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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 569-576
Neuroserpin reduces cerebral infarct volume and protects neurons
from ischemia-induced apoptosis
Manuel Yepes,
Maria Sandkvist,
Mike K. K. Wong,
Timothy A. Coleman,
Elizabeth Smith,
Stanley L. Cohan, and
Daniel A. Lawrence
Department of Biochemistry, American Red Cross Holland Laboratory,
Rockville, MD; Department of Protein Development, Human Genome Sciences
Inc, Rockville, MD; Department of Neurology, Georgetown University
Medical Center, Washington, DC.
Neuroserpin, a recently identified inhibitor of tissue-type
plasminogen activator (tPA), is primarily localized to neurons within
the central nervous system, where it is thought to regulate tPA
activity. In the present study neuroserpin expression and its potential
therapeutic benefits were examined in a rat model of stroke.
Neuroserpin expression increased in neurons surrounding the ischemic
core (ischemic penumbra) within 6 hours of occlusion of the middle
cerebral artery and remained elevated during the first week after the
ischemic insult. Injection of neuroserpin directly into the brain
immediately after infarct reduced stroke volume by 64% at 72 hours
compared with control animals. In untreated animals both tPA and
urokinase-type plasminogen activator (uPA) activity was significantly
increased within the region of infarct by 6 hours after reperfusion.
Activity of tPA then decreased to control levels by 72 hours, whereas
uPA activity continued to rise and was dramatically increased by 72 hours. Both tPA and uPA activity were significantly reduced in
neuroserpin-treated animals. Immunohistochemical staining of basement
membrane laminin with a monoclonal antibody directed toward a cryptic
epitope suggested that proteolysis of the basement membrane occurred as
early as 10 minutes after reperfusion and that intracerebral
administration of neuroserpin significantly reduced this proteolysis.
Neuroserpin also decreased apoptotic cell counts in the ischemic
penumbra by more than 50%. Thus, neuroserpin may be a naturally
occurring neuroprotective proteinase inhibitor, whose therapeutic
administration decreases stroke volume most likely by inhibiting
proteinase activity and subsequent apoptosis associated with focal
cerebral ischemia/reperfusion.
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