P2X7 Receptors Amplify CNS Damage in Neurodegenerative Diseases

Abstract

ATP is a (co)transmitter and signaling molecule in the CNS. It acts at a multitude of ligand-gated cationic channels termed P2X to induce rapid depolarization of the cell membrane. Within this receptor-channel family, the P2X7 receptor (R) allows the transmembrane fluxes of Na+, Ca2+, and K+, but also allows the slow permeation of larger organic molecules. This is supposed to cause necrosis by excessive Ca2+ influx, as well as depletion of intracellular ions and metabolites. Cell death may also occur by apoptosis due to the activation of the caspase enzymatic cascade. Because P2X7Rs are localized in the CNS preferentially on microglia, but also at a lower density on neuroglia (astrocytes, oligodendrocytes) the stimulation of this receptor leads to the release of neurodegeneration-inducing bioactive molecules such as pro-inflammatory cytokines, chemokines, proteases, reactive oxygen and nitrogen molecules, and the excitotoxic glutamate/ATP. Various neurodegenerative reactions of the brain/spinal cord following acute harmful events (mechanical CNS damage, ischemia, status epilepticus) or chronic neurodegenerative diseases (neuropathic pain, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis) lead to a massive release of ATP via the leaky plasma membrane of neural tissue. This causes cellular damage superimposed on the original consequences of neurodegeneration. Hence, blood-brain-barrier permeable pharmacological antagonists of P2X7Rs with excellent bioavailability are possible therapeutic agents for these diseases. The aim of this review article is to summarize our present state of knowledge on the involvement of P2X7R-mediated events in neurodegenerative illnesses endangering especially the life quality and duration of the aged human population.

Ion Channels as New Attractive Targets to Improve Re-Myelination Processes in the Brain

“…↑ OPC proliferation ↓ OPC differentiation [165] ↑ myelination [165,180] GABA B R ↑ proliferation and ↑ migration [181] ? ↑ differentiation [182] ATP/ADP P2X 7 R ↓ proliferation and ↑ migration [183] OL damage and myelin loss during ischemia or neuroinflammation [184,185] EAE-induced OL death by Ca 2+ overloading [186] P2Y 1 R ↑ migration [187,188] ? ↓ proliferation [188] P2Y 12 R ?…”

“…P2X 7 R activation mediates a rise in intracellular Ca 2+ , through direct influx by the channel pore, and activates multiple intracellular pathways, including MAPK, PKC, and PI3K, all involved in the regulation of OPC proliferation, differentiation and myelination. In addition, P2X 7 R also participates to OL damage and myelin loss during ischemia or neuroinflammation [ 184 , 185 ]. The facilitating role of P2X 7 R in OPC migration has been outlined by Feng et al who demonstrated that high concentrations of ATP or the P2X 7 R agonist BzATP increased the number of migrating OPCs in vitro, an effect abolished by pre-treatment with the P2X 7 R antagonist oxidized ATP [ 183 ].…”

Pannexin-1 Channels as Mediators of Neuroinflammation

“…It has also been proposed that an increase of calcium concentration from intracellular sources further activates Panx1 channels mediating an ATP-dependent ATP release, which further propagates calcium signaling to neighboring cells [ 22 ]. Moreover, Panx1 channels have been shown to form a complex with P2X7 purinergic receptors [ 88 ]; the latter are known to be molecular players that amplify CNS damage and neuroinflammation in various brain pathologies [ 89 ]. Various other plasma receptors or proteins involved brain pathologies, including NMDA receptors or caspases, have been linked to Panx1 channel activation ( Figure 2 ).…”

P2X Receptor-Dependent Modulation of Mast Cell and Glial Cell Activities in Neuroinflammation

“…Overall, P2XR activities in glial cells are yet unclear, with the exception of P2X7, which engagement initiates the release of mediators whose nature differs between species [ 101 , 133 ].…”