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

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 3

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The NMDA receptor blocker MK-801 blocked CSD and suppressed MMP-9 activi...
The NMDA receptor blocker MK-801 blocked CSD and suppressed MMP-9 activity. (A) Topical MK-801 was administered 15 minutes before CSD. No change in MMP-2 expression was detected. These results suggest that MMP-9 activity is related to CSD but not to the needle stab (n = 3). (B) The nonselective metalloprotease inhibitor GM6001 was administered intraperitoneally 1 and 4 hours after CSD (65 mg/kg for each). A marked reduction in MMP-9 activity was found by gel zymography 12 hours later (two of three samples showed decreased or no MMP level). These results indicate that CSD increased MMP activity in vivo.