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Research ArticleNEUROPHARMACOLOGY

Prevention of in Vivo Excitotoxicity by a Family of Trialkylglycines, a Novel Class of Neuroprotectants

Carmina Montoliu, Marc Humet, Juan-José Canales, Jozef Burda, Rosa Planells-Cases, Francisco Sánchez-Baeza, Teresa Carbonell, Enrique Pérez-Payá, Angel Messeguer, Antonio Ferrer-Montiel and Vicente Felipo
Journal of Pharmacology and Experimental Therapeutics April 2002, 301 (1) 29-36; DOI: https://doi.org/10.1124/jpet.301.1.29
Carmina Montoliu
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Marc Humet
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Juan-José Canales
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Jozef Burda
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Rosa Planells-Cases
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Francisco Sánchez-Baeza
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Teresa Carbonell
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Enrique Pérez-Payá
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Angel Messeguer
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Antonio Ferrer-Montiel
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Vicente Felipo
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Abstract

Excitotoxicity has been implicated in the etiology of ischemic stroke and chronic neurodegenerative disorders. Hence, the development of novel neuroprotectant molecules that ameliorate excitotoxic brain damage is vigorously pursued. We used a neuroprotection-based cellular assay to screen a synthetic combinatorial library ofN-alkylglycine trimers. Two compounds (6-1-2 and 6-1-10) that efficiently prevented excitotoxic neurodegeneration in vitro and in vivo were identified. Both molecules protected primary cultures of cerebellar neurons against glutamate-induced neuronal death with an efficiency equivalent toN-methyl-d-aspartate (NMDA) receptor antagonists. These trialkylglycines did not block appreciably the NMDA receptor channel, or attenuated glutamate-induced increase of Ca2+, or affect the glutamate-nitric oxide-cGMP pathway. Intraperitoneal injection of both peptoids in mice attenuated ≥80% ammonia-induced, NMDA receptor-mediated animal death. Furthermore, these two molecules reduced by ≥50% the neurodegeneration in striatum in a rat model of cerebral ischemia. Neuroprotection against ischemia was associated with decreased activation of caspase-3, reflecting prevention of apoptotic neuronal death. Collectively, the results reported indicate that these trialkylglycines are new neuroprotectant leads with important in vivo activity against excitotoxicity, and that they act on a novel, yet-unrecognized cellular target. These lead compounds may become tolerated drugs for the treatment of acute and chronic neurodegenerative diseases with fewer side effects than NMDA receptor antagonists.

Footnotes

  • This study was supported in part by grants from FundacióLa Marató de TV3 (to V.F and A.M); Grants PM98-0065, PM99-0018, and SAF97-0001 of the Ministerio de Educación y Ciencia and of Plan Nacional de I + D of Spain (to V.F.); grants from the Comisión Interministerial de Ciencia y Tecnologı́a and the European Commission (1FD97-0662-C02-01) (to A.F.-M. and E.P.-P.) and La Fundación La Caixa (98/027-00) (to A.F.-M.); and from Comisión Interministerial de Ciencia y Tecnologı́a (SAF98-0059) (to A.M.). J.J.-C. has a Contrato de Reincorporación of the Ministerio de Educación, Cultura y Deporte of Spain.

  • Abbreviations:
    NMDA
    N-methyl-d-aspartate
    MK-801
    (SR,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate
    • Received September 10, 2001.
    • Accepted December 13, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 1
1 Apr 2002
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Research ArticleNEUROPHARMACOLOGY

Prevention of in Vivo Excitotoxicity by a Family of Trialkylglycines, a Novel Class of Neuroprotectants

Carmina Montoliu, Marc Humet, Juan-José Canales, Jozef Burda, Rosa Planells-Cases, Francisco Sánchez-Baeza, Teresa Carbonell, Enrique Pérez-Payá, Angel Messeguer, Antonio Ferrer-Montiel and Vicente Felipo
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 29-36; DOI: https://doi.org/10.1124/jpet.301.1.29

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Research ArticleNEUROPHARMACOLOGY

Prevention of in Vivo Excitotoxicity by a Family of Trialkylglycines, a Novel Class of Neuroprotectants

Carmina Montoliu, Marc Humet, Juan-José Canales, Jozef Burda, Rosa Planells-Cases, Francisco Sánchez-Baeza, Teresa Carbonell, Enrique Pérez-Payá, Angel Messeguer, Antonio Ferrer-Montiel and Vicente Felipo
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 29-36; DOI: https://doi.org/10.1124/jpet.301.1.29
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