Chronic Intermittent Hypobaric Hypoxia Attenuates Irradiation Induced Hippocampus Damage in Mice

Abstract

To observe the manifestations of radiation induced hippocampus damage and the potential injury mechanisms in mice. To examine the protective effects with chronic intermittent hypobaric hypoxia (CIHH) on radiation induced hippocampus damage. A total of 48 male adult C57/BL mice were randomly divided into four groups as control group (group A), CIHH group (group B), irradiation group (group C) and CIHH plus irradiation group (group D). Whole brain irradiation was delivered to them with a single fraction of 10.0Gy. Before radiation, mice in Group B and Group D were treated with CIHH for 28 consecutive days. Thirty days later, the Mirros water maze test was used to evaluate the memory and cognitive function of the mice. Morphological alterations of hippocampal CA1 area were examined by Nissl staining. The expression level of mTOR, Beclin-1, LC3II/I as well as GRP78 and CHOP were quantitatively analyzed by Western blot. The expression of doublecortin (DCX) in the subgranular zone (SGZ) of dentate gyrus (DG) in hippocampus was detected by immunofluorescence to evaluate the neurogenesis. The time of escape latency was increased in group C when compared with group A, whereas it was decreased when compared to group D. The exploration time in the first quadrant within one minute of the mice in group C was significantly reduced than that in group A, the times of cross the platform within one minute was also decreased. The exploration time and the times of cross the platform within one minute were 14.12 ±0.82 S and 2.08 ±0.26 in group D, and were 7.42 ±0.73S and 0.83 ±0.24 times in group C. After irradiation was performed, pathological changes as swelling, nuclear deviation, disorder of cell structure, degeneration and necrosis in neuronal cells of CA1 in hippocampus could be observed by Nissl staining, whereas the damages in hippocampus were ameliorated in group D. In comprison with group A, The levels of GRP78, CHOP, Beclin-1 and LC3II/Iin hippocampus were significantly increased, but the expression of mTOR protein was decreased in group C. When compared with group D, the levels of GRP78, CHOP and mTOR were increased (P < 0.01 for both), and the expression of Beclin-1 and LC3II/Iwere reduced (P < 0.05 for both) in group C. Compared with group A, the expression of DCX in CA1 region of the hippocampus was significantly decreased than that in group C. After pretreatment with CIHH, the expression of it in group D was much higher than that in group C. Irradiation could cause histopathological damage in hippocampus in mice. The potential mechanisms of radiation induced hippocampus damage might be attributed to ER stress and neurogenesis reduction. Simultaneously, irradiation could activate autophagy in hippocampus, which might play a protective role by reducing the damage of ER stress. Pretreated with CIHH could attenuates irradiation induced hippocampus injury by inducting of autophagy as well as increasing the neurogenesis in CA1 region in mice.