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2,7-Bis-(4-amidinobenzylidene)-cycloheptan-1-one dihydrochloride, tPA stop, prevents tPA-enhanced excitotoxicity both in vitro and in vivo.
J Cereb Blood Flow Metab. 2004 Oct; 24(10):1153-9.JC

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.

Authors+Show Affiliations

Université de Caen, Center Cyceron, Caen Cedex, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15529015

Citation

Liot, Géraldine, et al. "2,7-Bis-(4-amidinobenzylidene)-cycloheptan-1-one Dihydrochloride, tPA Stop, Prevents tPA-enhanced Excitotoxicity Both in Vitro and in Vivo." Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, vol. 24, no. 10, 2004, pp. 1153-9.
Liot G, Benchenane K, Léveillé F, et al. 2,7-Bis-(4-amidinobenzylidene)-cycloheptan-1-one dihydrochloride, tPA stop, prevents tPA-enhanced excitotoxicity both in vitro and in vivo. J Cereb Blood Flow Metab. 2004;24(10):1153-9.
Liot, G., Benchenane, K., Léveillé, F., López-Atalaya, J. P., Fernández-Monreal, M., Ruocco, A., Mackenzie, E. T., Buisson, A., Ali, C., & Vivien, D. (2004). 2,7-Bis-(4-amidinobenzylidene)-cycloheptan-1-one dihydrochloride, tPA stop, prevents tPA-enhanced excitotoxicity both in vitro and in vivo. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 24(10), 1153-9.
Liot G, et al. 2,7-Bis-(4-amidinobenzylidene)-cycloheptan-1-one Dihydrochloride, tPA Stop, Prevents tPA-enhanced Excitotoxicity Both in Vitro and in Vivo. J Cereb Blood Flow Metab. 2004;24(10):1153-9. PubMed PMID: 15529015.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 2,7-Bis-(4-amidinobenzylidene)-cycloheptan-1-one dihydrochloride, tPA stop, prevents tPA-enhanced excitotoxicity both in vitro and in vivo. AU - Liot,Géraldine, AU - Benchenane,Karim, AU - Léveillé,Frédéric, AU - López-Atalaya,José P, AU - Fernández-Monreal,Mónica, AU - Ruocco,Antonio, AU - Mackenzie,Eric T, AU - Buisson,Alain, AU - Ali,Carine, AU - Vivien,Denis, PY - 2004/11/6/pubmed PY - 2004/12/16/medline PY - 2004/11/6/entrez SP - 1153 EP - 9 JF - Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism JO - J Cereb Blood Flow Metab VL - 24 IS - 10 N2 - 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. SN - 0271-678X UR - https://www.unboundmedicine.com/medline/citation/15529015/27_Bis__4_amidinobenzylidene__cycloheptan_1_one_dihydrochloride_tPA_stop_prevents_tPA_enhanced_excitotoxicity_both_in_vitro_and_in_vivo_ L2 - https://journals.sagepub.com/doi/10.1097/01.WCB.0000134476.93809.75?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -