Antidepressants as modulators of P2X7 receptor activity

According to the Pan American Health Organization, more than 300 million people suffer from depression worldwide. Despite the alarming numbers, current drug treatments produce partial results, as they focus on only one pillar of depression: neurotransmitters. Most current medications for depression focus only on stimulating increased levels of neurotransmitters related to feelings of well-being and happiness, such as serotonin and norepinephrine, which, despite providing relief, do not produce such impressive results for patients. A significant and scientifically endorsed point regarding depression is neuroinflammation. The relationship between inflammation in the body and the development or worsening of depression has been strongly reinforced by neuroscientific studies. Studies have also shown that depressed patients have increased levels of inflammatory cytokines. Antidepressants have already demonstrated anti-inflammatory activity, stimulating the production of anti-inflammatory cytokines and reducing the production of oxidative radicals, as in the case of fluoxetine and paroxetine. In depression, P2X7 receptor expression is increased. This receptor is activated, and greater expression produces a depressive phenotype, while its blockade has antidepressant effects. Therefore, we evaluated the in-silico interaction between antidepressants and the allosteric site of the P2X7 receptor. This finding reinforces the functional data in the literature that point to the inhibition of the P2X7 receptor. The molecular docking results showed that drugs containing the amino acids TYR295 and PHE95 are essential for a good interaction with the P2X7 receptor at its allosteric site. Furthermore, this study demonstrated that combining antidepressants with p2x7 receptor antagonists can attenuate neuroinflammation.