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

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Tumor necrosis factor-alpha (TNFa) and Fas are induced after traumatic brain injury (TBI); however, their functional roles are incompletely understood. Using controlled cortical impact (CCI) and mice deficient in TNFa, Fas, or both (TNFa/FasÀ/À), we hypothesized that TNFa and Fas receptor mediate secondary TBI in a redundant manner. Compared with wild type (WT), TNFa/FasÀ/À mice had improved motor performance from 1 to 4 days (P < 0.05), improved spatial memory acquisition at 8 to 14 days (P < 0.05), and decreased brain lesion size at 2 and 6 weeks after CCI (P < 0.05). Protection in TNFa/FasÀ/À mice from histopathological and motor deficits was reversed by reconstitution with recombinant TNFa before CCI, and TNFaÀ/À mice administered anti-Fas ligand antibodies had improved spatial memory acquisition versus similarly treated WT mice (P < 0.05). Tumor necrosis factor-alpha/FasÀ/À mice had decreased the numbers of cortical cells with plasmalemma damage at 6 h (P < 0.05 versus WT), and reduced matrix metalloproteinase-9 activity in injured brain at 48 and 72 h after CCI. In immature mice subjected to CCI, genetic inhibition of TNFa and Fas conferred beneficial effects on histopathology and spatial memory acquisition in adulthood (both P < 0.05 versus WT), suggesting that the beneficial effects of TNFa/Fas inhibition may be permanent. The data suggest that redundant signaling pathways initiated by TNFa and Fas play pivotal roles in the pathogenesis of TBI, and that biochemical mechanisms downstream of TNFa/Fas may be novel therapeutic targets to limit neurological sequelae in children and adults with severe TBI.