Ullah Rahim, Ali Gowhar, Ahmad Nisar, Akram Muhammad, Kumari Geeta, Amin Muhammad Usman, Umar Muhammad Naveed
Department of Pharmacy, University of Peshawar, Peshawar 25120, Pakistan.
Department of Pharmacy, National University of Pakistan, Pasrur Road, Sialkot 51310, Punjab, Pakistan.
Pharmaceuticals (Basel). 2020 Oct 19;13(10):318. doi: 10.3390/ph13100318.
Alzheimer's disease (AD) is an irreversible and chronic neurological disorder that gradually destroys memory and thinking skills. The research study was designed to investigate the underlying molecular signaling involved in the neuroprotective effects of cyclopentanone derivative i.e., 2-(hydroxyl-(3-nitrophenyl)methyl)cyclopentanone (3NCP) as a therapeutic agent for AD. In this study, In vivo studies were carried out on a well-known 5xFAD mice model using different behavioural test models such as open field, rotarod, Morris water maze (MWM), and Y-maze tests. Furthermore, in vitro cholinesterase inhibition activity assays were carried out. The frontal cortex (FC) and hippocampus (HC) homogenates were tested for the levels/activities of cholinesterases, glutathione (GSH), glutathione S-transferase (GST), and catalase. Furthermore, the hippocampal expression of inflammatory cytokines was observed via RT-PCR and western blot. The results of in vivo studies show an enhancement in the learning behavior. The 3NCP treatment reduced latency time in MWM and Y-maze tests, also increase spontaneous alternation indicate significant effect of 3NCP on memory. Furthermore, open field and rotarod studies revealed that 3NCP does not cause motor coordination deficit. The results of the in vitro studies revealed that the IC values of the 3NCP against acetylcholinesterase () and butyrylcholinesterase () were 16.17 and 20.51 µg/mL, respectively. This decline in and was further supported by ex vivo studies. Further, the 3NCP mitigates the GSH level, GST, and catalase activities in HC and FC. The mRNA and protein expression of inflammatory cytokines (IL-1β, IL-6, TNF-α) markedly declined in RT-PCR and western blotting. The results of the current study conclusively demonstrate that 3NCP reduces oxidative stress and mitigates neuroinflammation in 5xFAD mice, implying that 3NCP may be a potential therapeutic candidate for AD treatment in the future.
阿尔茨海默病（AD）是一种不可逆的慢性神经疾病，会逐渐破坏记忆和思维能力。本研究旨在探究环戊酮衍生物2-(羟基-(3-硝基苯基)甲基)环戊酮（3NCP）作为AD治疗药物的神经保护作用所涉及的潜在分子信号传导。在本研究中，使用旷场试验、转棒试验、莫里斯水迷宫（MWM）和Y迷宫试验等不同行为测试模型，在著名的5xFAD小鼠模型上进行了体内研究。此外，还进行了体外胆碱酯酶抑制活性测定。检测了额叶皮质（FC）和海马体（HC）匀浆中胆碱酯酶、谷胱甘肽（GSH）、谷胱甘肽S-转移酶（GST）和过氧化氢酶的水平/活性。此外，通过逆转录聚合酶链反应（RT-PCR）和蛋白质印迹法观察了海马体中炎性细胞因子的表达。体内研究结果显示学习行为有所增强。3NCP治疗缩短了MWM和Y迷宫试验中的潜伏期，还增加了自发交替率，表明3NCP对记忆有显著影响。此外，旷场试验和转棒试验表明3NCP不会导致运动协调缺陷。体外研究结果显示，3NCP对乙酰胆碱酯酶（ ）和丁酰胆碱酯酶（ ）的半数抑制浓度（IC）值分别为16.17和20.51 µg/mL。离体研究进一步支持了 和 的这种下降。此外，3NCP降低了HC和FC中的GSH水平、GST和过氧化氢酶活性。RT-PCR和蛋白质印迹法显示炎性细胞因子（白细胞介素-1β、白细胞介素-6、肿瘤坏死因子-α）的mRNA和蛋白质表达明显下降。本研究结果最终表明，3NCP可减轻5xFAD小鼠的氧化应激并缓解神经炎症，这意味着3NCP未来可能是AD治疗的潜在候选药物。
