SC79, the AKT Activator Protects Cerebral Ischemia in a Rat Model of Ischemia/Reperfusion Injury.
SC79, the AKT Activator Protects Cerebral Ischemia in a Rat Model of Ischemia/Reperfusion Injury.
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DOI：
10.12659/msm.910191
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发表时间：
2018-08-03
期刊：
影响因子：
--
通讯作者：
Zhou H
中科院分区：
文献类型：
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作者：
Luan Q;Pan L;He D;Gong X;Zhou H
激活AKT通路可减轻脑缺血/再灌注损伤时的脑损伤和神经细胞凋亡。SC79是一种新型、选择性、高效的Akt激活剂。本研究旨在观察SC79对大鼠脑I/R损伤的神经保护作用，并探讨其可能的机制。雄性SD大鼠脑缺血1h，再灌流0.5h~24h。建立脑I/R损伤动物模型，分别给予SC79或SC79联合LY294002治疗。Western blotting检测磷脂酰肌醇AKT(p-Akt)、bax和bcl2的表达水平。脑I/R后24小时，通过神经功能缺失评分(NDS)评价脑损伤程度。TTC(2，3，5-三苯基四氮唑)染色观察脑组织梗死率。用末端脱氧核苷酸转移酶介导的UTP缺口末端标记(TUNEL)染色检测细胞凋亡。P-Akt在脑I/R早期0.5h开始激活，4h达到最高水平，6h开始逐渐下降，12~24h达到并维持最低水平。Bax的表达从6h开始逐渐增强，在24h达到最高水平。Bcl2表达逐渐增强，4h达最高水平，6h后逐渐下降，24h降至最低。应用SC79可显著缩小脑梗塞体积，改善神经功能。LY294002与SC79联合应用可使SC79丧失抵抗脑I/R损伤的能力。SC79单独治疗可激活大脑中动脉闭塞(MCAO)小鼠的p-Akt，促进抗凋亡的bcl2，抑制抗凋亡的bax表达。但联合应用SC79和LY294002可抑制SC79诱导的p-Akt活性，抑制抗凋亡的bcl2，促进抗凋亡的bax的表达。此外，SC79单独治疗可减轻神经细胞的凋亡性死亡，但在SC79和LY294002联合治疗组中取消了这一作用。SC79可显著增加脑I/R损伤后Akt的活性，缩小脑梗塞体积，改善脑缺血后的神经功能。提示SC79有可能作为一种神经保护药物应用于临床。
Activation of AKT pathway attenuates brain damage and neuronal apoptosis during cerebral ischemia/reperfusion (I/R) injury. SC79 is a novel, selective and highly-efficient Akt activator. This study aimed to investigate the neuroprotective effect of SC79 against cerebral I/R injury in a rat model, and to explore the possible underlying mechanisms. Male Sprague-Dawley rats received cerebral ischemia for 1 hour, followed by brain reperfusion for 0.5–24 hours. The cerebral I/R injury animal model were treated with SC79 alone or SC79 in combination with LY294002. Western blots were used to detect the levels of expression of phosphatidylinositol AKT (p-Akt), Bax, and bcl-2. Twenty-four hours after cerebral I/R, the degree of brain injury was evaluated by detecting the neurological deficit score (NDS). The infarct rate of brain tissue was observed by TTC (2, 3, 5-triphenyltetrazolium chloride) staining. TUNEL (terminal deoxynucleotidyl transferase-mediated UTP nick end labeling) staining was used to detect cell apoptosis. p-Akt was activated during early cerebral I/R at 0.5 hours, and reached the highest levels at 4 hours, then gradually decreased from 6 hours, and reached and maintained the lowest levels at 12–24 hours. Bax expression was gradually increased from 6 hours and reached the highest level at 24 hours. However, bcl-2 expression was gradually increased and reached the highest levels at 4 hours, then gradually decreased from 6 hours, and reached the lowest levels at 24 hours. Administration of SC79 decreased infarct volumes and improved neurological function significantly. LY294002 in combination with SC79 lost the capability of SC79 to resist the cerebral I/R injury. SC79 treatment alone activated p-Akt and promoted anti-apoptotic bcl-2 and inhibited anti-apoptotic Bax expression in middle cerebral artery occlusion (MCAO) mice. However, combined SC79 and LY294002 treatment abolished SC79-induced p-Akt activity, inhibited anti-apoptotic bcl-2 and promoted anti-apoptotic Bax expression in MCAO mice. Furthermore, SC79 treatment alone attenuated apoptotic neuronal cell death, but abolished this effect in SC79 in combination with LY294002 treated groups. SC79 significantly increased Akt activation and reduced infarct volume and subsequently improved neurological function in ischemic brain after cerebral I/R injury in rats. These findings suggested that SC79 may be as a neuroprotective drug to be potentially used in the clinic.