell death. Once released, these nucleotides bind to and activate specific purinergic receptors termed P2 receptors where they mediate the release of gliotransmitters and drive neuronal hyperexcitation and neuroinflammatory processes. This includes the fast acting ionotropic P2X channels and slower-acting G-protein-coupled P2Y receptors. While the expression and function of P2X receptors has been well-established in experimental models of epilepsy, emerging evidence is now also suggesting a prominent role for the P2Y receptor subfamily in seizure generation and the maintenance of epilepsy. In this review we discuss data supporting a role for the P2Y receptor family in epilepsy and the most recent finding demonstrating their involvement during seizure-induced pathology and in epilepsy.
Highlights
The primary treatment for epilepsy is the use of anti-epileptic drugs (AEDs)
Recent studies have shown distinct changes in expression of the P2Y receptor family following status epilepticus and during seizures and a functional contribution has been postulated using broad-spectrum P2Y agonists (ADP and uridine5 -triphosphate (UTP)) (Alves et al, 2017) and P2Y12 knockout mice (Eyo et al, 2014), there are many key issues, which will have to be resolved before considering P2Y receptors as valid drug target. (i) Studies have demonstrated altered P2Y receptor expression following status epilepticus and during epilepsy (Alves et al, 2017)
To get a better picture about the potential role of P2Y signaling during seizure-related pathologies, we must determine what cell types express the receptor and their sub-cellular localization. (ii) Treatment of mice during status epilepticus with P2Y broad-spectrum agonists suggest a role of these receptors in seizure generation and seizure-induced pathology (Alves et al, 2017), we still do not know the role of individual P2Y receptors during seizures, with the only exception being the P2Y12 receptor (Eyo et al, 2014)
Summary
The primary treatment for epilepsy is the use of anti-epileptic drugs (AEDs). These drugs control seizures by shifting the balance of inhibitory and excitatory drive in the brain (Bialer et al, 2013). 30% of patients, are pharmacoresistant to all available AEDs and between 40 and 50% of patients on AEDs suffer adverse effects (Baker et al, 1997). Current major goals of epilepsy research are to develop treatment strategies that impact upon disease emergence and progression, show efficacy within the currently pharmacoresistant cohort and have a lower burden of adverse effects To this end, the role of neuroinflammation in icto- and epileptogenesis is. Status epilepticus is the second most common neurological emergency behind stroke, with an annual incidence of 10–41 cases per 100,000 (Hesdorffer et al, 1998) It is associated with high mortality (up to 20%), morbidity and considerable costs to the healthcare system (Betjemann and Lowenstein, 2015) and can cause severe damage to the brain, leading to serious neurological complications such as cognitive impairment (Korngut et al, 2007), and the development of chronic epilepsy (Hesdorffer et al, 1998). Because of the importance of these network changes, TLE is associated with a high prevalence of pharmacoresistance (Zhao et al, 2014)
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