神经炎症
迷迭香酸
氧化应激
药理学
细胞凋亡
半胱氨酸蛋白酶3
莫里斯水上航行任务
化学
脂质过氧化
神经退行性变
生物化学
炎症
医学
内分泌学
程序性细胞死亡
免疫学
内科学
抗氧化剂
海马结构
疾病
作者
Chetan Thingore,Viplav Kshirsagar,Malvika Gursahani,Archana R. Juvekar
标识
DOI:10.1016/j.jalz.2019.06.2622
摘要
AD is characterized by classical hallmarks like cell apoptosis, Amyloid β (Aβ) and Microtubule associated protein tau. Other significant findings are oxidative stress and neuroinflammation. Lipopolysaccharide (LPS), on systemic administration induces neuroinflammation and subsequent formation of Aβ, by binding to toll like receptors (TLRs). This leads to memory impairment in mice and therefore serves as an excellent model for memory impairment and AD. Rosmarinic acid displays anti-oxidant and anti-choline esterase (AChE) properties in-vitro. Conversely, Rosmarinic acid was explored in-vivo to inhibit caspase-3 mediated cell apoptosis in LPS induced neuroinflammatory model against AD and thus inhibiting cell apoptosis. Rosmarinic acid [RA] will be administered from day 1 for 21 days (5 mg/kg and 15 mg/kg). LPS will be administered to animals from day 15th for 7 days (250μg/kg i.p.). Administration of RA will continue for next 7 days (28th day). Efficacy of RA will be evaluated using Morris water Maze test and Novel Object Recognition test between days 22nd to day 28th. After scarification on 28th day, brain tissue homogenate will be estimated for depletion of Glutathione levels, decreased Lipid peroxidation; increased super oxide dismutase level and acetyl choline esterase inhibitory activity. ELISA will show levels of IL-6, TNF- α and caspase-3 mediated cell apoptosis. This will be further justified by brain histopathology (Hippocampal region). Computational studies involved docking of RA on Aβ monomers, AChE, GSK3β, caspase-3 and β- secretase. Rosmarinic acid dose dependently, reduced catastrophic effects caused by LPS estimated with behavioural tests. The results obtained were in synergy to those with biochemical tests and ELISA. Lipid peroxidation levels were significantly attenuated while; super oxide dismutase levels were augmented. Rosmarinic acid inhibited AChE activity significantly. Histopathology shows less neurodegeneration with respect to negative control. ELISA showed noteworthy increase in caspase-3 inhibition by RA. Further, RA also showed to have good binding to β- secretase, GSK3β and Aβ monomers in-silico. Rosmarinic acid possesses significant antioxidant, anti-inflammatory, antiapoptotic and AChE inhibitory activity at preclinical stage and can be discovered further for its potential use as prophylactic therapy in AD.
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