Journal
NEUROSCIENCE
Volume 150, Issue 1, Pages 50-57Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2007.06.029
Keywords
excitotoxicity; anolkis; neuron; caspase; matrix metalloproteinase
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Funding
- NINDS NIH HHS [R01-NS48422, R01-NS40529, R01-NS37074, P50-NS10828, R01 NS033335-13, R01 NS048426, R01 NS048426-04, R01-NS56458, R01 NS056458, R01 NS040529, R01 NS033335, P50 NS010828-320037, P50 NS010828, R01 NS048422, R01 NS037074] Funding Source: Medline
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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 wildtype 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. (c) 2007 IBRO. Published by Elsevier Ltd. All rights reserved.
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