Role of the pituitary-adrenal axis in granulocyte-colony stimulating factor-induced neuroprotection against hypoxia-ischemia in neonatal rats

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• 作者：Mé ; lissa S. Charles^a ; ^b ; Robert P. Ostrowski^b ; Anatol Manaenko^b ; Kamil Duris^b ; John H. Zhang^b ; ^c ; ^d ; Jiping Tang^b ; ^{jtang@llu.edu}
• 关键词：G-CSF ; Granulocyte-colony stimulating factor ; MET ; Metyrapone ; DEX ; Dexamethasone ; ACTH ; Adrenocorticotropic hormone ; HPA ; Hypothalamic&ndash ; pituitary adrenal ; Bcl-2 ; B cell lymphoma 2 ; Bax ; Bcl-2 associated protein X
• 刊名：Neurobiology of Disease
• 出版年：2012
• 期刊代码：80_09699961
• 类别：neu
• 出版时间：July, 2012
• 卷：47
• 期：1
• 页码：29-37
• 文件大小：1277 K

摘要

Several reports indicate that the activity of the hypothalamic-pituitary-adrenal axis (HPA) is increased after a brain insult and that its down-regulation can improve detrimental outcomes associated with ischemic brain injuries. Granulocyte-colony stimulating factor (G-CSF) is a neuroprotective drug shown in the na茂ve rat to regulate hormones of the HPA axis. In this study we investigate whether G-CSF confers its neuroprotective properties by influencing the HPA response after neonatal hypoxia-ischemia (HI). Following the Rice-Vannucci model, seven day old rats (P7) were subjected to unilateral carotid ligation followed by 2.5 h of hypoxia. To test our hypothesis, metyrapone was administered to inhibit the release of rodent specific glucocorticoid, corticosterone, at the adrenal level. Dexamethasone, a synthetic glucocorticoid, was administered to agonize the effects of corticosterone. Our results show that both G-CSF and metyrapone significantly reduced infarct volume while dexamethasone treatment did not reduce infarct size even when combined with G-CSF. The protective effects of G-CSF do not include blood brain barrier preservation as suggested by the brain edema results. G-CSF did not affect the pituitary released adrenocorticotropic hormone (ACTH) levels in the blood plasma at 4 h, but suppressed the increase of corticosterone in the blood. The administration of G-CSF and metyrapone increased weight gain, and significantly reduced the Bax/Bcl-2 ratio in the brain while dexamethasone reversed the effects of G-CSF. The combination of G-CSF and metyrapone significantly decreased caspase-3 protein levels in the brain, and the effect was antagonized by dexamethasone. We report that G-CSF is neuroprotective in neonatal HI by reducing infarct volume, by suppressing the HI-induced increase of the Bax/Bcl-2 ratio, and by decreasing corticosterone in the blood. Metyrapone was able to confer similar neuroprotection as G-CSF while dexamethasone reversed the effects of G-CSF. In conclusion, we show that decreasing HPA axis activity is neuroprotective after neonatal HI, which can be conferred by administering G-CSF.