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Cortical spreading depression activates and upregulates MMP-9
Yasemin Gursoy-Ozdemir, … , Eng H. Lo, Michael A. Moskowitz
Yasemin Gursoy-Ozdemir, … , Eng H. Lo, Michael A. Moskowitz
Published May 15, 2004
Citation Information: J Clin Invest. 2004;113(10):1447-1455. https://doi.org/10.1172/JCI21227.
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Article Neuroscience

Cortical spreading depression activates and upregulates MMP-9

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Abstract

Cortical spreading depression (CSD) is a propagating wave of neuronal and glial depolarization and has been implicated in disorders of neurovascular regulation such as stroke, head trauma, and migraine. In this study, we found that CSD alters blood-brain barrier (BBB) permeability by activating brain MMPs. Beginning at 3–6 hours, MMP-9 levels increased within cortex ipsilateral to the CSD, reaching a maximum at 24 hours and persisting for at least 48 hours. Gelatinolytic activity was detected earliest within the matrix of cortical blood vessels and later within neurons and pia arachnoid (≥3 hours), particularly within piriform cortex; this activity was suppressed by injection of the metalloprotease inhibitor GM6001 or in vitro by the addition of a zinc chelator (1,10-phenanthroline). At 3–24 hours, immunoreactive laminin, endothelial barrier antigen, and zona occludens-1 diminished in the ipsilateral cortex, suggesting that CSD altered proteins critical to the integrity of the BBB. At 3 hours after CSD, plasma protein leakage and brain edema developed contemporaneously. Albumin leakage was suppressed by the administration of GM6001. Protein leakage was not detected in MMP-9–null mice, implicating the MMP-9 isoform in barrier disruption. We conclude that intense neuronal and glial depolarization initiates a cascade that disrupts the BBB via an MMP-9–dependent mechanism.

Authors

Yasemin Gursoy-Ozdemir, Jianhua Qiu, Norihiro Matsuoka, Hayrunnisa Bolay, Daniela Bermpohl, Hongwei Jin, Xiaoying Wang, Gary A. Rosenberg, Eng H. Lo, Michael A. Moskowitz

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Figure 6

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CSD altered the immunostaining of laminin, ZO-1, and EBA within the bloo...
CSD altered the immunostaining of laminin, ZO-1, and EBA within the blood vessel wall. (A_C) Laminin (approximate molecular weight, 200 kDa), a basement membrane protein, was reduced ipsilateral to CSD on immunoblots (at 12 hours) compared with that of the sham group and compared with that of the contralateral side. Similarly, CSD decreased the immunostaining of laminin in blood vessels (C), indicating that CSD alters the antigenicity of an integral basement membrane protein (scale bars: 100 ∝m). (B) These images show colocalization of the tight junction protein ZO-1 with RECA and show that CSD decreases the extent of this colocalization (colocalization coefficient, 0.21 ± 0.03 for CSD versus 0.55 ± 0.05 for control; P < 0.05). Compared with the image of the opposite side (nCSD), the merged image after CSD shows large segments of blood vessels with green fluorescence only (arrows; scale bars: 20 ∝m). (C) EBA immunostaining was also reduced in cortical blood vessels after CSD. This decrease often indicates impaired BBB function (scale bars: 100 ∝m).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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