Relationship between irradiation-induced neuro-inflammatory environments and impaired cognitive function in the developing brain of mice

Abstract

Purpose: Radiation-induced brain injury (RIBI) is the most common side-effect after cranial radiation therapy (CRT). In the present study, the RIBI mice model was established and the changes in the expression of tumor necrosis factor alpha (TNF-α) and interleukin-1beta (IL-1β) mRNA, and the related signal pathways in the hippocampus of this model were investigated.

Materials and methods: 10 Gy CRT or sham-irradiation was given to the three-week old mice. The water maze test was used to test the RIBI model in mice. The expression of pro-inflammatory cytokines was detected by real-time polymerase chain reaction (PCR) in vivo. The changes of microglial activation and neurogensis in the hippocampus were analyzed by immunofluorescence and immunohistochemistry. The cytoplasm to nuclei translocation of Nuclear factor kappa B (NF-κB), and the protein expressions of IkappaB-alpha (IκB-α), NF-κB essential modulator (NEMO), p53-induced protein with a death domain (PIDD), TNF-α and IL-1β were examined by Western blotting. A RIBI model was established by Morris water maze test 6 weeks after 10 Gy CRT in three-week old C57BL/6J mice.

Results: The mRNA and protein expression levels of TNF-α and IL-1β reached the peak during the early phase after CRT. Increases in cytokine levels also were observed after irradiation of mouse BV-2 microglial cells. Neurogensis was significantly inhibited in the hippocampus with an increase of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells. The total number of microglia was decreased after CRT, but microglial activation was significantly increased. Western blotting revealed, in the RIBI mice, the expression of IκB-α was down-regulated, accompanied by the up-regulated expression of NEMO and regulated auto-proteolysis of PIDD. Also the NF-κB pathway activation was observed in BV-2 cells after irradiation.

Conclusions: CRT-induced pro-inflammatory cytokines release in the brain tissues and inhibition of neurogenesis in the hippocampus might be contributed by the microglial activation and play an important role in RIBI.

Keywords::

• Cranial radiation therapy
• microglial activation
• neurogenesis
• NF-κB
• proinflammatory cytokines

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

This work was supported by grants from National Nature Science Foundation of China (30800283, 81172595), Post doctor foundation of China (20100480905) and grant from post doctor special foundation of China (201104440).