TIMP-1 attenuates blood-brain barrier permeability in mice with acute liver failure

Feng Chen, Evette S. Radisky, Pritam Das, Jyotica Batra, Toshiyuki Hata, Tomohide Hori, Ann Marie T. Baine, Lindsay Gardner, Mei Y. Yue, Guojun Bu, Gregory Del Zoppo, Tushar C. Patel, Justin H. Nguyen

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Blood-brain barrier (BBB) dysfunction in acute liver failure (ALF) results in increased BBB permeability that often precludes the patients from obtaining a life-saving liver transplantation. It remains controversial whether matrix metalloproteinase-9 (MMP-9) from the injured liver contributes to the deregulation of BBB function in ALF. We selectively upregulated a physiologic inhibitor of MMP-9 (TIMP-1) with a single intracerebroventricular injection of TIMP-1 cDNA plasmids at 48 and 72 hours, or with pegylated-TIMP-1 protein. Acute liver failure was induced with tumor necrosis factor-α and D-(+)-galactosamine in mice. Permeability of BBB was assessed with sodium fluorescein (NaF) extravasation. We found a significant increase in TIMP-1 within the central nervous system (CNS) after the administration of TIMP-1 cDNA plasmids and that increased TIMP-1 within the CNS resulted in an attenuation of BBB permeability, a reduction in activation of epidermal growth factor receptor and p38 mitogen-activated protein kinase signals, and a restoration of the tight junction protein occludin in mice with experimental ALF. Pegylated TIMP-1 provided similar protection against BBB permeability in mice with ALF. Our results provided a proof of principle that MMP-9 contributes to the BBB dysfunction in ALF and suggests a potential therapeutic role of TIMP-1 in ALF.

Original languageEnglish (US)
Pages (from-to)1041-1049
Number of pages9
JournalJournal of Cerebral Blood Flow and Metabolism
Issue number7
StatePublished - Jul 2013


  • BBB permeability
  • TIMP-1
  • acute liver failure
  • tight junction

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine


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