Matrix metalloproteinase-9 gene knock-out protects the immature brain after cerebral hypoxia-ischemia.
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 degrees 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.
Svedin
Pernilla
P
Department of Neuroscience and Physiology, Perinatal Center, Sahlgrenska Academy, Göteborg University, 405 30 Göteborg, Sweden.
Hagberg
Henrik
H
Sävman
Karin
K
Zhu
Changlian
C
Mallard
Carina
C
D000818:Animals; D000831:Animals, Newborn; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000503:physiopathology; D001921:Brain / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D045304:Cytochromes c / Q000378:metabolism; D004660:Encephalitis / Q000209:etiology / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D007150:Immunohistochemistry / Q000379:methods; D007211:Indoles; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D004676:Myelin Basic Protein / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D018709:Statistics, Nonparametric; D013997:Time Factors
D051033:Apoptosis Inducing Factor; D007211:Indoles; D004676:Myelin Basic Protein; D016900:Neurofilament Proteins; D012333:RNA, Messenger; C007293:DAPI; D045304:Cytochromes c; D053148:Caspase 3; D020780:Matrix Metalloproteinase 9