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The Journal of Neuroscience, February 14, 2007, 27(7):1511-1518; doi:10.1523/JNEUROSCI.4391-06.2007

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Development/Plasticity/Repair
Matrix Metalloproteinase-9 Gene Knock-out Protects the Immature Brain after Cerebral Hypoxia–Ischemia

Pernilla Svedin,¹ Henrik Hagberg,² Karin Sävman,² Changlian Zhu,^3,4 and Carina Mallard¹

Departments of ¹Neuroscience and Physiology and ²Clinical Sciences, Perinatal Center, Sahlgrenska Academy, and ³Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Göteborg University, 405 30 Göteborg, Sweden, and ⁴Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China

Correspondence should be addressed to Dr. Carina Mallard, Perinatal Center, Department of Neuroscience and Physiology, Sahlgrenska Academy, Göteborg University, P.O. Box 432, 405 30 Göteborg, Sweden. Email: carina.mallard{at}gu.se

Inhibition of matrix metalloproteinase-9 (MMP-9) protects the adult brain after cerebral ischemia. However, the role of MMP-9 in the immature brain after hypoxia–ischemia (HI) is unknown. We exposed MMP-9^(–/–) [MMP-9 knock-out (KO)] and wild-type (WT) mice to HI on postnatal day 9. HI was induced by unilateral ligation of the left carotid artery followed by hypoxia (10% O₂; 36°C). Gelatin zymography showed that MMP-9 activity was transiently increased at 24 h after HI in the ipsilateral hemisphere and MMP-9-positive cells were colocalized with activated microglia. Seven days after 50 min of HI, cerebral tissue volume loss was reduced in MMP-9 KO (21.8 ± 1.7 mm³; n = 22) compared with WT (32.3 ± 2.1 mm³; n = 22; p < 0.001) pups, and loss of white-matter components was reduced in MMP-9 KO compared with WT pups (neurofilament: WT, 50.9 ± 5.4%; KO, 18.4 ± 3.1%; p < 0.0001; myelin basic protein: WT, 57.5 ± 5.8%; KO, 23.2 ± 3.5%; p = 0.0001). The neuropathological changes were associated with a delayed and diminished leakage of the blood–brain barrier (BBB) and a decrease in inflammation in MMP-9-deficient animals. In contrast, the neuroprotective effects after HI in MMP-9-deficient animals were not linked to either caspase-dependent (caspase-3 and cytochrome c) or caspase-independent (apoptosis-inducing factor) processes. This study demonstrates that excessive activation of MMP-9 is deleterious to the immature brain, which is associated with the degree of BBB leakage and inflammation. In contrast, apoptosis does not appear to be a major contributing factor.

Key words: neonatal; inflammation; cerebral palsy; apoptosis; caspase; extracellular matrix

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Received Oct. 9, 2006; revised Dec. 18, 2006; accepted Jan. 2, 2007.

Correspondence should be addressed to Dr. Carina Mallard, Perinatal Center, Department of Neuroscience and Physiology, Sahlgrenska Academy, Göteborg University, P.O. Box 432, 405 30 Göteborg, Sweden. Email: carina.mallard{at}gu.se

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