重酒石酸卡巴拉汀与盐酸多奈哌齐对阿尔兹海默症患者认知功能及血清 缓激肽水平的影响

目的:探讨重酒石酸卡巴拉汀联合盐酸多奈哌齐对阿尔兹海默症患者认知功能及血清缓激肽水平的影响。方法:收集我院就诊或住院治疗的96例阿尔兹海默症患者,随机分为实验组和对照组,每组48例。对照组患者给予盐酸多奈哌齐片治疗,实验组患者在对照组基础上给予重酒石酸卡巴拉汀胶囊治疗。观察并比较两组患者治疗前后简易智能状态量表(MMSE)评分、痴呆量表(Blessed-Roth)评分、阿尔兹海默症评定量表(ADAS-Cog)评分以及血清缓激肽(BK)水平的变化情况。结果:与治疗前相比,两组患者治疗后MMSE评分升高(P0.05),Blessed-Roth评分以及ADAS-Cog评分下降(P0.05),血清BK水平下降(P0.05);与对照组相比,实验组患者的MMSE评分较高(P0.05),Blessed-Roth评分,ADAS-Cog评分以及血清BK水平较低(P0.05);结论:重酒石酸卡巴拉汀联合盐酸多奈哌齐能够更有效改善阿尔兹海默症患者的认知功能,可与其降低血清BK水平有关。     

卡巴拉汀对阿尔茨海默病模型小鼠肠道菌群及认知功能的影响

摘要 目的：探究卡巴拉汀对阿尔茨海默病模型小鼠肠道菌群及认知功能的影响。方法：将所选取的大鼠随机分组,第一组,模型组（MO组）：该组大鼠制作阿尔茨海默病大鼠模型;第二组,假手术组（SS组）：该组大鼠在颅脑处做切口后不做任何处理;第三组,治疗组（TR组）：该组大鼠制作阿尔茨海默病模型后给予卡巴拉汀进行治疗,每组5只。通过避暗实验、qRT-PCR法、流式细胞仪、水迷宫行为测试、Western blot法等方法分析三组小鼠被动学习记忆能力、空间学习记忆能力、脑细胞凋亡情况、肠道菌群分布情况、TNF-α、IL-6的蛋白含量的差异性来探究卡巴拉汀对阿尔茨海默病模型小鼠肠道菌群及认知功能的影响。结果：由表可知,SS组、TR组、MO组小鼠潜伏期分别为158.39±84.26、127.54±71.84、65.82±21.03 s,错误次数分别为0.75±0.14、1.21±0.35、1.79±0.67,SS组小鼠潜伏期最长,错误次数最少,MO组则与之相反,TR组与MO组相比较,TR组被动学习记忆能力显著比MO组优良(P<0.05)。实验结果显示,SS组小鼠潜伏期时间最长,错误次数最少,MO组小鼠潜伏期时间最短,错误次数最多,TR组与MO组相比较,TR组空间学习记忆能力显著比MO组优良(P<0.05)。检测结果显示,SS组、TR组、MO组小鼠脑细胞凋亡率分别为13.59 %、43.68 %、89.38 %。SS组小鼠脑细胞凋亡数量最少,MO组小鼠脑细胞大量凋亡,MO组与TR组、SS组相比较细胞凋亡率显著下降,TR组与MO组相比较,TR组小鼠脑细胞凋亡数量显著比MO组少(均P＜0.05)。qRT-PCR检测结果显示,SS组、TR组、MO组小鼠肠道菌群分布有显著差异,SS组小鼠肠道内双歧杆菌、乳酸杆菌数量最多,大肠杆菌数量最少,MO组小鼠肠道细菌与之相反,MO组与TR组相比较,TR组小鼠肠道菌群分布优于MO组(均P<0.05)。通过Western blot法,对SS组、TR组、MO组小鼠脑细胞内的TNF-α、IL-6蛋白进行免疫印迹,灰度显示,SS组的TNF-α、IL-6蛋白含量最低,MO组蛋白含量最高,MO组和SS组、TR组相比较,脑细胞中TNF-α、IL-6蛋白表达水平显著上升,TR组与SS组相比较,TR组显著比SS组高(均P<0.05)。结论：卡巴拉汀对阿尔茨海默病模型小鼠有显著治疗作用,能够对小鼠的认知功能、肠道菌群有改善效果。     

Insights into (S)-rivastigmine inhibition of butyrylcholinesterase (BuChE): Molecular docking and saturation transfer difference NMR (STD-NMR)

Rivastigmine is a very important drug prescribed for the treatment of Alzheimer’s disease (AD) symptoms. It is a dual inhibitor, in that it inhibits both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). For our screening program on the discovery of new rivastigmine analogue hits for human butyrylcholinesterase (hBuChE) inhibition, we investigated the interaction of this inhibitor with BuChE using the complimentary approach of the biophysical method, saturation transfer difference (STD)-NMR and molecular docking. This allowed us to obtain essential information on the key binding interactions between the inhibitor and the enzyme to be used for screening of hit compounds. The main conclusions obtained from this integrated study was that the most dominant interactions were (a) H-bonding between the carbamate carbonyl of the inhibitor and the NH group of the imidazole unit of H434, (b) stacking of the aromatic unit of the inhibitor and the W82 aromatic unit in the choline binding pocket via π-π interactions and (c) possible CH/π interactions between the benzylic methyl group and the N-methyl groups of the inhibitor and W82 of the enzyme.     

Preparation and optimization of rivastigmine-loaded tocopherol succinate-based solid lipid nanoparticles

Rivastigmine hydrogen tartrate (RHT) is a pseudo-irreversible inhibitor of cholinesterase and is used for the treatment of Alzheimer's. However, RHT delivery to the brain is limited by the blood–brain barrier (BBB). The purpose of this study was to improve the brain-targeting delivery of RHT by producing and optimizing rivastigmine hydrogen tartrate-loaded tocopherol succinate-based solid lipid nanoparticles (RHT-SLNs). RHT-SLNs were prepared using the microemulsion technique. The impact of significant variables, such as surfactant concentration and drug/lipid ratio, on the size of RHT-SLNs and their drug loading and encapsulation efficiency was analysed using a five-level central composite design (CCD). The minimum size of particles and the maximum efficiency of loading and encapsulation were defined according to models derived from a statistical analysis performed under optimal predicted conditions. The experimental results of optimized RHT-SLNs showed an appropriate particle size of 15.6?nm, 72.4% drug encapsulation efficiency and 6.8% loading efficiency, which revealed a good correlation between the experimental and predicted values. Furthermore, in vitro release studies showed a sustained release of RHT from RHT-SLNs.