The Influence Of Exenatide On The Cognitive Impairment Induced By Aluminum Chloride And D-galactose In Mice

Cognitive impairment and dementia are the main symptoms of neurodegenerative diseases such as Alzheimer's disease,vascular dementia and Parkinson's disease,which are age associated.Because of clinical manifestations of obstacle in language,motor,cognitive and other aspects,these diseases seriously affect the life quality of the patients.With the increasing aging of the global population,such diseases are not only a medical problem but also impose a heavy burden on society.Recent studies have shown that GLP-1 receptor agonists can effectively delay the occurrence and development of neurodegenerative diseases and relieve the symptoms associated with the disease,which has become a research hotspot.The GLP-1 receptor is widely distributed in the human body and largely expressed on the surface of nerve cells.It has been reported that a variety of GLP-1 receptor agonists(eg,exenatide,liraglutide)and DPP4-1 inhibitors can significantly reduce neuronal damage caused by amyloid beta deposition and Tau phosphorylation in the hippocampus and cortex,and effectively improving memory and cognitive ability in Alzheimer's disease animal models.The research also found that GLP-1 receptor agonists have different therapeutic effects on animal models prepared by different mechanism.Oxidative stress is one of the major causes of aging and cognitive impairment.In this study,the method of combination of D-galactose and aluminum chloride was used to indece the cognitive impairment in mice model by oxidative stress.Exenatide(EX-4)was used as a model drug to evaluate therapeutic effects of GLP-1 receptor agonists on this model.And the preliminary mechanism was also studied.The results of the study showed that D-galactose and aluminum chloride administered for ten weeks,resulting in aging-related symptoms in mice,such as motor reducing and hair losing.HE staining of hippocampal slices showed that the model mice had obvious neuronal damage.However,the A? plaques which have been reported in other studies were not found.The mice's behavior was investigated by the electric Y maze and the water maze.The results showed that learning and memory ability and cognitive function were significantly decreased in model mice,while the evasion accuracy in the electric Y maze test and the key indicators in water maze,such as residence time in target quadrant and the times of platform location crosses,were significantly improved by EX-4 treated.The neuroblastoma cell(SH-SY5Y)which expresses the GLP-1 receptor was used to study the preliminary mechanism.The results showed that EX-4 had a significant pro-proliferative effect on SH-SY5 Y cells,and had significant protective effect on H2O2-induced oxidative stress injury,which could be suppressed by the GLP-1R inhibitor.While the similar results were not found in the ZR cells which don't express the GLP-1 receptor.In summary,the present study confirms that GLP-1 receptor agonists have a protective effect on cognitive impairment in mice induced by the combination of Dgalactose and aluminum chloride.The protective effect is related to anti-oxidative stress induced by GLP-1 receptor activation.This study laid the foundation for the application of exenatide in the treatment of cognitive impairment related to oxidative stress.