Neuroserpin, a neuroprotective factor in focal ischemic stroke

Because recent studies have indicated that tissue plasminogen activator (tP A) aggravates neurodegenerative processes in many neural pathologies, we st udied whether the endogenous tPA antagonist neuroserpin has a neuroprotecti ve effect in an animal model of focal ischemic stroke. After induction of a focal ischemic stroke in the mouse by occlusion of the midddle cerebral ar tery, we found that microglial cells accumulated in the marginal zone of th e infarct are the most important source for both plasminogen activators, tP A and uPA. To investigate the effect of neuroserpin on the size and the his tology of the infarct we produced transgenic mice overexpressing neuroserpi n approximately sixfold in the nervous system. In the brain of these mice t he total tPA activity in the uninjured tissue was strongly reduced. After i nduction of a focal ischemic stroke in the transgenic mice by a permanent o cclusion of the middle cerebral artery (MCA), the infarcts were 30% smaller than in the wild-type mice. Immunohistochemical analyses and in situ hybri dization revealed an attenuation of the microglial activation in the reacti ve zone. Concomitantly, the microglial production of tPA and uPA, as well a s the PA-activity in the infarct region was markedly reduced. Thus, our res ults indicate that neuroserpin reduces microglial activation and, therefore , the PA activity and has a neuroprotective role after focal ischemic strok e.