Vol. 301, Issue 1, 29-36, April 2002

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

Laboratory of Neurobiology, Instituto de Investigaciones Citológicas, Fundación Valenciana de investigaciones Biomedicas, Valencia, Spain (C.M., J.-J.C., J.B., V.F.); Institut d'Investigacions Químiques i Ambientals de Barcelona, Consejo Superior de Investigaciones Cientificas, Barcelona, Spain (M.H., F.S.-B., A.M.); Centro de Biología Molecular y Celular, Universidad Miguel Hernández, Alicante, Spain (R.P.-C., A.F.-M.); and Departamento de Bioquímica y Biología Molecular, Universidad de Valencia, Valencia, Spain (T.C., E.P.-P.)

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 of N-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 to N-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.