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(Stroke. 2006;37:1888.)
© 2006 American Heart Association, Inc.

Original Contributions

Cathepsin and Calpain Inhibitor E64d Attenuates Matrix Metalloproteinase-9 Activity After Focal Cerebral Ischemia in Rats

Tamiji Tsubokawa, MD, PhD; Ihsan Solaroglu, MD; Hiroshi Yatsushige, MD; Julian Cahill, MB; Kenichiro Yata, MD John H. Zhang, MD, PhD

From the Department of Physiology and Pharmacology (T.T., I.S., H.Y., J.C., K.Y., J.H.Z.), Division of Neurosurgery (J.H.Z.), and Department of Anesthesiology (J.H.Z.), Loma Linda University School of Medicine, California.

Correspondence to John H. Zhang MD, PhD, Division of Neurosurgery, Loma Linda University Medical Center, 11234 Anderson St, Room 2562B, Loma Linda, CA 92354. E-mail johnzhang3910{at}yahoo.com

Background and Purpose— Matrix metalloproteinases (MMPs) and cysteine proteases (calpain and cathepsin B) play an important role in cell death and are upregulated after focal cerebral ischemia. Because there is a significant interaction between MMP-9 with calpain and cathepsin B, we investigated the role of E64d (a calpain and cathepsin B inhibitor) on MMP-9 activation in the rat focal ischemia model.

Methods— Male Sprague-Dawley rats were subjected to 2 hours of middle cerebral artery occlusion by using the suture insertion method followed by 22 hours of reperfusion. In the treatment group, a single dose of E64d (5 mg/kg IP) was administrated 30 minutes before the induction of focal ischemia, whereas the nontreatment group received dimethyl sulfoxide only. The neurological deficits, infarct volumes, Evans blue extravasation, brain edema, and MMP-9 activation in the brain were determined.

Results— Pretreatment with E64d produced a significant reduction in the cerebral infarction volume (353.1±19.8 versus 210.3±23.7 mm³) and the neurological deficits. Immunofluorescence studies showed MMP-9, calpain, and cathepsin B activation colocalized to both neurons and the neurovascular endothelial cells after ischemia, which was reduced by E64d.

Conclusion— These results suggest that E64d treatment provides a neuroprotective effect to rats after transient focal cerebral ischemia by inhibiting the upregulation of MMP-9.

Key Words: blood–brain barrier • calpain • cathepsin B • ischemia • matrix metalloproteinases

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