Chen Zhuo, Huang Chao, Ding Wenbin
Invasive Technology Department, Nantong First People's Hospital, The Second Affiliated Hospital of Nantong University, #6 North Road Hai'er Xiang, Nantong, 226001, Jiangsu, China.
Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, 226001, Jiangsu, China.
Neurochem Res. 2016 Dec;41(12):3322-3332. doi: 10.1007/s11064-016-2064-0. Epub 2016 Sep 28.
Memory impairment is a common symptom in patients with neurodegenerative disorders, and its suppression could be beneficial to improve the quality of life of those patients. Z-guggulsterone, a compound extracted from the resin of plant Commiphora whighitii, exhibits numerous pharmacological effects in clinical practice, such as treatment of inflammation, arthritis, obesity and lipid metabolism disorders. However, the role and possible mechanism of Z-guggulsterone on brain-associated memory impairments are largely unknown. This issue was addressed in the present study in a memory impairment model induced by scopolamine, a muscarinic acetylcholine receptor antagonist, using the passive avoidance, Y-maze and Morris water maze tests. Results showed that scopolamine significantly decreased the step-through latency and spontaneous alternation of C57BL/6J mice in passive avoidance and Y-maze test, whereas increased the mean escape latency and decreased the swimming time in target quadrant in Morris water maze test. Pretreatment of mice with Z-guggulsterone at doses of 30 and 60 mg/kg effectively reversed the scopolamine-induced memory impairments. Mechanistic studies revealed that Z-guggulsterone pretreatment reversed the scopolamine-induced increase in acetylcholinesterase (AchE) activity, as well as decreases in brain-derived neurotrophic factor (BDNF) protein expression and cAMP response element-binding protein (CREB), extracellular regulated kinase 1/2 (ERK1/2) and protein kinase B (Akt) phosphorylation levels in the hippocampus and cortex. Inhibition of the BDNF signal, however, blocked the memory-enhancing effect of Z-guggulsterone. Therefore, these findings demonstrate that Z-guggulsterone attenuates the scopolamine-induced memory impairments mainly through activation of the CREB-BDNF signaling pathway, thereby exhibiting memory-improving effects.
记忆障碍是神经退行性疾病患者的常见症状，抑制记忆障碍可能有助于改善这些患者的生活质量。Z-古古甾酮是从植物没药树树脂中提取的一种化合物，在临床实践中具有多种药理作用，如治疗炎症、关节炎、肥胖和脂质代谢紊乱。然而，Z-古古甾酮对与大脑相关的记忆障碍的作用及可能机制在很大程度上尚不清楚。本研究在东莨菪碱（一种毒蕈碱型乙酰胆碱受体拮抗剂）诱导的记忆障碍模型中，通过被动回避试验、Y迷宫试验和莫里斯水迷宫试验对这一问题进行了探讨。结果显示，在被动回避试验和Y迷宫试验中，东莨菪碱显著缩短了C57BL/6J小鼠的穿箱潜伏期和自发交替率，而在莫里斯水迷宫试验中，东莨菪碱延长了平均逃避潜伏期并缩短了在目标象限的游泳时间。用30和60mg/kg剂量的Z-古古甾酮预处理小鼠可有效逆转东莨菪碱诱导的记忆障碍。机制研究表明，Z-古古甾酮预处理可逆转东莨菪碱诱导的乙酰胆碱酯酶（AchE）活性增加，以及海马和皮层中脑源性神经营养因子（BDNF）蛋白表达、cAMP反应元件结合蛋白（CREB）、细胞外调节激酶1/2（ERK1/2）和蛋白激酶B（Akt）磷酸化水平的降低。然而，抑制BDNF信号可阻断Z-古古甾酮的记忆增强作用。因此，这些发现表明，Z-古古甾酮主要通过激活CREB-BDNF信号通路减轻东莨菪碱诱导的记忆障碍，从而发挥改善记忆的作用。
