TY - JOUR T1 - Prevention of in Vivo Excitotoxicity by a Family of Trialkylglycines, a Novel Class of Neuroprotectants JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 29 LP - 36 DO - 10.1124/jpet.301.1.29 VL - 301 IS - 1 AU - Carmina Montoliu AU - Marc Humet AU - Juan-José Canales AU - Jozef Burda AU - Rosa Planells-Cases AU - Francisco Sánchez-Baeza AU - Teresa Carbonell AU - Enrique Pérez-Payá AU - Angel Messeguer AU - Antonio Ferrer-Montiel AU - Vicente Felipo Y1 - 2002/04/01 UR - http://jpet.aspetjournals.org/content/301/1/29.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -