P2X7 receptors from the perspective of NLRP3 inflammasome pathway in depression: Potential role of cannabidiol

Many patients with depressive disorder do not respond to conventional antidepressant treatment. There is an ongoing interest in investigating potential mechanisms of treatment resistance in depression to provide alternative treatment options involving inflammatory mechanisms. Increasing evidence implicates the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome as a critical factor in neuroinflammation. ATP-induced P2X7 receptor (P2X7R) activation is a major trigger for inflammation, activating the canonical NLRP3 inflammatory cascade. Psychosocial stress, the primary environmental risk factor for depression, is associated with changes in ATP-mediated P2X7R signaling. Depression and stress response can be alleviated by Cannabidiol (CBD). CBD has an anti-inflammatory activity related to the regulation of NLRP3 inflammasome activation. However, CBD's effects on the inflammasome pathway are poorly understood in central nervous system (CNS) cells, including microglia, astrocytes, and neurons. This review will emphasize some findings for neuroinflammation and NLRP3 inflammasome pathway involvement in depression, particularly addressing the ATP-induced P2X7R activation. Moreover, we will underline evidence for the effect of CBD on depression and address its potential impacts on neuroinflammation through the NLRP3 inflammasome cascade.