A Possible Causal Involvement of Neuroinflammatory, Purinergic P2X7 Receptors in Psychiatric Disorders

Abstract

P2X7 receptors (Rs) are prominent members of the P2XR family, which after binding ATP, open non-selective cationic channels, thereby allowing the transmembrane passage of Na+, Ca²⁺, and K+. Long-lasting and repetitive stimulation of the receptor by its agonist leads to the formation of large membrane pores permeable for organic cations of up to 900 Da molecular size. These pores are believed to play a role in apoptosis and inflammation. P2X7Rs are located primarily at peripheral macrophages and microglial cells, the resident macrophages of the CNS. The coactivation of toll-like receptors 4 (TLR4) by lipopolysaccharide, a constituent of the cell membrane of gram-negative bacteria, and the P2X7R by ATP leads to the generation and release of the proinflammatory cytokines interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α. Together with the microglial release of chemokines, reactive oxygen and nitrogen species, proteases, and excitotoxic glutamate, these cytokines result in neurodegeneration. P2X7Rs were found not only to amplify various neurodegenerative illnesses, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, but also to participate in a range of psychiatric diseases, such as major depression, bipolar disorder, schizophrenia, and autism spectrum disorder. Based on the prevention/reversal of neuroinflammation, pharmacological antagonists of P2X7Rs and their genetic deletion in animal experiments counteract these deleterious psychiatric conditions. Hence, brain penetrant P2X7R antagonists are potential therapeutics for psychiatric diseases, although the available evidence still needs to be extended and validated by further clinical data.

Keywords: P2X7 receptor; clinical data; interleukin-1β; neurodegeneration; neuroinflammation; psychiatric disorders.

Fig. (1)

A simplified scheme of P2X7R functions in microglia, astrocytes, and probably also neurons to induce neuroinflammation as a causative factor of major depression, bipolar disorder, schizophrenia, and autism spectrum disorder (ASD). P2X7Rs are none-selective cationic channels activated by high concentrations of ATP to allow the transmembrane fluxes of Na⁺, Ca²⁺, and K⁺. This receptor is, in addition, able to become permeable to large molecules of up to 900 Da on long-lasting or repetitive occupation by ATP. Especially in microglia, P2X7Rs stimulate the P2X7R/NLRP3 inflammasome/caspase-1/interleukin 1β (IL-1β)-pathway after co-activation of toll-like receptor 4 (TLR4) with lipopolysaccharide. The release of the pro-inflammatory cytokines, IL-1β, IL-18, and tumor necrosis factor-α (TNF-α), leads to neuroinflammation.