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SYMPOSIA

New Functions for an Old Enzyme: Nonhemostatic Roles for Tissue-Type Plasminogen Activator in the Central Nervous System

Department of Surgery, University of Maryland School of Medicine, Rockville, Maryland 20855

To whom requests for reprints should be addressed at ¹ Department of Surgery, University of Maryland School of Medicine, 15601 Crabbs Branch Way, Rockville, MD 20855. E-Mail: Lawrenced{at}USA.redcross.org

Tissue-type plasminogen activator (tPA) is a highly specific serine proteinase that activates the zymogen plasminogen to the broad-specificity proteinase plasmin. Tissue-type plasminogen activator is found not only in the blood, where its primary function is as a thrombolytic enzyme, but also in the central nervous system (CNS), where it promotes events associated with synaptic plasticity and acts as a regulator of the permeability of the neurovascular unit. Tissue-type plasminogen activator has also been associated with pathological events in the CNS such as cerebral ischemia and seizures. Neuroserpin is an inhibitory serpin that reacts preferentially with tPA and is located in regions of the brain where either tPA message or tPA protein are also found, indicating that neuroserpin is the selective inhibitor of tPA in the CNS. There is a growing body of evidence demonstrating the participation of tPA in a number of physiological and pathological events in the CNS, as well as the role of neuroserpin as the natural regulator of tPA’s activity in these processes. This review will focus on nonhemostatic roles of tPA in the CNS with emphasis on its newly described function as a regulator of permeability of the neurovascular unit and on the regulatory role of neuroserpin in these events.

Key Words: tissue-type plasminogen activator • neuroserpin • plasminogen • cerebral ischemia • seizures • cerebral edema