Mechanism Of 1-deoxynojirimycin On Neuroprotection In Alzheimer’s Disease

β-amyloid deposition and neuroinflammation play a crucial part in Alzheimer’s disease(AD).Modern studies have found a certain correlation between Alzheimer’s disease and metabolic diseases such as diabetes,and it is trying to find effective drugs from hypoglycemic drugs in order to find new efficacy.Morus alba L.and Commelina communis L.are traditional chinese medicines used in the treatment of diabetes.Both of them contain 1-deoxynojirimycin(DNJ),which has been proved to be the active ingredient of hypoglycemic.With the deepening of research,DNJ not only has the effect of lowering blood glucose and improving insulin resistance,but also has the pharmacological effects of anti-aging,anti-virus and anti-bacterial.Currently,N-hydroxyethyl-1-deoxynojirimycin(miglitol)and metformin hydrochloride are also used for reducing blood glucose.Therefore,this study aims to explore the effect and mechanism of Morus alba L.and other hypoglycemic drugs on the pathological changes associated with Alzheimer’s disease,especially P-amyloid deposition and neuroinflammation.The main contents of this study are as follows:In this study,based on the wild type N2 model of Caenorhabditis elegans,the anti-aging effects of crude extracts of Morus alba L.,total alkaloid of Commelina communis L.,1-deoxynojirimycin,miglitol and metformin hydrochloride at different concentrations are studied with life span as the index.The results show that the crude extracts of Morus alba L.,miglitol and total alkaloid of Commelina commzunis L.have no obvious effect,while DNJ have anti-aging effects,and metformin hydrochloride significantly shortens the lifespan of elegans.This experiment continues to use the senescence-accelerated-prone mouse 8(SAMP8)mice as the animal model of Alzheimer’s disease to study the influence and mechanism of DNJ and metformin hydrochloride on the pathological changes associated with Alzheimer’s disease.Compared to senescence-accelerated-resistant mouse 1(SAMR1)mice,the 12-month-old SAMP8 mice exhibits impaired spatial memory in Morris water maze test;increased Aβdeposition and microglia activation in immunohistochemical staining;declines in brain-derived neurotrophic factor(BDNF),tyrosine kinase receptors(TrkB)and astrocytes levels of hippocampus,increased BACE-1 expression by western blotting analysis;elevated level of inflammatory factors,including interleukin-1β(IL-1β),interleukin-6(IL-6)and tumor necrosis factor α(TNF-α)in the brain by ELISA.The 10-month-old SAMP8 mice are orally given either DNJ(40,160mg/kg/day)or metformin hydrochloride(1000mg/kg/day)for two months.The results show that metformin hydrochloride had no improvement on the learning and memory ability of SAMP8 mice.While 160mg/kg/day DNJ significantly improves the learning and memory ability of SAMP8 mice,inhibits the expression of BACE-1,Aβ deposition,the level of microglial cells and neuroinflammation,and up-regulates the BDNF/TrkB signaling pathway in the hippocampus,having a neuroprotective effect.Finally,B6C3-APP/PS1 double-transgenic mice are used to further study the effect and mechanism of DNJ and metformin hydrochloride on early-onset familial AD.Th e results show that the learning and memory functions of B6C3-APP/PS1 mice are not impaired in the 6-month-old intelligence water maze,9-month-old Morris water maze and 12-month-old Morris water maze test.However,according to the immunohistochemical staining,Aβ deposition has already appeared in brain of the 9-month-old B6C3-APP/PS1 mice.DNJ prophylaxis for 23 weeks,DNJ treatment for 8 weeks and metformin hydrochloride treatment for 8 weeks do not improve the deposition significantly.It indicates that DNJ and metformin hydrochloride have no obvious relief on Aβ deposition in early-onset familial Alzheimer’s disease.In conclusion,this study is based on different animal models to screen Morus alba L.and other hypoglycemic drugs,and study the effect and mechanism on the pathological changes associated with Alzheimer’s disease.This study finds that the crude extracts of Morus alba L.,miglitol,total alkaloid of Commelina communis L.and metformin hydrochloride have no improvement.While DNJ has an anti-aging effect and can improve the learning and memory abilities of SAMP8 mice,reduce Aβ deposition,alleviate neuroinflammation,playing a neuroprotective role,but has no significant relief on Aβ deposition in early-onset familial Alzheimer’s disease.These research findings of the present study provide an important reference for the development of therapeutic drugs in Alzheimer ’s disease.