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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 5

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CSD increased gelatinolytic activity within the vascular matrix. (A_D) D...
CSD increased gelatinolytic activity within the vascular matrix. (A_D) Distribution of DQ gelatin_cleaving activity (in situ zymography) was compared on single sections, with the locations of cells identified by staining with specific cell markers: astrocytes, GFAP; neurons, NeuN; endothelial cells, RECA; smooth muscle cells, SMA. Cell markers were visualized by Cy-3 conjugated secondary antibody and were stained red in color. Boxed areas from merged confocal images (Merged column) are shown at higher magnification in the far right column (Inset). Gelatin cleaving activity was prominent in the walls of blood vessels and within surrounding neurons. Cleaving activity was rarely found colocalized with GFAP-positive cells. The figure shows one example. Infrequent activity was detected in endothelial cells and smooth muscle cells but predominantly within the vascular matrix. Sections were obtained 12 hours after CSD. Arrows point to areas showing colocalization. Scale bars: 20 ∝m.

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

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