Reduction of hippocampal cell death and proteolytic responses in tissue plasminogen activator knockout mice after transient global cerebral ischemia

S. R. Lee, J. Lok, A. Rosell, H. Y. Kim, Y. Murata, D. Atochin, P. L. Huang, X. Wang, C. Ayata, M. A. Moskowitz, E. H. Lo

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Knockout mice deficient in tissue plasminogen activator (tPA) are protected against hippocampal excitotoxicity. But it is unknown whether similar neuroprotection occurs after transient global cerebral ischemia, which is known to selectively affect the hippocampus. In this study, we tested the hypothesis that hippocampal cell death in tPA knockout mice would be reduced after transient global cerebral ischemia, and this neuroprotection would occur concomitantly with amelioration of both intra- and extracellular proteolytic cascades. Wild-type and tPA knockout mice were subjected to 20 min of transient bilateral occlusions of the common carotid arteries. Three days later, Nissl and terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling staining demonstrated that hippocampal cell death was significantly reduced in tPA knockout brains compared with wild-type brains. Caspase-3 and the two major brain gelatinases (matrix metalloproteinase (MMP)-9 and MMP-2) were assessed as representative measurements of intra- and extracellular proteolysis. Post-ischemic levels of caspase-3, MMP-9 and MMP-2 were similarly reduced in tPA knockouts compared with wild-type hippocampi. Taken together, these data suggest that endogenous tPA contributes to hippocampal injury after cerebral ischemia, and these pathophysiologic pathways may involve links to aberrant activation of caspases and MMPs.

Original languageEnglish
Pages (from-to)50-57
Number of pages8
JournalNeuroscience
Volume150
Issue number1
DOIs
Publication statusPublished - 30 Nov 2007
Externally publishedYes

Fingerprint

Transient Ischemic Attack
Tissue Plasminogen Activator
Knockout Mice
Cell Death
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Caspase 3
Hippocampus
Brain
Gelatinases
DNA Nucleotidylexotransferase
Common Carotid Artery
Biotin
Caspases
Brain Ischemia
Matrix Metalloproteinases
Proteolysis
Staining and Labeling
Wounds and Injuries

Keywords

  • anoikis
  • caspase
  • excitotoxicity
  • matrix metalloproteinase
  • neuron

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Reduction of hippocampal cell death and proteolytic responses in tissue plasminogen activator knockout mice after transient global cerebral ischemia. / Lee, S. R.; Lok, J.; Rosell, A.; Kim, H. Y.; Murata, Y.; Atochin, D.; Huang, P. L.; Wang, X.; Ayata, C.; Moskowitz, M. A.; Lo, E. H.

In: Neuroscience, Vol. 150, No. 1, 30.11.2007, p. 50-57.

Research output: Contribution to journalArticle

Lee, S. R. ; Lok, J. ; Rosell, A. ; Kim, H. Y. ; Murata, Y. ; Atochin, D. ; Huang, P. L. ; Wang, X. ; Ayata, C. ; Moskowitz, M. A. ; Lo, E. H. / Reduction of hippocampal cell death and proteolytic responses in tissue plasminogen activator knockout mice after transient global cerebral ischemia. In: Neuroscience. 2007 ; Vol. 150, No. 1. pp. 50-57.
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