Abstract |
Tissue-type plasminogen activator (tPA) is available for the treatment of thromboembolic stroke in humans. However, adverse effects of tPA have been observed in animal models of ischemic brain injuries. In the present study, we have used a synthetic tPA inhibitor, named 2,7-bis-(4-amidino-benzylidene)-cycloheptan-1-one dihydrochloride ( tPA stop), to investigate the role of endogenous tPA in the cerebral parenchyma. In mouse cortical cell cultures, we observed that although tPA stop reduced N-methyl-D-aspartic acid ( NMDA)-mediated excitotoxic neuronal death, it failed to modulate alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazole propanoic acid or kainate-mediated necrosis. In addition, we found that tPA stop could prevent the deleterious effects of both endogenous and exogenous tPA during NMDA exposure. At the functional level, tPA stop was found to prevent tPA-dependent potentiation of NMDA receptor-evoked calcium influx. The relevance of those findings was strengthened by the observation of a massive reduction of NMDA-induced excitotoxic lesion in rats when tPA stop was co-injected. Altogether, these data demonstrate that the blockade of the endogenous proteolytic activity of tPA in the cerebral parenchyma could be a powerful neuroprotective strategy raised against brain pathologies associated with excitotoxicity.
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Authors | Géraldine Liot, Karim Benchenane, Frédéric Léveillé, José P López-Atalaya, Mónica Fernández-Monreal, Antonio Ruocco, Eric T Mackenzie, Alain Buisson, Carine Ali, Denis Vivien |
Journal | Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
(J Cereb Blood Flow Metab)
Vol. 24
Issue 10
Pg. 1153-9
(Oct 2004)
ISSN: 0271-678X [Print] United States |
PMID | 15529015
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cycloheptanes
- Excitatory Amino Acid Agonists
- Neurotoxins
- Serine Proteinase Inhibitors
- tPA stop
- N-Methylaspartate
- Tissue Plasminogen Activator
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Topics |
- Animals
- Brain Ischemia
(drug therapy, metabolism)
- Cell Death
(drug effects, physiology)
- Cells, Cultured
- Cycloheptanes
- Excitatory Amino Acid Agonists
(toxicity)
- In Vitro Techniques
- Male
- Mice
- N-Methylaspartate
(toxicity)
- Neurons
(cytology)
- Neurotoxins
(toxicity)
- Rats
- Rats, Sprague-Dawley
- Serine Proteinase Inhibitors
(pharmacology)
- Signal Transduction
(drug effects, physiology)
- Tissue Plasminogen Activator
(antagonists & inhibitors, metabolism)
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