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Effect of chronic intermittent hypoxia on the expression of Nip3, cell apoptosis, beta-amyloid protein deposit in mice brain cortex.

BACKGROUND
Chronic intermittent hypoxia (CIH) is the most important pathophysiologic feature of sleep apnea syndrome (SAS). To explore the relationship between SAS and dementia, the effects of CIH on the expression of Nip3, neuron apoptosis and beta-amyloid protein deposit in the brain cortex of the frontal lobe of mice were evaluated in this study.


METHODS
Thirty male ICR mice were divided into four groups: control group (A, n = 10, sham hypoxia/reoxygenation), 2 weeks CIH group (B, n = 5), 4 weeks CIH group (C, n = 5), and 8 weeks CIH group (D, n = 10). The ICR mice were placed in a chamber and exposed to intermittent hypoxia (oxygen concentration changed periodically from (21.72 +/- 0.55)% to (6.84 +/- 0.47)% every two minutes, eight hours per day). Neuron apoptosis of the cortex of the frontal lobe was detected by means of terminal deoxy-nucleotidyl transferase-mediated in situ end labeling (TUNEL). Immunohistochemical staining was performed for measuring expression of Nip3 and beta-amyloid protein. The ultrastructure of neurons was observed under a transmission electron microscope.


RESULTS
TUNEL positive neurons in each square millimeter in the cortex of the frontal lobe were categorized by median or Ri into group A (1, 5.5), group B (133, 13), group C (252, 21), and group D (318, 24). There were significant differences among the above four groups (P = 0.000). The significance test was performed between the control group and each CIH group respectively: group A and B (P > 0.05); group A and C (P < 0.01); and group A and D (P < 0.005). The number of apoptotic neurons kept increasing in the ICR mice under CIH condition, and reached the peak in the group D, but there was no significant difference between groups B and C, between groups B and D, and between groups C and D. Nip3 positive neurons in each square millimeter in the cortex of the frontal lobe in each group were calculated by median or Ri as follows: group A (2, 5.5), group B (117, 13), group C (227, 26.2), and group D (479, 21.4). There were significant differences among the four groups (P = 0.000). The statistical test was performed between the control group and each CIH group respectively: groups A and B (P > 0.05); groups A and C (P < 0.005); and groups A and D (P < 0.005). There was no significant difference between groups B and C, groups B and D, and groups C and D. The expression of Nip3 was closely correlated with neuron apoptosis in the brain (P < 0.05). The expression of beta-amyloid protein in the brain of mice was negative in all CIH groups and the control group. Ultrastructure observation showed karyopyknosis of nucleus, swelling of chondriosomes, deposit of lipofuscins and degeneration of neural sheath in all CIH groups but not in the control group.


CONCLUSION
The results of this study indicate that CIH could up-regulate the expression of Nip3, and result in neuron apoptosis and ultrastructural changes in neurons of the frontal cortex.