Gu Youquan, Chen Jun, Wang Tianhong, Zhou Chaoning, Liu Zhaodong, Ma Lanhua
Department of Neurology, Donggang Branch of The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China.
Department of Neurology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China.
Exp Ther Med. 2016 Dec;12(6):3767-3772. doi: 10.3892/etm.2016.3821. Epub 2016 Oct 19.
Traumatic brain injury (TBI) is the predominant cause of mortality in young adults and children living in China. TBI induces inflammatory responses; in addition, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 are important pro-inflammatory cytokines. Considering the observation that Hsp-70 overexpression can exert neuroprotection, identifying a drug that is able to induce the upregulation of Hsp70 has the potential to be a promising therapy for the treatment of neurological diseases. Thus, the present study assessed the clinical effectiveness of an anticancer drug and Hsp70 activator, 17-allylamino-demethoxygeldanamycin (17-AAG), to evaluate its potential as a treatment for patients with TBI. The aim of present study was to determine the neuroprotective effects of 17-AAG following trauma and to investigate the underlying mechanisms of action. To establish rat models, rats were subjected to a controlled cortical impact injury and randomly divided into vehicle or 17-AAG groups. In the 17-AAG group, rats were administered with an intraperitoneal injection of 17-AAG (80 mg/kg) immediately following the establishment of TBI. The motor function was measured using Neurologic Severity Score, and neuronal death was evaluated using immunofluorescence. The expression levels of GLT-1, Bcl-2 and Hsp-70 were detected by western blot analysis and the expression levels of inflammatory cytokines were quantified using ELISA. The present study determined that 17-AAG significantly reduced brain edema and motor neurological deficits (P<0.05), in addition to increasing neuronal survival. The aforementioned findings are associated with a downregulation of the expression levels of pro-inflammatory cytokines TNF-α, IL-1β and IL-6. Conversely, no significant changes of glutamate transporter-1 expression were observed. The present results suggest that 17-AAG treatment may provide a neuroprotective effect by reducing inflammation following TBI.
创伤性脑损伤（TBI）是中国年轻成年人和儿童死亡的主要原因。TBI会引发炎症反应；此外，肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和IL-6是重要的促炎细胞因子。鉴于热休克蛋白70（Hsp-70）过表达可发挥神经保护作用，确定一种能够诱导Hsp70上调的药物有可能成为治疗神经疾病的一种有前景的疗法。因此，本研究评估了一种抗癌药物兼Hsp70激活剂17-烯丙基氨基-去甲氧基格尔德霉素（17-AAG）的临床疗效，以评估其作为TBI患者治疗药物的潜力。本研究的目的是确定17-AAG在创伤后的神经保护作用，并探究其潜在的作用机制。为建立大鼠模型，对大鼠进行控制性皮质撞击损伤，并随机分为溶剂对照组或17-AAG组。在17-AAG组中，大鼠在TBI模型建立后立即腹腔注射17-AAG（80mg/kg）。使用神经严重程度评分来测量运动功能，并通过免疫荧光评估神经元死亡情况。通过蛋白质免疫印迹分析检测谷氨酸转运体-1（GLT-1）、Bcl-2和Hsp-70的表达水平，并用酶联免疫吸附测定法（ELISA）对炎性细胞因子的表达水平进行定量分析。本研究确定，17-AAG除了可提高神经元存活率外，还能显著减轻脑水肿和运动神经功能缺损（P<0.05）。上述结果与促炎细胞因子TNF-α、IL-1β和IL-6表达水平的下调有关。相反，未观察到谷氨酸转运体-1表达有显著变化。目前的结果表明，17-AAG治疗可能通过减轻TBI后的炎症反应来提供神经保护作用。
