Choe Kyonghwan, Park Jun Sung, Park Hyun Young, Tahir Muhammad, Park Tae Ju, Kim Myeong Ok
Division of Life Science and Applied Life Science (BK21 FOUR), College of Natural Sciences, Gyeongsang National University, Jinju-si, Republic of Korea.
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, Netherlands.
Front Nutr. 2024 Jul 10;11:1414696. doi: 10.3389/fnut.2024.1414696. eCollection 2024.
Neuroinflammation includes the activation of immune glial cells in the central nervous system, release pro-inflammatory cytokines, which disrupt normal neural function and contribute to various neurological disorders, including Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, and stroke. AD is characterized by various factors including amyloidogenesis, synaptic dysfunction, memory impairment and neuroinflammation. Lipopolysaccharide (LPS) constitutes a vital element of membrane of the gram-negative bacterial cell, triggering vigorous neuroinflammation and facilitating neurodegeneration. Lupeol, a naturally occurring pentacyclic triterpene, has demonstrated several pharmacological properties, notably its anti-inflammatory activity. In this study, we evaluated the anti-inflammatory and anti-Alzheimer activity of lupeol in lipopolysaccharide (LPS)-injected mice model. LPS (250ug/kg) was administered intraperitoneally to C57BL/6 N male mice for 1 week to induce neuroinflammation and cognitive impairment. For biochemical analysis, acetylcholinesterase (AChE) assay, western blotting and confocal microscopy were performed. AChE, western blot and immunofluorescence results showed that lupeol treatment (50 mg/kg) along with LPS administration significantly inhibited the LPS-induced activation of neuroinflammatory mediators and cytokines like nuclear factor (NF-κB), tumor necrosis factor (TNF-α), cyclooxygenase (COX-2) and interleukin (IL-1β). Furthermore, we found that LPS-induced systemic inflammation lead to Alzheimer's symptoms as LPS treatment enhances level of amyloid beta (Aβ), amyloid precursor protein (APP), Beta-site APP cleaving enzyme (BACE-1) and hyperphosphorylated Tau (p-Tau). Lupeol treatment reversed the LPS-induced elevated level of Aβ, APP, BACE-1 and p-Tau in the hippocampus, showing anti-Alzheimer's properties. It is also determined that lupeol prevented LPS-induced synaptic dysfunction via enhanced expression of pre-and post-synaptic markers like SNAP-23, synaptophysin and PSD-95. Overall, our study shows that lupeol prevents memory impairment and synaptic dysfunction via inhibition of neuroinflammatory processes. Hence, we suggest that lupeol might be a useful therapeutic agent in prevention of neuroinflammation-induced neurological disorders like AD.
神经炎症包括中枢神经系统中免疫胶质细胞的激活，释放促炎细胞因子，这会破坏正常神经功能并导致各种神经疾病，包括阿尔茨海默病（AD）、帕金森病、多发性硬化症和中风。AD的特征包括多种因素，如淀粉样蛋白生成、突触功能障碍、记忆损害和神经炎症。脂多糖（LPS）是革兰氏阴性细菌细胞膜的重要组成部分，可引发强烈的神经炎症并促进神经退行性变。羽扇豆醇是一种天然存在的五环三萜，已显示出多种药理特性，尤其是其抗炎活性。在本研究中，我们评估了羽扇豆醇在注射脂多糖（LPS）的小鼠模型中的抗炎和抗阿尔茨海默病活性。将LPS（250μg/kg）腹腔注射给C57BL/6 N雄性小鼠1周，以诱导神经炎症和认知障碍。进行了生化分析、乙酰胆碱酯酶（AChE）测定、蛋白质印迹和共聚焦显微镜检查。AChE、蛋白质印迹和免疫荧光结果表明，羽扇豆醇治疗（50mg/kg）与LPS给药一起显著抑制了LPS诱导的神经炎症介质和细胞因子如核因子（NF-κB）、肿瘤坏死因子（TNF-α）、环氧化酶（COX-2）和白细胞介素（IL-1β）的激活。此外，我们发现LPS诱导的全身炎症导致阿尔茨海默病症状，因为LPS治疗会提高β淀粉样蛋白（Aβ）、淀粉样前体蛋白（APP）、β位点APP裂解酶（BACE-1）和过度磷酸化的 Tau（p-Tau）水平。羽扇豆醇治疗逆转了LPS诱导的海马中Aβ、APP、BACE-1和p-Tau水平的升高，显示出抗阿尔茨海默病特性。还确定羽扇豆醇通过增强突触前和突触后标志物如SNAP-23、突触素和PSD-95的表达来预防LPS诱导的突触功能障碍。总体而言，我们的研究表明羽扇豆醇通过抑制神经炎症过程预防记忆损害和突触功能障碍。因此，我们认为羽扇豆醇可能是预防神经炎症诱导的神经疾病如AD的有用治疗剂。
