Neuroserpin, a neuroprotective factor in focal ischemic stroke

Mol Cell Neurosci. 2001 Nov;18(5):443-57. doi: 10.1006/mcne.2001.1028.

Abstract

Because recent studies have indicated that tissue plasminogen activator (tPA) aggravates neurodegenerative processes in many neural pathologies, we studied whether the endogenous tPA antagonist neuroserpin has a neuroprotective effect in an animal model of focal ischemic stroke. After induction of a focal ischemic stroke in the mouse by occlusion of the middle cerebral artery, we found that microglial cells accumulated in the marginal zone of the infarct are the most important source for both plasminogen activators, tPA and uPA. To investigate the effect of neuroserpin on the size and the histology of the infarct we produced transgenic mice overexpressing neuroserpin approximately sixfold in the nervous system. In the brain of these mice the total tPA activity in the uninjured tissue was strongly reduced. After induction of a focal ischemic stroke in the transgenic mice by a permanent occlusion of the middle cerebral artery (MCA), the infarcts were 30% smaller than in the wild-type mice. Immunohistochemical analyses and in situ hybridization revealed an attenuation of the microglial activation in the reactive zone. Concomitantly, the microglial production of tPA and uPA, as well as the PA-activity in the infarct region was markedly reduced. Thus, our results indicate that neuroserpin reduces microglial activation and, therefore, the PA activity and has a neuroprotective role after focal ischemic stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism*
  • Brain / pathology
  • Brain / physiopathology
  • Brain Ischemia / genetics
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology
  • Cerebral Infarction / genetics
  • Cerebral Infarction / metabolism
  • Cerebral Infarction / pathology
  • Down-Regulation / physiology
  • Gene Expression Regulation / physiology
  • Gliosis / genetics
  • Gliosis / metabolism
  • Gliosis / pathology
  • Infarction, Middle Cerebral Artery / genetics
  • Infarction, Middle Cerebral Artery / metabolism*
  • Infarction, Middle Cerebral Artery / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / metabolism*
  • Microglia / pathology
  • Models, Neurological
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / pathology
  • Neuropeptides / genetics
  • Neuropeptides / metabolism*
  • Neuroprotective Agents / metabolism*
  • Serpins / genetics
  • Serpins / metabolism*
  • Tissue Plasminogen Activator / metabolism
  • Urokinase-Type Plasminogen Activator / metabolism

Substances

  • Neuropeptides
  • Neuroprotective Agents
  • Serpins
  • neuroserpin
  • Tissue Plasminogen Activator
  • Urokinase-Type Plasminogen Activator