H3 antagonists and postoperative cognitive dysfunction

Since histamine (HA) was first synthesized in 1907 and isolated as a bacterial contaminant of an extract of ergot in 1910, its role in health and disease and its molecular mechanism of action have been unraveled, leading to the formulation of an array of drugs with immense therapeutic value. HA is produced by decarboxylation of histidine, and its biological actions are mediated through four HA receptors, namely, H(1), H(2), H(3), and H(4) based on their sequence, their link to differential intracellular signaling mechanisms, and their unique pharmacological properties. H(1) and H(2) receptors have been targeted for treating allergic conditions and peptic ulcers, respectively. The discovery of a third HA receptor subtype (H(3)R) by molecular biologists in 1983, structurally a member of the G-protein-coupled receptor family, has led to the development of many potent and selective H(3) receptor antagonists having the potential to treat a wide spectrum of neurological diseases including postoperative cognitive dysfunction.