Salidroside improves behavioral and histological outcomes and reduces apoptosis via PI3K/Akt signaling after experimental traumatic brain injury.
Salidroside improves behavioral and histological outcomes and reduces apoptosis via PI3K/Akt signaling after experimental traumatic brain injury.
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DOI：
10.1371/journal.pone.0045763
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Liao NC
中科院分区：
文献类型：
--
作者：
Chen SF;Tsai HJ;Hung TH;Chen CC;Lee CY;Wu CH;Wang PY;Liao NC
创伤性脑损伤可引起一系列复杂的细胞凋亡级联反应，从而导致继发性组织损伤。本研究的目的是研究红景天苷对实验性脑损伤后行为和组织学结果、脑水肿和细胞凋亡的影响，以及磷脂酰肌醇3-激酶/蛋白激酶B(PI3K)/Akt信号通路的可能参与。控制性皮质撞击伤小鼠于伤后10min腹腔注射红景天苷(20 mg/kg或50 mg/kg)或溶媒。进行行为学、组织学分析和脑含水量测定。分析PI3K/Akt信号相关分子、凋亡相关蛋白、细胞色素C(CytoC)和Smac/Diablo的水平。应用PI3K抑制剂LY294002研究其保护作用机制。红景天苷对原代培养神经元牵张损伤的保护作用也进行了研究。至伤后第28天，红景天苷20 mg/kg治疗可显著促进大鼠功能恢复，减轻脑组织损伤。红景天苷还能显著减少1d的神经元死亡、细胞凋亡和脑水肿。这些变化与1d和3d时caspase-3、CytoC和Smac/Diablo的显著减少有关。红景天苷在1d增加Ser473上Akt的磷酸化，在3d增加线粒体Bcl2/Bax的比值，在3d增强Thr308上Akt的磷酸化。这种作用被预先注射LY294002所抵消。此外，在损伤后3h或6h延迟给予红景天苷可减少第1天的神经元损伤。红景天苷治疗也降低了体外培养的神经元对牵张损伤的易感性。损伤后红景天苷至少部分通过PI3K/Akt信号通路改善了脑损伤后的长期行为和组织学结果，并减少了脑水肿和细胞凋亡。
Traumatic brain injury (TBI) induces a complex sequence of apopototic cascades that contribute to secondary tissue damage. The aim of this study was to investigate the effects of salidroside, a phenolic glycoside with potent anti-apoptotic properties, on behavioral and histological outcomes, brain edema, and apoptosis following experimental TBI and the possible involvement of the phosphoinositide 3-kinase/protein kinase B (PI3K)/Akt signaling pathway. Mice subjected to controlled cortical impact injury received intraperitoneal salidroside (20, or 50 mg/kg) or vehicle injection 10 min after injury. Behavioral studies, histology analysis and brain water content assessment were performed. Levels of PI3K/Akt signaling-related molecules, apoptosis-related proteins, cytochrome C (CytoC), and Smac/DIABLO were also analyzed. LY294002, a PI3K inhibitor, was administered to examine the mechanism of protection. The protective effect of salidroside was also investigated in primary cultured neurons subjected to stretch injury. Treatment with 20 mg/kg salidroside_significantly improved functional recovery and reduced brain tissue damage up to post-injury day 28. Salidroside_also significantly reduced neuronal death, apoptosis, and brain edema at day 1. These changes were associated with significant decreases in cleaved caspase-3, CytoC, and Smac/DIABLO at days 1 and 3. Salidroside increased phosphorylation of Akt on Ser473 and the mitochondrial Bcl-2/Bax ratio at day 1, and enhanced phosphorylation of Akt on Thr308 at day 3. This beneficial effect was abolished by pre-injection of LY294002. Moreover, delayed administration of salidroside at 3 or 6 h post-injury reduced neuronal damage at day 1. Salidroside treatment also decreased neuronal vulnerability to stretch-induced injury in vitro. Post-injury salidroside improved long-term behavioral and histological outcomes and reduced brain edema and apoptosis following TBI, at least partially via the PI3K/Akt signaling pathway.