title: Prevention of in vivo excitotoxicity by a family of trialkylglycines, a novel class of neuroprotectants.
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 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 Ca(2+), or affect the glutamate-nitric oxide-cGMP pathway. Intraperitoneal injection of both peptoids in mice attenuated > or = 80% ammonia-induced, NMDA receptor-mediated animal death. Furthermore, these two molecules reduced by > or = 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.
authors.affiliation: Laboratory of Neurobiology, Instituto de Investigaciones Citológicas, Fundación Valenciana de investigaciones Biomedicas, Valencia, Spain.
authors.forename: Carmina
authors.initials: C
authors.lastname: Montoliu
authors.forename: Marc
authors.initials: M
authors.lastname: Humet
authors.forename: Juan-José
authors.initials: JJ
authors.lastname: Canales
authors.forename: Jozef
authors.initials: J
authors.lastname: Burda
authors.forename: Rosa
authors.initials: R
authors.lastname: Planells-Cases
authors.forename: Francisco
authors.initials: F
authors.lastname: Sánchez-Baeza
authors.forename: Teresa
authors.initials: T
authors.lastname: Carbonell
authors.forename: Enrique
authors.initials: E
authors.lastname: Pérez-Payá
authors.forename: Angel
authors.initials: A
authors.lastname: Messeguer
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferrer-Montiel
authors.forename: Vicente
authors.initials: V
authors.lastname: Felipo
mesh_terms: D000641:Ammonia / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D020650:Combinatorial Chemistry Techniques; D006152:Cyclic GMP / Q000096:biosynthesis; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D018846:Excitatory Amino Acids / Q000138:chemical synthesis / Q000633:toxicity*; D018698:Glutamic Acid / Q000633:toxicity; D007274:Injections, Intraperitoneal; D051379:Mice; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009842:Oligopeptides / Q000627:therapeutic use*; D034444:Peptoids; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D016622:Silver Staining
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018846:Excitatory Amino Acids; D018696:Neuroprotective Agents; D009842:Oligopeptides; D034444:Peptoids; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D000641:Ammonia; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D006152:Cyclic GMP; D002118:Calcium