期刊
NEURO-ONCOLOGY
卷 13, 期 5, 页码 459-470出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/neuonc/nor016
关键词
cranial irradiation; DNA damage and repair; GSK3; neuroprotection; nonhomologous end joining
资金
- Radiological Society of North America [RR0813]
- Vanderbilt Institute for Clinical and Translational Research
- CTSA [UL1RR024975]
- University of Alabama-Birmingham School of Medicine
Prevention of cranial radiation-induced morbidity following the treatment of primary and metastatic brain cancers, including long-term neurocognitive deficiencies, remains challenging. Previously, we have shown that inhibition of glycogen synthase kinase 3 beta (GSK3 beta) results in protection of hippocampal neurons from radiation (IR)-induced apoptosis and attenuation of neurocognitive dysfunction resulting from cranial IR. In this study, we examined whether regulation of the repair of IR-induced DNA damage is one of the mechanisms involved in the radioprotective effects of neurons by inhibition of GSK3 beta. Specifically, this study showed that inhibition of GSK3 beta accelerated double strand-break (DSB) repair efficiency in irradiated mouse hippocampal neurons, as assessed by the neutral comet assay. This coincided with attenuation of IR-induced gamma-H2AX foci, a well characterized in situ marker of DSBs. To confirm the effect of GSK3 activity on the efficacy of DSB repair, we further demonstrated that biochemical or genetic inhibition of GSK3 activity resulted in enhanced capacity in nonhomologous end-joining mediated repair of DSBs in hippocampal neurons. Importantly, none of these effects were observed in malignant glioma cells. Taken together, these results suggested that enhanced repair of IR-induced DNA damage may be a novel mechanism by which inhibition of GSK3 beta specifically protects hippocampal neurons from IR-induced apoptosis. Furthermore, these findings warrant future investigations of the molecular mechanisms underlying the role of GSK3 beta in the DSB repair of normal neurons and the potential clinical application of neuroprotection with GSK3 beta inhibitors during cranial IR.
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