Radiosensitivity of the developing central nervous system: an important question in radiation protection

The high radiosensitivity of the human developing brain has been demonstrated by epidemiological data . The maximal incidence of microcephaly and mental retardation in the Hiroshima and Nagasaki cohort was observed among survivors exposed between 8 and 15 weeks of gestation. Experimental studies indicate that this period corresponds to gestational days (g.d.) 14-18 in the rat. Apoptosis, the typical mode of radiation-induced cell death in developing Central Nervous System (CNS), is closely related with the oxidative status. Enhanced radiation-induced generation of reactive oxygen and nitrogen species (ROS/RNS) has been observed after low-dose radiation exposure, leading to the amplification of signal transduction and further molecular and cellular radiation-responses. This study is an attempt to address the participation of ROS/RNS in the early radiation-induced apoptosis of neural cortical precursors. Cortical cells obtained from Wistar rat fetuses at 17 g.d. were irradiated with a dose of 2 Gy at a dose-rate of 0.3 Gy/minute. Nitric oxide (NO) content estimated by measuring the stable products NO2 and NO3 released to the culture medium, has shown a time-dependent accumulation from 30 min post-irradiation (pi). ROS/RNS content was determined by luminol-dependent chemiluminescence. A significant decrease of chemiluminescence was evident 30 min pi, reaching basal levels at 120 min, followed by an important augmentation by 4 hs after irradiation. The early decrease in ROS/RNS was not observed in samples irradiated in the presence of L-NAME, an inhibitor of nitric oxide synthase. Incubations with superoxide dismutase (SOD) and catalase (CAT) decreased significantly the chemiluminescence in irradiated samples. Apoptotic cell death, already evident from 4 hs pi., was significantly increased in irradiated cells after incubation with L-NAME. We conclude that ROS/RNS play a pivotal role in the early signaling pathway leading to a radiation-induced cell death of cortical precursors. (author)