Neuroinflammation and Microglial Constitutive COX-1 Inhibition

Neuroinflammation, as the erliest stage of neurological and neurodegenerative diseases, takes place about 15-20 years before the appearance of specific neurodegenerative clinical symptoms. Among the known mechanisms involved into the neuroinflammatory complex network, the cyclooxygenase-1 (COX-1) plays a previously unrecognized role in the neuroinflammation as demonstrated by the attenuation of the inflammatory response and neuronal loss due to the genetic ablation or pharmacological inhibition of COX-1 activity. The lack of drugs to treat diseases involving the central nervous system also resides into the shield exerted by the blood brain barrier matrix. BBB has also a low permeability, and the development of drugs able to penetrate through its network is one of the challenges of all scientists involved in projecting medicines having active principle ingredients targeting the CNS diseases. A commonly used strategy to overcome this drawback consists to incorporate into the pharmacological active molecule a sugar moiety (i.e. glucose or galactose), in turn capable to carry the entire molecule into the CNS by the GLUT-1 carrier, which is located on the membrane of the endothelial cells. In this context, a set of novel compounds endowed with inhibitory activity with cyclooxygenase-1 and GLUT-1 substrate will be presented. Specifically, their design rationale and biological activity will particularly detailed