Neuronal death enhanced by N-methyl-D-aspartate antagonists.
Glutamate promotes neuronal survival during brain development and destroys neurons after injuries in the mature brain. Glutamate antagonists are in human clinical trials aiming to demonstrate limitation of neuronal injury after head trauma, which consists of both rapid and slowly progressing neurodegeneration. Furthermore, glutamate antagonists are considered for neuroprotection in chronic neurodegenerative disorders with slowly progressing cell death only. Therefore, humans suffering from Huntington's disease, characterized by slowly progressing neurodegeneration of the basal ganglia, are subjected to trials with glutamate antagonists. Here we demonstrate that progressive neurodegeneration in the basal ganglia induced by the mitochondrial toxin 3-nitropropionate or in the hippocampus by traumatic brain injury is enhanced by N-methyl-d-aspartate antagonists but ameliorated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate antagonists. These observations reveal that N-methyl-d-aspartate antagonists may increase neurodestruction in mature brain undergoing slowly progressing neurodegeneration, whereas blockade of the action of glutamate at alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors may be neuroprotective.
Ikonomidou
C
C
Department of Pediatric Neurology, Children's Hospital, Charité-Virchow Clinics, Humboldt University, Augustenburger Platz 1, D-13353 Berlin, Germany. hrissanthi.ikonomidou@charite.de
Stefovska
V
V
Turski
L
L
D000818:Animals; D001930:Brain Injuries / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008559:Memantine / Q000494:pharmacology; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology; D009574:Nitro Compounds; D010879:Piperazines / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014947:Wounds and Injuries; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000037:antagonists & inhibitors
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009574:Nitro Compounds; D010879:Piperazines; D011422:Propionates; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; C015392:3-nitropropionic acid; D008559:Memantine