Evalution Of Neuroprotective Effects Of Benzo Oxazole Derivatives

Alzheimer’s disease（AD）is a chronic and irreversible disease caused by degeneration of central nervous tissue,and it frequently occurs in middle-aged and elderly people.However,the pathological mechanism is not completely clear so far.Alzheimer’s disease has become one of the most difficult diseases to cure with the aging of the population in our country.So far,no medicine can reverse the onset of Alzheimer’s disease or stop the damage to the nervous system.Therefore,the research and development of drugs for the treatment of Alzheimer’s disease with low toxicity and strong neuroprotection is of great significance.This study explored the neuroprotective effects of a series of new benzoxazole derivatives and provided new ideas for the treatment of Alzheimer’s disease drugs.By adding β-amyloid（amyloid β-protein,Aβ）to establish a cell model of PC12nerve cells,the derivative 5a-5v was intervened,and the positive control drug was donepezil.Through MTT method and Western blot method,benzoxazole derivatives were used to inhibit the pathogenesis and neuroprotection of Alzheimer’s disease.Experiments show that when the concentration of the derivative is 30μg/m L,the cell viability of 13 of the synthesized benzoxazole derivatives is greater than 80%,low overall toxicity.Aβ_25-35 was added to construct a cell model.When the derivative concentration was 5μg/m L,compared with the concentration of 10μg/m L,the derivatives 5c,5o,and 5t had significant effectiveness.The derivative 5c was screened by MTT method to have better low toxicity and effectiveness on PC12 nerve cells induced by Aβ_25-35.By Western blotting,the effects of derivative 5c on Alzheimer’s disease-related pathway proteins GAPDH,Thr181-p-tau,Thr205-p-tau,Ser396-p-tau,Total-tau,GSK-3β,p-GSK-3β,p-AKT,AKT,p-NF-κB,NF-κB,i NOS,RAGE,Bcl-2,Bax and BACE1 influence,reveal the preliminary mechanism that the derivative 5c may exert.The results show that 5c inhibits the abnormal expression of related proteins,so the possible mechanism of action is to inhibit the hyperphosphorylation of Tau protein,while inhibiting β-amyloid deposition through proteolytic enzymes,delaying and relieving the symptoms of Alzheimer’s disease.Derivative 5c can also inhibit the activation of AKT,reduce the inflammatory response and oxidative stress of NF-κB,and inhibit the occurrence of neuroinflammatory injury sites.The derivative 5c modulates Alzheimer’s disease-related proteins in the body,and ultimately changes the abnormal expression of the P13K/AKT/NF-κB/GSK-3βsignaling pathway,and improves the inflammatory response and damage of PC12 nerve cells induced by Aβ_25-35.In addition,in vivo experiments conducted a series of studies on zebrafish mortality,hatching rate,heart rate,and tactile sensitivity.It was found that the derivative 5c showed good low toxicity and toxicity to PC12 cells induced by Aβ_25-35 in the zebrafish experiment.Lower than the positive drug donepezil.In summary,the derivative 5c has a good neuroprotective effect and is expected to be a candidate drug for the treatment of Alzheimer’s disease.