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 7

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CSD causes Evans blue leakage and edema within cerebral cortex. (A) Evan...
CSD causes Evans blue leakage and edema within cerebral cortex. (A) Evans blue was injected 15 minutes prior to the onset of CSD. The vital dye (Evans blue) was extracted from cortical tissues at the indicated time points. There was a statistically significant difference (*, see below) between leakage into the CSD cortex and that of the sham group or the contralateral side. (B) Plasma proteins leak from cortical blood vessels after CSD. The number of vessels (>10 ∝m in diameter) in which leakage was detected on both CSD and non-CSD (contralateral) cortex are shown for six animals (P < 0.05). Confocal images show one vessel leaking Evans blue on the CSD side and a non-leaking vessel on the non-CSD side (scale bars: 100 ∝m). (C) Evans blue leakage was long lasting. When injected at 21 hours after CSD, vital dye was detected in CSD cortex 3 hours later and it was higher than that of sham cortex and the non-CSD side (n = 5; P < 0.05). (D) CSD caused a time-dependent increase in edema, as expressed by percentage water content (wet-dry/wet) brain weights. At 3, 6, and 24 hours, edema measured in piriform cortex increased on the CSD side compared with that of the non-CSD side and sham group. Asterisk denotes significant difference compared with contralateral cortex or to the sham group in A_D; P < 0.05.