Inhibition of MMP-9 by a selective gelatinase inhibitor protects neurovasculature from embolic focal cerebral ischemia

Jiankun Cui,Fanjun Meng,Shahriar Mobashery,Rong Hu,Mayland Chang,Mijoon Lee,Or Hadass,Wei Wu,Chunyang Zhang,Shanyan Chen,Grace Y Sun,Gregory J Blair,Tareq Lehmidi,Zezong Gu

doi:10.1186/1750-1326-7-21

Jiankun Cui, Fanjun Meng + Show 12 more

Open Access

https://doi.org/10.1186/1750-1326-7-21

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Abstract

BackgroundCerebral ischemia has been shown to induce activation of matrix metalloproteinases (MMPs), particularly MMP-9, which is associated with impairment of the neurovasculature, resulting in blood–brain barrier breakdown, hemorrhage and neurodegeneration. We previously reported that the thiirane inhibitor SB-3CT, which is selective for gelatinases (MMP-2 and −9), could antagonize neuronal apoptosis after transient focal cerebral ischemia.ResultsHere, we used a fibrin-rich clot to occlude the middle cerebral artery (MCA) and assessed the effects of SB-3CT on the neurovasculature. Results show that neurobehavioral deficits and infarct volumes induced by embolic ischemia are comparable to those induced by the filament-occluded transient MCA model. Confocal microscopy indicated embolus-blocked brain microvasculature and neuronal cell death. Post-ischemic SB-3CT treatment attenuated infarct volume, ameliorated neurobehavioral outcomes, and antagonized the increases in levels of proform and activated MMP-9. Embolic ischemia caused degradation of the neurovascular matrix component laminin and tight-junction protein ZO-1, contraction of pericytes, and loss of lectin-positive brain microvessels. Despite the presence of the embolus, SB-3CT mitigated these outcomes and reduced hemorrhagic volumes. Interestingly, SB-3CT treatment for seven days protected against neuronal laminin degradation and protected neurons from ischemic cell death.ConclusionThese results demonstrate considerable promise for the thiirane class of selective gelatinase inhibitors as potential therapeutic agents in stroke therapy.

Highlights

Cerebral ischemia has been shown to induce activation of matrix metalloproteinases (MMPs), MMP-9, which is associated with impairment of the neurovasculature, resulting in blood–brain barrier breakdown, hemorrhage and neurodegeneration
Embolus-induced focal cerebral ischemia in mice To evaluate the effects of the selective gelatinase inhibitor SB-3CT, we employed a modified version of a previously described embolic focal ischemic model [34]
SB-3CT protects laminin-positive pericytes from embolus-induced ischemic lesion by relieving them from gelatinase-mediated lumen contraction after embolic middle cerebral artery (MCA) occlusion We have previously shown that degradation of laminin after focal cerebral ischemia involves MMP-9 activation [29]

Summary

Introduction

Cerebral ischemia has been shown to induce activation of matrix metalloproteinases (MMPs), MMP-9, which is associated with impairment of the neurovasculature, resulting in blood–brain barrier breakdown, hemorrhage and neurodegeneration. Cerebral ischemia initiates cascades of pathological events, including vasogenic edema, disruption of the blood–brain barrier (BBB), intracerebral hemorrhage (ICH), astroglial activation, and neuronal death [2,3]. The molecular mechanisms underlying these outcomes have not yet been fully addressed, there is considerable evidence supporting the important role of matrix metalloproteinases (MMPs) in mediating ischemia-induced neurovasculature impairment. Increased expression and activation of MMPs, and gelatinases in particular, are likely to play critical roles in excitotoxicity-induced disruption of cell-matrix homeostasis and neuronal cell death [4,5]. MMPs play a role in thrombolysis-mediated BBB leakage and edema, resulting in ICH. Gelatinases function in neurovascular remodeling and microvascular recanalization [2,7,8]

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