PDF(Pubmed)
Abstract：
BACKGROUND: Dexamethasone-induced neurotoxicity has been previously reported. However, the molecular mechanisms are still not completely understood.
OBJECTIVE: The current work aimed to investigate the modulatory effects of α- and β-adrenergic receptors on dexamethasone-induced neurotoxicity in rats focused on changes in β-arrestin2 and molecular markers of neural injury in cerebral cortex.
METHODS: Male Wistar rats were subcutaneously injected with dexamethasone (10 mg/kg/day) for 7 days to induce neural injury in the cerebral cortex. The experiment involved 5 groups: control, dexamethasone, carvedilol, propranolol, and doxazosin. In the last 3 groups, drugs were given 2 hours before dexamethasone injection. At the end of experiment, brain samples were collected for measurement of brain derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), kinase activity of protein kinase B (Akt), diacylglycerol (DAG), α-smooth muscle actin (α-SMA), Smad3, β-amyloid and phospho-tau protein levels in addition to histopathological examination of brain tissue using hematoxylin-eosin, Nissl, and Sirius red stains. Moreover, β-arrestin2 levels in the cerebral cortex were measured using immunohistochemical examination.
RESULTS: Dexamethasone slightly reduced brain weight and significantly decreased BDNF, Akt kinase activity and β-arrestin2 but markedly induced degeneration of cortical neurons and significantly increased GFAP, DAG, α-SMA, Smad3, β-amyloid and phospho-tau protein levels compared to controls. Carvedilol, propranolol, and doxazosin reversed all dexamethasone-induced molecular changes and slightly ameliorated the histopathological changes. Carvedilol significantly increased brain weight and β-arrestin2 levels compared to dexamethasone, propranolol, and doxazosin groups.
CONCLUSIONS: blocking α- and/or β-adrenergic receptors alleviate dexamethasone-induced neurotoxicity despite their distinct effects on β-arrestin2 levels in the cerebral cortex.
OBJECTIVE: The current work aimed to investigate the modulatory effects of α- and β-adrenergic receptors on dexamethasone-induced neurotoxicity in rats focused on changes in β-arrestin2 and molecular markers of neural injury in cerebral cortex.
METHODS: Male Wistar rats were subcutaneously injected with dexamethasone (10 mg/kg/day) for 7 days to induce neural injury in the cerebral cortex. The experiment involved 5 groups: control, dexamethasone, carvedilol, propranolol, and doxazosin. In the last 3 groups, drugs were given 2 hours before dexamethasone injection. At the end of experiment, brain samples were collected for measurement of brain derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), kinase activity of protein kinase B (Akt), diacylglycerol (DAG), α-smooth muscle actin (α-SMA), Smad3, β-amyloid and phospho-tau protein levels in addition to histopathological examination of brain tissue using hematoxylin-eosin, Nissl, and Sirius red stains. Moreover, β-arrestin2 levels in the cerebral cortex were measured using immunohistochemical examination.
RESULTS: Dexamethasone slightly reduced brain weight and significantly decreased BDNF, Akt kinase activity and β-arrestin2 but markedly induced degeneration of cortical neurons and significantly increased GFAP, DAG, α-SMA, Smad3, β-amyloid and phospho-tau protein levels compared to controls. Carvedilol, propranolol, and doxazosin reversed all dexamethasone-induced molecular changes and slightly ameliorated the histopathological changes. Carvedilol significantly increased brain weight and β-arrestin2 levels compared to dexamethasone, propranolol, and doxazosin groups.
CONCLUSIONS: blocking α- and/or β-adrenergic receptors alleviate dexamethasone-induced neurotoxicity despite their distinct effects on β-arrestin2 levels in the cerebral cortex.
摘要：
背景：先前已经报道了地塞米松诱导的神经毒性。然而,分子机制仍未完全了解。
目的：本研究旨在研究α-和β-肾上腺素受体对地塞米松所致大鼠神经毒性的调节作用，重点是β-arrestin2和大脑皮质神经损伤分子标志物的变化。
方法：雄性Wistar大鼠皮下注射地塞米松（10mg/kg/天）7天，引起大脑皮质神经损伤。实验涉及5组：对照组，地塞米松,卡维地洛,普萘洛尔,还有多沙唑嗪.在最后三组中，地塞米松注射前2小时给予药物治疗.实验结束时,收集脑样本用于测量脑源性神经营养因子（BDNF），胶质纤维酸性蛋白（GFAP），蛋白激酶B（Akt）的激酶活性，二酰基甘油（DAG），α-平滑肌肌动蛋白（α-SMA），Smad3，β-淀粉样蛋白和磷酸-tau蛋白水平，除了使用苏木精-伊红对脑组织进行组织病理学检查外，Nissl,和小天狼星的红色污渍。此外，使用免疫组织化学检查测量大脑皮层中的β-arrestin2水平。
结果：地塞米松轻微减轻脑重量，显著降低BDNF，Akt激酶活性和β-arrestin2但显著诱导皮层神经元变性和显著增加GFAP,DAG,α-SMA,与对照相比,Smad3、β-淀粉样蛋白和磷酸-tau蛋白水平。卡维地洛,普萘洛尔,多沙唑嗪逆转了所有地塞米松诱导的分子变化，并轻微改善了组织病理学变化。与地塞米松相比，卡维地洛显著增加脑重量和β-arrestin2水平，普萘洛尔,和多沙唑嗪组。
结论：阻断α-和/或β-肾上腺素能受体减轻了地塞米松诱导的神经毒性，尽管它们对大脑皮质中的β-arrestin2水平有明显影响。
目的：本研究旨在研究α-和β-肾上腺素受体对地塞米松所致大鼠神经毒性的调节作用，重点是β-arrestin2和大脑皮质神经损伤分子标志物的变化。
方法：雄性Wistar大鼠皮下注射地塞米松（10mg/kg/天）7天，引起大脑皮质神经损伤。实验涉及5组：对照组，地塞米松,卡维地洛,普萘洛尔,还有多沙唑嗪.在最后三组中，地塞米松注射前2小时给予药物治疗.实验结束时,收集脑样本用于测量脑源性神经营养因子（BDNF），胶质纤维酸性蛋白（GFAP），蛋白激酶B（Akt）的激酶活性，二酰基甘油（DAG），α-平滑肌肌动蛋白（α-SMA），Smad3，β-淀粉样蛋白和磷酸-tau蛋白水平，除了使用苏木精-伊红对脑组织进行组织病理学检查外，Nissl,和小天狼星的红色污渍。此外，使用免疫组织化学检查测量大脑皮层中的β-arrestin2水平。
结果：地塞米松轻微减轻脑重量，显著降低BDNF，Akt激酶活性和β-arrestin2但显著诱导皮层神经元变性和显著增加GFAP,DAG,α-SMA,与对照相比,Smad3、β-淀粉样蛋白和磷酸-tau蛋白水平。卡维地洛,普萘洛尔,多沙唑嗪逆转了所有地塞米松诱导的分子变化，并轻微改善了组织病理学变化。与地塞米松相比，卡维地洛显著增加脑重量和β-arrestin2水平，普萘洛尔,和多沙唑嗪组。
结论：阻断α-和/或β-肾上腺素能受体减轻了地塞米松诱导的神经毒性，尽管它们对大脑皮质中的β-arrestin2水平有明显影响。
