Doxycycline inhibits matrix metalloproteinase-9 and laminin degradation after transient global cerebral ischemia

Neurobiol Dis. 2009 May;34(2):189-98. doi: 10.1016/j.nbd.2008.12.012. Epub 2009 Jan 6.

Abstract

Doxycycline, a tetracycline antibiotic inhibits matrix metalloproteinase (MMP) and reduces neuronal damage in focal brain ischemia. This study was undertaken to assess if doxycycline reduces delayed neuronal damage following transient global cerebral ischemia through MMP inhibition. C57BL/6 mice were subjected to 20 min global cerebral ischemia. Doxycycline was administered to mice 30 min before and 2 h after ischemia. In TUNEL assay, damaged neurons were also apparent in the CA1 and CA2 areas and doxycycline reduced TUNEL-positive neurons. Gelatin gel and in situ zymography showed upregulation of gelatinase activity after ischemia. Doxycycline significantly inhibited MMP-9 activity in gel zymography and also suppressed in situ gelatinase activity. Laminin degradation was remarkable in CA1 and CA2 areas after ischemia and doxycycline reduced the laminin degradation and neuronal loss. Our data suggest that doxycycline may provide a neuroprotection against global cerebral ischemia since it reduces perineuronal laminin degradation by inhibiting MMP-9 activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / metabolism
  • Brain Ischemia / physiopathology
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cerebral Infarction / drug therapy
  • Cerebral Infarction / metabolism
  • Cerebral Infarction / physiopathology
  • Cytoprotection / drug effects
  • Cytoprotection / physiology
  • Disease Models, Animal
  • Doxycycline / pharmacology*
  • Doxycycline / therapeutic use
  • Drug Administration Schedule
  • In Situ Nick-End Labeling
  • Laminin / drug effects*
  • Laminin / metabolism
  • Matrix Metalloproteinase 2 / drug effects
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors*
  • Mice
  • Mice, Inbred C57BL
  • Nerve Degeneration / drug therapy*
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / physiopathology
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Treatment Outcome

Substances

  • Anti-Bacterial Agents
  • Laminin
  • Matrix Metalloproteinase Inhibitors
  • Neuroprotective Agents
  • Matrix Metalloproteinase 2
  • Mmp2 protein, mouse
  • Matrix Metalloproteinase 9
  • Doxycycline