Several lines of scientific data suggest a correlation between neuroinflammation and CNS disorders such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, epilepsy, chronic pain and neuropsychiatric disorders (depression, bipolar disorder and schizophrenia). Many of these CNS diseases are comorbid with classical peripheral inflammatory disorders such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, to name a few. The scientific underpinning of this comorbidity in patients is perhaps driven by a compromised immune surveillance system wherein the immune cells and cytokines/chemokines in the periphery cross-talk to the CNS either directly (BBB integrity compromise) or indirectly via modulating meningeal immunity. In addition, there is an inherent ‘central’ component of neuroinflammation that is driven by microglial cells within the CNS. As such, neuroinflammatory drug targets on microglia cells within the CNS have been an emerging area of research within the neuroscience community, both in academia, industry and in public-private consortia.

P2X7 is an ATP activated ion channel, that is expressed abundantly on microglia (and peripheral immune cells) and is a critical mediator of neuroinflammation via release of NLRP3 dependent IL-1β and IL-18 [1]. In several preclinical models of stress in rodents, independent research groups have demonstrated an activated NLRP3-IL1β pathway; as such intervention of this pro-inflammatory pathway by targeting the P2X7 ion channel with CNS penetrant antagonists have demonstrated efficacy in models of psychiatric diseases [2] and provides optimism for novel therapeutic options for patients with mood disorders. When ATP is present in high concentrations in extracellular space as a danger signal, the P2X7-NLRP3- IL1β signaling is activated initiating the microglial neuroinflammatory cascade. The functional expression of this pathway may or may not be associated with enhanced expression of P2X7 at the protein level and an absence of P2X7 upregulation should not be taken as proof of absence of P2X7 in the disease process. Patients with inflammatory burden and activated immune cells with enhanced IL-1β and IL-18 signaling, ought to be tested in controlled clinical studies with doses of P2X7 antagonists that satisfy target engagement of brain P2X7 channels in humans.

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