The P2X7 receptor in depression: Novel insights and therapeutic implications

Major depressive disorder (MDD) is a heterogeneous mental disorder involving multiple pathogenic mechanisms. Current first-line antidepressant medications suffer from slow onset of action, limited effectiveness, and high side effects, necessitating the search for new therapeutic targets. Targeting cytokines or receptors is increasingly recognized in innovative depression treatment protocols. The P2X7 receptor (P2X7R) plays a key role in central nervous system signaling and is considered a potential therapeutic target for depression. Recent studies have focused on the fact that P2X7R modulates inflammatory and immune responses, which may contribute to the development of depression. However, the full extent of P2X7R's involvement in depression remains unclear. This review provides a comprehensive overview of the discovery, structure, and properties of P2X7R. We delve into the role of P2X7R in the pathogenesis of depression, focusing on neuroinflammation, oxidative stress, mitochondrial dysfunction, and reduced synaptic plasticity. Additionally, we discuss the clinical applications of P2X7R antagonists. By highlighting the significant role and therapeutic potential of the P2X7 receptor as a pharmacological target for depression, this review aims to provide new research perspectives and theoretical basis for the development of antidepressant drugs.