Abstract
Tissue-type plasminogen activator (tPA) is a serine protease that cleaves plasminogen into active plasmin. In plasma, the primary function of plasmin is the digestion of fibrin, and therefore, tPA is used as a thrombolytic agent for acute treatment of ischemic stroke. However, apart from its fibrinolytic action, tPA is widely distributed in the CNS1 and involved in mechanisms of synaptic regulation, synaptic plasticity, and neural injury.2,3 These extravascular effects of tPA have to be taken into account when treating patients with ischemic stroke with this agent because there is experimental evidence that tPA administered parenterally has access to both normal and injured brain parenchyma.4,5 Therefore, there is considerable interest in developing drugs that may neutralize the neurotoxic extravascular effects of tPA. Neuroserpin is a serine protease inhibitor that specifically inhibits the actions of tPA in the CNS.6 The interactions between tPA and neuroserpin may be important not only in the setting of acute injury but also in neurodegenerative disorders. Mutations of the neuroserpin gene are linked to familial encephalopathy with neuroserpin inclusion bodies (FENIB),7,8 and neuroserpin has a protective effect on a genetic mouse model of motor neuron disease.9 The focus of this review is on the effects of tPA on synaptic transmission and plasticity, its potentially deleterious effects in the setting of acute brain injury, and the genetic disorders where tPA–neuroserpin interactions may have a pathogenic role. Several reviews comprehensively cover these topics.2,3,6,8 Tissue-type plasminogen activator is widely expressed in neurons and glial cells of the human CNS, including the neocortex, hippocampus, hypothalamus, thalamus, cerebellum, pontine nuclei, medulla, and sympathetic ganglia.1 There is in vitro evidence that tPA is released from neurons and glial cells and has a major role in synaptic plasticity3 (figure and table). Tissue plasminogen activator is …
Published Version
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