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Significance Therapies that boost brain plasticity and repair processes without deleterious side effects have the potential to transform the clinical management of stroke. Here we report that tissue plasminogen activator (tPA), known as a clot buster for clinical treatment of ischemic stroke, exerts additional neurorestorative effects in a murine model of stroke by stimulating axonal regeneration and facilitating functional recovery. Importantly, functional restoration was independent of tPA’s proteolytic activity—a mutant, protease-inactive form of tPA, tPA-S478A, was as effective as regular tPA. Results of our preclinical studies support the view that tPA-S478A has the therapeutic potential to enhance brain regeneration and functional restoration in stroke victims. Unlike regular tPA, tPA-S478A does not bear the risk of inducing intracerebral hemorrhage.

Protease-independent action of tissue plasminogen activator in brain plasticity and neurological recovery after ischemic stroke