Figure 1.

The two-hit model of neuroinflammation. The ATP-mediated enhancement of neuroinflammation can be explained through the two-hit model. A variety of insults, such as bacterial LPS, various cytokines, or amyloid peptides, can act as the first hit, resulting in microglial activation, COX-2 induction and PGE₂ release. The second hit, following neuronal injury, death or persistent glial cell activation, results in the release of ATP, which acts on both neuronal and glial P2 receptors, leading to enhanced microglial PGE₂ release. NSAIDs target COX enzymes affecting the housekeeping roles of PGE₂. ATP potentiates the effects of first hit multi-fold, and thus, would be the most relevant target for therapeutic intervention. By acting on P2 receptors, PBAIDs are believed to reduce PGE₂ to pre-inflammatory levels without affecting the activity of COX enzymes.