The purinergic P2X7 receptor as a potential drug target to combat neuroinflammation in neurodegenerative diseases

Abstract

Neurodegenerative diseases (NDDs) represent a huge social burden, particularly in Alzheimer's disease (AD) in which all proposed treatments investigated in murine models have failed during clinical trials (CTs). Thus, novel therapeutic strategies remain crucial. Neuroinflammation is a common pathogenic feature of NDDs. As purinergic P2X7 receptors (P2X7Rs) are gatekeepers of inflammation, they could be developed as drug targets for NDDs. Herein, we review this challenging hypothesis and comment on the numerous studies that have investigated P2X7Rs, emphasizing their molecular structure and functions, as well as their role in inflammation. Then, we elaborate on research undertaken in the field of medicinal chemistry to determine potential P2X7R antagonists. Subsequently, we review the state of neuroinflammation and P2X7R expression in the brain, in animal models and patients suffering from AD, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. Next, we summarize the in vivo studies testing the hypothesis that by

Glial Purinergic Signaling in Neurodegeneration

“…The targeting of purinergic signaling-i.e., signaling pathways mediated by extracellular nucleotides and nucleosides such as ATP or adenosine-belongs to these novel emerging therapeutic strategies (10). All CNS cell types, including glial cells, express purinergic receptors and purinergic signaling influences key CNS functions [for review see Agostinho et al (11)] such as synaptic transmission, proliferation, maturation and neuroinflammation (12) that are altered in neurodegeneration.…”

Inhibition of P2X7 Purinergic Receptor Ameliorates Fibromyalgia Syndrome by Suppressing NLRP3 Pathway

“…In this regard, purinergic signaling is often associated with pain and inflammatory responses [ 29 ]. For instance, the purine molecule ATP has been demonstrated to play an important role in regulating nociceptive transmission in different regions of the spinal cord and brain, and promotes the release of mediators involving pain [ 12 , 30 , 31 ].…”

Antagonistic Roles of P2X7 and P2Y2 Receptors in Neurodegenerative Diseases

“…Several BBB-permeant small molecule P2X7R antagonists were developed (for a review, see Andrejew et al, 2020), and some of them are undergoing clinical trials for the treatment of neurodegeneration: CE22,535, already tested in phase 2 and 3 clinical trials; and JNJ541754467 tested in a phase 1 clinical trial (for a detailed review, see Calzaferri et al, 2020). Therapeutic P2Y2R agonists include diquafosol (Lau et al, 2014) and Denufosol tetrasodium (Deterding et al, 2007).…”