Department of Neurosciences and Ageing Biology and Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow 226031, India.
Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, India.
Biochem J. 2021 Apr 16;478(7):1435-1451. doi: 10.1042/BCJ20200754.
Rivastigmine is a clinical drug for patients of Alzheimer's disease (AD) exerting its inhibitory effect on acetylcholinesterase activity however, its effect on other disease-related pathological mechanisms are not yet known. This study was conducted to evaluate the effect of rivastigmine on protein aggregation and degradation related mechanisms employing streptozotocin (STZ) induced experimental rat model. The known inhibitory effect of rivastigmine on cognition and acetylcholinesterase activity was observed in both cortex and hippocampus and further its effect on tau level, amyloid aggregation, biochemical alterations, endoplasmic reticulum (ER) stress, calcium homeostasis, proteasome activity and apoptosis was estimated. STZ administration in rat brain caused significant cognitive impairment, augmented acetylcholinesterase activity, tau phosphorylation and amyloid aggregation which were significantly inhibited with rivastigmine treatment. STZ also caused significant biochemical alterations which were attenuated with rivastigmine treatment. Since AD pathology is related to protein aggregation and we have found disease-related amyloid aggregation, further the investigation was done to decipher the ER functionality and apoptotic signalling. STZ caused significantly altered level of ER stress related markers (GRP78, GADD153 and caspase-12) which were significantly inhibited with rivastigmine treatment. Furthermore, the effect of rivastigmine was estimated on proteasome activity in both regions. Rivastigmine treatment significantly enhances the proteasome activity and may contributes in removal of amyloid aggregation. In conclusion, findings suggested that along with inhibitory effect of rivastigmine on acetylcholinesterase activity and up to some extent on cognition, it has significant effect on disease-related biochemical alterations, ER functionality, protein degradation machinery and neuronal apoptosis.
重酒石酸卡巴拉汀是一种用于治疗阿尔茨海默病（AD）患者的临床药物，它通过抑制乙酰胆碱酯酶的活性发挥作用，但对其他与疾病相关的病理机制的影响尚不清楚。本研究旨在评估重酒石酸卡巴拉汀对蛋白质聚集和降解相关机制的影响，采用链脲佐菌素（STZ）诱导的实验性大鼠模型。研究结果显示，重酒石酸卡巴拉汀在大脑皮质和海马区均表现出对认知和乙酰胆碱酯酶活性的抑制作用，并进一步观察其对 tau 水平、淀粉样蛋白聚集、生化改变、内质网（ER）应激、钙稳态、蛋白酶体活性和细胞凋亡的影响。STZ 脑内给药导致大鼠认知功能显著受损，乙酰胆碱酯酶活性升高，tau 磷酸化和淀粉样蛋白聚集增加，重酒石酸卡巴拉汀治疗可显著抑制这些变化。STZ 还导致了明显的生化改变，重酒石酸卡巴拉汀治疗可减轻这些改变。由于 AD 病理学与蛋白质聚集有关，我们发现了与疾病相关的淀粉样蛋白聚集，因此进一步的研究旨在阐明 ER 功能和细胞凋亡信号。STZ 导致 ER 应激相关标志物（GRP78、GADD153 和 caspase-12）的水平发生显著改变，重酒石酸卡巴拉汀治疗可显著抑制这些改变。此外，还研究了重酒石酸卡巴拉汀对两个区域蛋白酶体活性的影响。重酒石酸卡巴拉汀治疗可显著增强蛋白酶体活性，并可能有助于清除淀粉样蛋白聚集。总之，研究结果表明，除了重酒石酸卡巴拉汀对乙酰胆碱酯酶活性的抑制作用以及在一定程度上对认知的影响外，它还对与疾病相关的生化改变、ER 功能、蛋白质降解机制和神经元凋亡有显著影响。
