Study On The Anti-alzheimer’s Disease Activity Of Sesquiterpene Lactone OABL And Imidazolylphenonexime Ether T-4a

Alzheimer’s disease(AD)is a neurodegenerative disease with clinical symptoms including memory loss,language and cognitive impairment,which poses a serious threat to the health and social development of the elderly.The pathogenesis of AD is still unclear.Its two typical pathological features are abnormal deposition of beta-amyloid(Aβ)and excessive phosphoric acid of Tau protein.In addition,neuroinflammation and oxidative stress have been linked to neuron loss and cognitive impairment.At present,people have carried out in-depth studies on AD from different perspectives,but there is still a lack of drugs to slow the disease process or cure Alzheimer’s disease.Previous phenotypic screening studies found that 1,6-O,O-diacetylbritannilactone(OABL)and imidazolylphenonexime ether(T-4a)showed significant anti-neuroinflammatory activity and good blood-brain barrier permeability in vitro.However,the interventional role of OABL and T-4a in neurodegenerative diseases and their mechanisms have rarely been reported.In this study,5xFAD mice were used as a model to study the improvement effect and mechanism of OABL and T-4a on cognitive and memory impairment in AD mice.The main research results are as follows:(1)In lipopolysaccharide(LPS)-induced neuroinflammatory model of microglia(BV-2cells),OABL showed a strong anti-inflammatory effect via suppressing of NF-κB signaling pathway and promoting the microglia conversion from M1 to M2 phenotype,with low cytotoxicity.In addition,OABL had a significant neuroprotective effect on oxidative stress.(2)The 5xFAD mouse model was used to explore the improvement effect of OABL on brain cognitive dysfunction.The cognitive memory function of AD mice was evaluated by water maze test.The results showed that OABL significantly improved the spatial memory ability of AD mice.The morphology and synaptic structure of brain neurons in mice were observed by H&E staining and transmission electron microscopy.The results showed that OABL significantly improved the damage of neurons and synaptic plasticity in AD mice.The deposition of beta-amyloid(Aβ)was observed by ELISA,immunofluorescence staining and sulfurin S staining.According to the quantitative results,the accumulation of Aβ in AD mice was higher than that in WT mice,and OABL intervention significantly reduced the deposition of Aβ in the brain of AD mice.The possible mechanism is to inhibit the expression of β-secretase 1(BACE-1).The levels of inflammation and oxidative stress in the brain of mice were evaluated by immunofluorescence staining,Western blot and q RT-PCR.The results showed that OABL significantly inhibited the activation of glial cells,and inhibited the levels of inflammation and oxidative stress in the brain of AD mice.(3)To explore the improvement of imidazolylphenonexime ether(T-4a)on brain cognitive dysfunction and anxiety-like behavior in 5xFAD mice.The cognitive memory function and anxiety-like behavior of AD mice were evaluated by behavioral experiments(Barnes maze test,Y maze test,elevated plus-maze test and marble-burying test).The results showed that T-4a improved spatial memory ability,working memory ability and anxiety symptoms of AD mice.H&E staining,immunofluorescence staining and Western blot were used to observe the neuron injury,the deposition of Aβ and the level of inflammation in the brain of mice.The results showed that low dose and high dose T-4a treatment could both improve the neuron injury and reduce the accumulation of Aβ and the level of inflammation in the brain of AD mice.In conclusion,sesquiterpene lactone OABL and imidazolylphenonexime ether(T-4a)have neuroprotective effects and can reduce Aβ deposition,synaptic plasticity injury,neuronal injury,oxidative stress response and cognitive and memory impairment in AD mice.In comparison,the activity of T-4a is more significant and has the potential to improve anxiety,which provides a reference for the creation of neurological drugs.