NSAIDs: Learning new tricks from old drugs

Nonsteroidal anti‐inflammatory drugs (NSAIDs) comprise a heterogeneous group of pharmacological agents used for the symptomatic treatment of fever, pain, and inflammation. Although the main mechanism of action of NSAIDs consists of inhibiting prostaglandin synthesis by blocking the enzyme cyclooxygenase (COX), clinical, and experimental data strongly indicate the existence of additional mechanisms. Some of the COX‐independent effects are related to the ability of NSAIDs to penetrate biological membranes and disrupt important molecular interactions necessary for a wide array of cellular functions, including cell adhesion. These effects, in particular those that interfere with l‐selectin function in neutrophils during the inflammatory response, may contribute to the anti‐inflammatory properties that NSAIDs exert in vivo. Recent contributions in this field have shown that the anti‐l‐selectin effect of NSAIDs is related to the NADPH‐oxidase‐dependent generation of superoxide anion at the plasma membrane. These findings might represent a novel approach for developing new and effective anti‐inflammatory compounds with a better safety profile than the currently available NSAIDs.