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The Journal of Neuroscience, January 1, 1998, 18(1):147-155

Response of Postmitotic Neurons to X-Irradiation: Implications for the Role of DNA Damage in Neuronal Apoptosis

Glenn T. Gobbel^{1, 2}, Mattia Bellinzona¹, Axel R. Vogt², Nalin Gupta¹, John R. Fike¹, and Pak H. Chan^{1, 2}

Brain Tumor Research Center and CNS Injury and Brain Edema Research Center, Departments of ¹ Neurological Surgery and ² Neurology, University of California, San Francisco, California 94143

The molecular changes responsible for inducing neuronal apoptosis are unknown. Rat cortical neurons were treated with x-irradiation 7 d after isolation to test for the role of DNA damage in neuronal death. The response of neurons to x-irradiation was compared with that of astrocytes that had been isolated 3 weeks earlier from newborn rats. At the time of irradiation, the neurons appeared well differentiated morphologically and were predominantly (90-95%) noncycling, based on flow cytometric analysis. There was a similar, linear increase in DNA double-strand breaks with increasing radiation dose in neurons and astrocytes. However, whereas doses as low as 2 Gy induced typical apoptotic changes in neurons, including nuclear fragmentation and/or internucleosomal DNA fragmentation, doses as high as 32 Gy caused little or no apoptosis in astrocytes. Radiation-induced apoptosis of neurons started 4-8 hr after irradiation, was maximal at 12 hr, and was dependent on dose up to 16 Gy. It was prevented when cycloheximide, a protein synthesis inhibitor, was added up to 6 hr after irradiation. In addition to their distinct apoptotic response, neurons rejoined radiation-induced DNA double-strand breaks more slowly than astrocytes. Treatment with benzamide to inhibit ADP-ribosylation and strand break repair increased apoptosis; splitting the dose of radiation to allow increased time for DNA repair decreased apoptosis. These data suggest that DNA damage may induce neuronal apoptosis, that the extent of damage may determine the degree of apoptosis induced, and that slow repair of damage may play a role in the susceptibility of neurons to apoptosis.

Key words: rat; neuron; astrocyte; ADP-ribosylation; benzamide; DNA damage; apoptosis; x-irradiation

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Copyright © 1998 Society for Neuroscience  0270-6474/98/181147-09$05.00/0

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