Chen Hua, Yang Yong, Yao Hong-Hong, Tang Xing-Chun, Ding Jian-Hua, Wang Hai, Hu Gang
Laboratory of Neuropharmacology, Department of Anatomy, Histology and Pharmacology, Nanjing Medical University, Nanjing 210029, China.
Acta Pharmacol Sin. 2006 Jun;27(6):665-72. doi: 10.1111/j.1745-7254.2006.00356.x.
To investigate the protective role of iptakalim, a novel ATP sensitive potassium channel opener, on global cerebral ischemia-evoked insult in gerbils and glutamate-induced PC12 cell injury.
Global cerebral ischemia was induced by occluding the bilateral common carotid arteries in gerbils for 5 min. The open field maze and T-maze were employed to investigate the experimental therapeutic value of iptakalim on ischemic brain insult (n=8). The pyramidal cells in the hippocampal CA1 regions were counted to assess the protective effects of iptakalim. Glutamate released from the gerbil hippocampus and PC12 cells were determined by HPLC. Intracellular calcium was measured by Fluo-3 AM with A Bio-Rad Radiance 2100TM confocal system in conjunction with a Nikon TE300 microscope. Astrocyte glutamate uptake measurements were determined by liquid scintillation counting.
Iptakalim (0.5-4.0 mg/kg per day, ip) could reduce the high locomotor activity evoked by ischemia and improve global cerebral ischemia-induced working memory impairments. Histological studies revealed that iptakalim could increase the survival neuron in the hippocampus CA1 zone in a dose-dependent manner. Moreover, iptakalim could reverse ischemia-evoked increases of glutamate in the hippocampus of gerbils. In an in vitro study, iptakalim protected PC12 cells against glutamate-induced excitotoxicity, reduced the Ca(2+) increases, and enhanced the glutamate uptake activity of primary cultured astrocytes.
Iptakalim plays a key role in preventing global cerebral ischemia-evoked insults in gerbils and glutamate-induced PC12 cell injury by anti-excitotoxicity. Iptakalim might be a promising novel candidate for the prevention and/or treatment of stroke.
研究新型ATP敏感性钾通道开放剂埃他卡林对沙土鼠全脑缺血所致损伤及谷氨酸诱导的PC12细胞损伤的保护作用。
通过夹闭沙土鼠双侧颈总动脉5分钟诱导全脑缺血。采用旷场迷宫和T型迷宫研究埃他卡林对缺血性脑损伤的实验治疗价值（n = 8）。计数海马CA1区锥体细胞以评估埃他卡林的保护作用。采用高效液相色谱法测定沙土鼠海马和PC12细胞释放的谷氨酸。利用Bio-Rad Radiance 2100TM共聚焦系统结合尼康TE300显微镜，采用Fluo-3 AM测量细胞内钙。通过液体闪烁计数法测定星形胶质细胞对谷氨酸的摄取量。
埃他卡林（每天0.5 - 4.0毫克/千克，腹腔注射）可降低缺血诱发的高运动活性，并改善全脑缺血所致的工作记忆障碍。组织学研究显示，埃他卡林可剂量依赖性增加海马CA1区存活神经元数量。此外，埃他卡林可逆转沙土鼠海马缺血诱发的谷氨酸增加。在体外研究中，埃他卡林保护PC12细胞免受谷氨酸诱导的兴奋性毒性，降低细胞内钙升高，并增强原代培养星形胶质细胞的谷氨酸摄取活性。
埃他卡林通过抗兴奋性毒性在预防沙土鼠全脑缺血诱发的损伤及谷氨酸诱导的PC12细胞损伤中起关键作用。埃他卡林可能是预防和/或治疗中风的一种有前景的新型候选药物。
