Rehman Inayat Ur, Ahmad Riaz, Khan Ibrahim, Lee Hyeon Jin, Park Jungsung, Ullah Rahat, Choi Myeong Jun, Kang Hee Young, Kim Myeong Ok
Division of Life Sciences and Applied Life Science (BK 21 Four), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea.
Research and Development Center, Axceso Bio-pharma co, Anyang 14056, Korea.
Biomedicines. 2021 Apr 10;9(4):408. doi: 10.3390/biomedicines9040408.
Alzheimer's disease (AD) is the most predominant age-related neurodegenerative disease, pathologically characterized by the accumulation of aggregates of amyloid beta Aβ and tau hyperphosphorylation in the brain. It is considered to be the primary cause of cognitive dysfunction. The aggregation of Aβ leads to neuronal inflammation and apoptosis. Since vitamins are basic dietary nutrients that organisms need for their growth, survival, and other metabolic functions, in this study, the underlying neuroprotective mechanism of nicotinamide (NAM) Vitamin B3 against Aβ -induced neurotoxicity was investigated in mouse brains. Intracerebroventricular (i.c.v.) Aβ injection elicited neuronal dysfunctions that led to memory impairment and neurodegeneration in mouse brains. After 24 h after Aβ injection, the mice were treated with NAM (250 mg/kg intraperitoneally) for 1 week. For biochemical and Western blot studies, the mice were directly sacrificed, while for confocal and "immunohistochemical staining", mice were perfused transcardially with 4% paraformaldehyde. Our biochemical, immunofluorescence, and immunohistochemical results showed that NAM can ameliorate neuronal inflammation and apoptosis by reducing oxidative stress through lowering malondialdehyde and 2,7-dichlorofluorescein levels in an Aβ-injected mouse brains, where the regulation of p-JNK further regulated inflammatory marker proteins (TNF-α, IL-1β, transcription factor NF-kB) and apoptotic marker proteins (Bax, caspase 3, PARP1). Furthermore, NAM + Aβ treatment for 1 week increased the amount of survival neurons and reduced neuronal cell death in Nissl staining. We also analyzed memory dysfunction via behavioral studies and the analysis showed that NAM could prevent Aβ -induced memory deficits. Collectively, the results of this study suggest that NAM may be a potential preventive and therapeutic candidate for Aβ -induced reactive oxygen species (ROS)-mediated neuroinflammation, neurodegeneration, and neurotoxicity in an adult mouse model.
阿尔茨海默病（AD）是最主要的与年龄相关的神经退行性疾病，其病理特征是大脑中β淀粉样蛋白（Aβ）聚集体的积累和tau蛋白的过度磷酸化。它被认为是认知功能障碍的主要原因。Aβ的聚集会导致神经元炎症和凋亡。由于维生素是生物体生长、生存及其他代谢功能所需的基本膳食营养素，在本研究中，我们在小鼠脑内研究了烟酰胺（NAM，维生素B3）对Aβ诱导的神经毒性的潜在神经保护机制。脑室内（i.c.v.）注射Aβ会引发神经元功能障碍，导致小鼠脑内记忆损伤和神经退行性变。在注射Aβ后24小时，给小鼠腹腔注射NAM（250mg/kg），持续1周。用于生化和蛋白质印迹研究的小鼠直接处死，而用于共聚焦和免疫组织化学染色的小鼠则通过心脏灌注4%多聚甲醛。我们的生化、免疫荧光和免疫组织化学结果表明，在注射Aβ的小鼠脑内，NAM可通过降低丙二醛和2,7 - 二氯荧光素水平来减轻氧化应激，从而改善神经元炎症和凋亡，其中p - JNK的调节进一步调控了炎症标记蛋白（TNF -α、IL - 1β、转录因子NF - kB）和凋亡标记蛋白（Bax、caspase 3、PARP1）。此外，NAM + Aβ处理1周增加了尼氏染色中存活神经元的数量并减少了神经元细胞死亡。我们还通过行为学研究分析了记忆功能障碍，结果表明NAM可预防Aβ诱导的记忆缺陷。总体而言，本研究结果表明，在成年小鼠模型中，NAM可能是预防和治疗Aβ诱导的活性氧（ROS）介导的神经炎症、神经退行性变和神经毒性的潜在候选药物。
