The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression

Abstract

Seven P2X ion channel nucleotide receptor subtypes have been cloned and characterised. P2X7 receptors (P2X7R) are unusual in that there are extra amino acids in the intracellular C terminus. Low concentrations of ATP open cation channels sometimes leading to cell proliferation, whereas high concentrations of ATP open large pores that release inflammatory cytokines and can lead to apoptotic cell death. Since many diseases involve inflammation and immune responses, and the P2X7R regulates inflammation, there has been recent interest in the pathophysiological roles of P2X7R and the potential of P2X7R antagonists to treat a variety of diseases. These include neurodegenerative diseases, psychiatric disorders, epilepsy and a number of diseases of peripheral organs, including the cardiovascular, airways, kidney, liver, bladder, skin and musculoskeletal. The potential of P2X7R drugs to treat tumour progression is discussed.

Involvement of P2X7 receptors in satellite glial cells of dorsal root ganglia in the BmK I -induced pain model of rats

“…It has been generally assumed that pro-inflammatory cytokines, including IL-1β and TNF-α, play an important role in the initiation and maintenance of inflammatory (Albuquerque et al 2017) and neuropathic pain (Xie et al 2017; Wu et al 2017b). It has been demonstrated that P2X7 receptors can mediate the release of IL-1β (Burnstock and Knight 2018). Our results found that the expression of IL-1β was increased in the BmK I-induced rats.…”

Interleukin-1β is a potential therapeutic target for periodontitis: a narrative review

“…147,148 The P2X7 receptor antagonist has potential in the treatment of chronic pain, inflammation and cancer. 149,150 The P2X7 receptor antagonists oATP and A-740003 inhibit eATP-induced IL-1β secretion in P. gingivalis-infected macrophages. 38 An antagonist of the P2X7 receptor, AZ106006120, reduces neutrophil infiltration and the secretion of pro-inflammatory cytokines in a mouse model of acute lung injury.…”

P2 Receptors as Therapeutic Targets in the Salivary Gland: From Physiology to Dysfunction

“…In exocrine tissues, such as salivary gland, lacrimal gland and pancreas, purinergic receptor-mediated ion fluxes and cross-talk with muscarinic receptor signaling have been suggested to modulate secretory function (Novak et al, 2010;Burnstock and Novak, 2012;Hodges and Dartt, 2016). Whereas intracellular nucleotides are well-known for their role in metabolism and enzyme function, it wasn't until the 1970s that plasma membrane receptors were postulated to respond to extracellular nucleotides, including ATP and ADP, and were suggested to be responsible for non-cholinergic, non-adrenergic neurotransmission (Burnstock et al, 1972;Burnstock, 1976). Under normal conditions, extracellular nucleotides are present at minute concentrations due to the presence of ectonucleotidases (Robson et al, 2006;Zimmermann et al, 2012).…”

“…P2X7 receptor (P2X7R) antagonists have been previously investigated in phase 2 clinical trials for treatment of inflammatory and autoimmune diseases, including chronic obstructive pulmonary disorder, rheumatoid arthritis and Crohn's disease (Arulkumaran et al, 2011;Keystone et al, 2012). Recent advances in the development of neuropermeable P2X7R antagonists have stimulated interest in the use of these compounds to treat neuroinflammatory and neuropsychiatric disorders (Chrovian et al, 2014;Burnstock and Knight, 2018;Bhattacharya and Ceusters, 2019). The P2X3 receptor (P2X3R) contributes to hypersensitivity of lung afferent sensory fibers that mediate cough initiation and phase 2 clinical trials have demonstrated that the P2X3R antagonist gefapixant (AF-219) reduces refractory chronic cough in afflicted patients by 75% (Weigand et al, 2012;Abdulqawi et al, 2015).…”