Abstract
BACKGROUND: Patients with primary and metastatic brain tumors that survive may experience cognitive problems including progressive impairments in memory, attention, and executive function attributed to radiation-induced brain injury. Irradiation is known to bring tumor cells into senescence, a state of permanent proliferation arrest that is accompanied by metabolic changes and a secretory phenotype, which may cause inflammation. We hypothesize that senescence in the healthy brain, caused by whole brain radiotherapy (WBRT), plays an important role in cognitive problems. MATERIAL AND METHODS: In this pilot experiment the effect of three different dosages (12, 30 and 60 Gy) of fractionated WBRT was assessed at different intervals after irradiation using male C57BL/6JRj mice. We performed senescence associated β-glucosidase (SA-β-gal) staining, cytokine ELISA assays, RT-qPCRs and immunohistochemistry to identify cellular senescence in the healthy brain. RESULTS: Unexpectedly, no clear indications of induced cellular senescence in the brain could be observed by assessing SA-β-gal, cytokines and senescence markers on RNA and protein level. However, we found persistent DNA damage foci, microglial activation, a reduction in oligodendrocyte precursor cells and neurogenesis in the subvertricular zone. CONCLUSION: No clear evidence for cellular senescence after WBRT was detected in the mouse brain, whereas profound effects were found on glia, neurogenesis and DNA damage. Difficulties in detecting cellular senescence might be explained by differences in presence of so-called markers for cellular senescence in the brain, or the rare nature of senescence in vivo. In future studies neurobiological changes will be assessed at later time points after WBRT, using a senescence reporter mouse and will be combined with behavioral studies.