Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury

被引:311
作者
Wang, XY
Jung, JC
Asahi, M
Chwang, W
Russo, L
Moskowitz, MA
Dixon, CE
Fini, ME
Lo, EH
机构
[1] Massachusetts Gen Hosp, Dept Neurol, Neuroprotect Res Lab, Charlestown, MA 02129 USA
[2] Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, Charlestown, MA 02129 USA
[3] Harvard Univ, Sch Med, Program Neurosci, Charlestown, MA 02129 USA
[4] Tufts Univ, Sch Med, New England Eye Ctr, Vis Res Labs, Boston, MA 02111 USA
[5] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Stroke & Neurovasc Regulat Lab, Charlestown, MA USA
[6] Univ Pittsburgh, Dept Neurol Surg, Brain Trauma Res Ctr, Pittsburgh, PA 15260 USA
关键词
brain trauma; controlled cortical impact; extracellular matrix; proteolysis; neurodegeneration; mouse;
D O I
10.1523/JNEUROSCI.20-18-07037.2000
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Matrix metalloproteinases (MMPs) belong to a class of extracellular proteinases responsible for maintaining and remodeling the extracellular matrix. In addition to multiple functions in normal physiology, abnormal MMP expression and activity may also participate in the pathophysiology of cerebral disease. Here, we show that MMP-9 (gelatinase B; EC. 3.4.24.35) contributes to the pathophysiology of traumatic brain injury. After controlled cortical impact in mice, MMP-9 was increased in traumatized brain. Total MMP-9 levels at 24 hr were significantly increased as measured by a substrate cleavage assay. Zymograms showed that MMP-9 was elevated as early as 3 hr after traumatic brain injury, reaching a maximum at aproximate 24 hr. Increased MMP-9 levels persisted for up to 1 week. Western blot analysis indicated increased profiles of MMP-9 expression that corresponded with the zymographic data. Knock-out mice deficient in MMP-9 gene expression were compared with wild-type littermates in terms of morphological and motor outcomes after trauma. Motor outcomes were measured at 1, 2, and 7 d after traumatic brain injury by the use of a rotarod device. MMP-9 knock-out mice had less motor deficits than wild-type mice. At 7 d, traumatic brain lesion volumes on Nissl-stained histological sections were significantly smaller in MMP-9 knock-out mice. These data demonstrate that MMP-9 contributes to the pathophysiology of traumatic brain injury and suggest that interruption of the MMP proteolytic cascade may be a possible therapeutic approach for preventing the secondary progression of damage after brain trauma.
引用
收藏
页码:7037 / 7042
页数:6
相关论文
共 54 条
  • [1] The role of inflammation and cytokines in brain injury
    Arvin, B
    Neville, LF
    Barone, FC
    Feuerstein, GZ
    [J]. NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS, 1996, 20 (03) : 445 - 452
  • [2] Bethea JR, 1998, J NEUROSCI, V18, P3251
  • [3] REGIONAL CEREBRAL BLOOD-FLOW AFTER CONTROLLED CORTICAL IMPACT INJURY IN RATS
    BRYAN, RM
    CHERIAN, L
    ROBERTSON, C
    [J]. ANESTHESIA AND ANALGESIA, 1995, 80 (04) : 687 - 695
  • [4] Expression of endothelial adhesion molecules and recruitment of neutrophils after traumatic brain injury in rats
    Carlos, TM
    Clark, RSB
    FranicolaHiggins, D
    Schiding, JK
    Kochanekt, PM
    [J]. JOURNAL OF LEUKOCYTE BIOLOGY, 1997, 61 (03) : 279 - 285
  • [5] Importance of posttraumatic hypothermia and hyperthermia on the inflammatory response after fluid percussion brain injury: Biochemical and immunocytochemical studies
    Chatzipanteli, K
    Alonso, OF
    Kraydieh, S
    Dietrich, WD
    [J]. JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2000, 20 (03) : 531 - 542
  • [6] Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin
    Chen, ZL
    Strickland, S
    [J]. CELL, 1997, 91 (07) : 917 - 925
  • [7] Clark RSB, 1997, J NEUROSCI, V17, P9172
  • [8] Apoptotic morphology of dentate gyrus granule cells following experimental cortical impact injury in rats: Possible role in spatial memory deficits
    Colicos, MA
    Dash, PK
    [J]. BRAIN RESEARCH, 1996, 739 (1-2) : 120 - 131
  • [9] Conti AC, 1998, J NEUROSCI, V18, P5663
  • [10] Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys
    Crowe, MJ
    Bresnahan, JC
    Shuman, SL
    Masters, JN
    Beattie, MS
    [J]. NATURE MEDICINE, 1997, 3 (01) : 73 - 76