Gu You-Yu, Huang Ping, Li Quan, Liu Yu-Ying, Liu George, Wang Yu-Hui, Yi Ming, Yan Li, Wei Xiao-Hong, Yang Lei, Hu Bai-He, Zhao Xin-Rong, Chang Xin, Sun Kai, Pan Chun-Shui, Cui Yuan-Chen, Chen Qing-Fang, Wang Chuan-She, Fan Jing-Yu, Ma Zhi-Zhong, Han Jing-Yan
Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China.
Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China.
Front Physiol. 2018 Jun 1;9:658. doi: 10.3389/fphys.2018.00658. eCollection 2018.
The purpose of the study was to explore the effect and the underlying mechanism of YangXue QingNao Wan (YXQNW) and Silibinin Capsules (SC), the two Chinese medicines, on cognitive impairment in older people with familial hyperlipidaemia. Fourteen month-old female LDLR (+/-) golden Syrian hamsters were used with their wild type as control. YXQNW (0.5 g/kg/day), SC (0.1 g/kg/day), or YXQNW (0.5 g/kg/day) + SC (0.1 g/kg/day) were administrated orally for 30 days. To assess the effects of the two drugs on plasma lipid content and cognitive ability, plasma TC, TG, LDL-C, and HDL-C were measured, and Y maze task was carried out both before and after administration. After administering of the drugs for 30 days, to evaluate the effect of the two drugs on disturbed blood flow caused by hyperlipidemia, the cerebral blood flow (CBF) was measured. To assess blood-brain barrier integrity, albumin leakage in middle cerebral artery (MCA) area was determined. To evaluate the effect of the drugs on impaired microvessels, the number and morphology of microvessels were assessed in hippocampus area. To further evaluate the ultrastructure of microvessels in hippocampus, transmission electron microscopy (TEM) and scanning electron microscopy (SEM) were carried out. To assess the profiles of claudin-5 and occludin in hippocampus, we performed immunofluorescence. Finally, to assess the expression of claudin-5, JAM-1, occludin and ZO-1 in hippocampus, western blot was carried out. The results showed that YXQNW, SC, and YXQNW + SC improved cognitive impairment of aged LDLR (+/-) golden Syrian hamsters without lowering plasma TC and LDL-C. YXQNW, SC, and YXQNW + SC attenuated albumin leakage in MCA area and neuronal damage in hippocampus, concomitant with an increase in CBF, a decrease of perivascular edema and an up-regulated expression of claudin-5, occludin and ZO-1. In conclusion, YXQNW, SC, and YXQNW + SC are able to improve cognitive ability in aged LDLR (+/-) golden Syrian hamsters via mechanisms involving maintaining blood-brain barrier integrity. These findings provide evidence suggesting YXQNW or SC as a potential regime to counteract the cognitive impairment caused by familial hypercholesterolemia.
本研究旨在探讨两种中药养血清脑丸（YXQNW）和水飞蓟宾胶囊（SC）对老年家族性高脂血症患者认知功能障碍的影响及潜在机制。选用14月龄雌性低密度脂蛋白受体（LDLR）杂合子金黄叙利亚仓鼠，以其野生型作为对照。将YXQNW（0.5 g/kg/天）、SC（0.1 g/kg/天）或YXQNW（0.5 g/kg/天）+ SC（0.1 g/kg/天）口服给药30天。为评估这两种药物对血脂含量和认知能力的影响，测定血浆总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL-C）和高密度脂蛋白胆固醇（HDL-C），并在给药前后进行Y迷宫实验。给药30天后，为评估这两种药物对高脂血症引起的血流紊乱的影响，测量脑血流量（CBF）。为评估血脑屏障的完整性，测定大脑中动脉（MCA）区域的白蛋白渗漏情况。为评估药物对受损微血管的影响，评估海马区微血管的数量和形态。为进一步评估海马区微血管的超微结构，进行透射电子显微镜（TEM）和扫描电子显微镜（SEM）检查。为评估海马区闭合蛋白-5（claudin-5）和闭锁蛋白（occludin）的表达情况，进行免疫荧光实验。最后，为评估海马区claudin-5、连接黏附分子-1（JAM-1）、occludin和紧密连接蛋白-1（ZO-1）的表达，进行蛋白质免疫印迹实验。结果显示，YXQNW、SC以及YXQNW + SC可改善老年LDLR杂合子金黄叙利亚仓鼠的认知功能障碍，且不降低血浆TC和LDL-C。YXQNW、SC以及YXQNW + SC可减轻MCA区域的白蛋白渗漏和海马区的神经元损伤，同时CBF增加、血管周围水肿减轻，claudin-5、occludin和ZO-1的表达上调。总之，YXQNW、SC以及YXQNW + SC能够通过维持血脑屏障完整性的机制提高老年LDLR杂合子金黄叙利亚仓鼠的认知能力。这些研究结果为YXQNW或SC作为对抗家族性高胆固醇血症所致认知功能障碍的潜在治疗方案提供了证据。
