Published Online
on June 8, 2006

A more recent version of this article appeared on July 1, 2006

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Submitted on April 12, 2006
Accepted on April 21, 2006

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; and 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.

^* To whom correspondence should be addressed. 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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