tPA as an effector of microglial activation

Tissue Plasminogen Activator (tPA) is currently the only FDA approved treatment of thrombotic stroke. It is expressed at high levels in the murine brain parenchyma by neurons and microglia, and is thought to regulate physiological processes that include tissue remodeling, plasticity and neurite outgrowth. Such functions have been attributed to its ability to initiate proteolytic cascades that lead to the processing or degradation of extracellular matrix proteins and possibly other substrates. Other roles of tPA involve non-proteolytic events, such as protein-protein interactions, in functions like microglial activation, interaction with zinc, seizures from ethanol withdrawal. However, it has also been implicated in brain pathologies, that proceed via an excitotoxic mechanism, thus raising concern about its use as a safe therapeutic agent. Understanding the role(s) of tPA, both proteolytic and non-proteolytic, as well as the function of activated microglia would allow to elucidate aspects of physiologic and pathologic brain function and could potentially improve the available therapies of neurological disease.