title: Non-conventional apoptotic response to ionising radiation mediated by             N-methyl D-aspartate receptors in immature neuronal cells.
abstract: During cortical development, N-methyl D-aspartate (NMDA) receptors are highly             involved in neuronal maturation and synapse establishment. Their implication in             the phenomenon of excitotoxicity has been extensively described in several neurodegenerative             diseases due to the permissive entry of Ca2+ ions and massive accumulation in             the intracellular compartment, which is highly toxic to cells. Ionising radiation             is also a source of stress to the cells, particularly immature neurons. Their             capacity to induce cell death has been described for various cell types either             by directly damaging the DNA or indirectly through the generation of reactive             oxygen species responsible for the activation of a battery of stress response             effectors leading in certain cases, to cell death. In this study, in order to             determine whether a link exists between NMDA receptors-mediated excitotoxicity             and radiation-induced cell death, we evaluated radiation-induced cell death in vitro             and in vivo in maturing neurons during the fetal period. Cell death induction             was assessed by TUNEL, caspase-3 activity and DNA ladder assays, with or without             the administration of dizocilpine (MK-801), a non-competitive NMDA receptor antagonist             which blocks neuronal Ca2+ influx. To further investigate the possible involvement             of Ca2+-dependent enzyme activation, known to occur at high Ca2+ concentrations,             we examined the protective effect of a calpain inhibitor on cell death induced             by radiation. Doses ranging from 0.2 to 0.6 Gy of X-rays elicited a clear apoptotic             response that was prevented by the injection of dizocilpine (MK-801) or calpain             inhibitor. These data demonstrate the involvement of NMDA receptors in radiation-induced             neuronal death by the activation of downstream effectors, including calpain-related             pathways. An increased apoptotic process elicited by radiation, occurring independently             of the normal developmental scheme, may eliminate post-mitotic but immature neuronal             cells and deeply impair the establishment of the neuronal network, which in the             case of cortical development is critical for cognitive capacities.
authors: Radiobiology Unit, Molecular and Cellular Biology Expert Group,                     Institute for Environment, Health and Safety, Belgian Nuclear Research                     Centre, SCK•CEN, B-2400 Mol, Belgium.
authors: Nada
authors: N
authors: Samari
authors: Louis
authors: L
authors: De Saint-Georges
authors: Giuseppe
authors: G
authors: Pani
authors: Sarah
authors: S
authors: Baatout
authors: Luc
authors: L
authors: Leyns
authors: Mohammed Abderrafi
authors: MA
authors: Benotmane
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects*; D001921:Brain / Q000528:radiation effects*; D002154:Calpain / Q000378:metabolism; D053148:Caspase 3 / Q000032:analysis; D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000528:radiation effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D006023:Glycoproteins / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D011839:Radiation, Ionizing; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: D006023:Glycoproteins; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; C039304:calpain inhibitors; D016291:Dizocilpine Maleate; D002154:Calpain; D053148:Caspase 3