RT Journal Article
SR Electronic
T1 Matrix Metalloproteinase-9 Gene Knock-out Protects the Immature Brain after Cerebral Hypoxia–Ischemia
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 1511
OP 1518
DO 10.1523/JNEUROSCI.4391-06.2007
VO 27
IS 7
A1 Svedin, Pernilla
A1 Hagberg, Henrik
A1 Sävman, Karin
A1 Zhu, Changlian
A1 Mallard, Carina
YR 2007
UL http://www.jneurosci.org/content/27/7/1511.abstract
AB 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.