Abstract
Despite the progress made in the development of new antiepileptic drugs (AEDs), the biggest challenges that epilepsy presents to drug development have remained unchanged for the last 80 years: finding a treatment with potential for modifying disease progression and reducing the percentage of patients resistant to all pharmacological interventions. The mechanism of action of the majority of AEDs is based on blocking Na+ and/or Ca2+ channels, promotion of GABA or inhibition of glutamate signaling. In order for further progress to be made, however, a fuller picture of epilepsy will need to be considered, including changes to blood–brain barrier permeability, synaptic plasticity, network reorganization, and gliosis. In particular, brain inflammation has attracted much attention over recent years. Emerging evidence demonstrates a causal role for brain inflammation in lowering seizure thresholds and driving epileptogenesis. Consistent with this, intervening in pro-inflammatory cascades has shown promise in animal models of epilepsy, with clinical trials of anti-inflammatory agents already underway. The ATP-gated purinergic P2X7 receptor (P2X7) has been proposed as a novel drug target for a host of neurological conditions, including epilepsy. Constitutive expression of P2X7 in the CNS is mainly on microglia, but neuronal and astroglial expression has also been suggested. Its function as a gatekeeper of inflammation is most clearly understood, however, it also plays a number of other important roles pertinent to icto- and epileptogenesis: depolarization of the cell membrane, release of macromolecules, induction of apoptosis and synaptic reorganization. Changes in P2X7 expression have been reported following prolonged seizures (status epilepticus) and during chronic epilepsy in both experimental models and patients. While much of the early work focused on the study of P2X7 during status epilepticus, there is now mounting data showing involvement of this receptor during epilepsy. The present short review will discuss the most recent findings concerning P2X7 expression and function during epilepsy and the clinical potential for P2X7 antagonists as novel AEDs.
Highlights
Reviewed by: Robert Wykes, UCL Institute of Neurology, UK Thomas Grutter, University of Strasbourg, CNRS, France
Despite the progress made in the development of new antiepileptic drugs (AEDs), the biggest challenges that epilepsy presents to drug development have remained unchanged for the last 80 years: finding a treatment with potential for modifying disease progression and reducing the percentage of patients resistant to all pharmacological interventions
kainic acid (KA) model, we found that hippocampal P2X7 up-regulation, achieved through the inhibition of a P2X7-suppressing microRNA, resulted in a more severe epileptic phenotype (JimenezMateos et al, 2015)
Summary
For newly diagnosed patients suffering from epilepsy, antiepileptic drugs (AEDs) are the frontline treatment (Wiebe and Jette, 2012). While the model of epilepsy as an imbalance between excitation and inhibition has served as the backbone for rational drug design, new AEDs have continued to enter the market, improving control of seizures, limiting adverse effects and broadening the available pharmacological armamentarium. This has offered greater scope for physicians to prescribe drugs tailored to the particular needs of a patient, such as avoiding complications with pregnancy (Patel and Pennell, 2016) or the exacerbation of co-morbidities, such as depression (Blond et al, 2016). Anticonvulsive effects of drugs which interfere with inflammatory signaling (Vezzani et al, 2000; Balosso et al, 2008; Marchi et al, 2009; Maroso et al, 2010; Bedner et al, 2015) demonstrate the potential for targeting inflammatory signaling pathways in epilepsy
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