P2X7 Receptor Signaling Pathway as a Therapeutic Target for Neurodegenerative Diseases

Abstract

A recent study suggested that neuroinflammation plays a major role in the pathogenesis of a number of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Although the precise mechanism is obscure, dysregulation of the signaling transduction pathway in microglia may enhance inflammation, leading to synaptic dysfunction and ultimately to neuronal cell death. The expression and function of the P2X7 receptor (P2X7R), an ATP-gated ion channel abundantly expressed in microglia in the brain, is significantly up-regulated in the postmortem brain of Alzheimer's disease patients and various neurodegenerative disease animal models. This supports the role of the P2X7R pathway in the progression of neurodegeneration. Blocking P2X7R using brilliant blue G, a P2X7R antagonist that can cross the blood-brain barrier, has been shown to result in the amelioration of neuropathology in various animal models. Taken together, these results raise the possibility that the P2X7R signaling pathway could be a therapeutic target for treating various neurodegenerative diseases.

Natural compounds with P2X7 receptor-modulating properties

“…*P < 0.05, significantly different from corresponding ATP (DMSO) controls demyelinating diseases, brain trauma, neuropathic pain and mood disorders. Intriguingly, although most reports imply that P2X7 inhibition may exert beneficial effects under these conditions [7,[26][27][28], others found opposing effects [29]. In various tumour cell lines and tissues, notably melanoma cells (including A375), breast cancer or mouse glioma, (over)expression of P2X7 has been reported.…”

P2X7 receptors in cerebral ischemia

“…Seven distinct ionotropic P2X (P2X [1][2][3][4][5][6][7] and eight distinct metabotropic P2Y receptor subunits (P2Y 1,2,4,6,[11][12][13][14], classified by electrophysiological properties and their amino-acid sequence homology, have been cloned from mammals [4] .…”

“…Of the P2X family, the P2X 7 receptor (P2X 7 R) has specific structural and pharmacological features and may play a prominent role in the progression of various neurological disorders, such as cerebral ischemic injury (stroke), [3,7,8] . In the past few years, the potential role of this receptor in neuronal functions during cerebral ischemic stroke has received considerable attention.…”

“…Most indicate that up-regulation or overactivation of P2X 7 Rs aggravate the brain tissue damage and sensorimotor deficit through several mechanisms such as Ca 2+ overload which induces excitotoxic neuronal death or apoptosis, and receptor antagonists play a protective role [1,4,[9][10][11][12] . However, a few reports are contradictory [13,14] .…”

“…In the following we thus review the unique properties of P2X 7 Rs compared to other P2X receptor family members, the possible mechanisms of their actions in cerebral ischemia, and the potential therapeutic exploitation of P2X 7 R antagonists.…”