Study On The Effect Of Setmelanotide On Improving Cognitive Dysfunction In Db/db Mice

Objective: Diabetes mellitus may lead to cognitive dysfunction,but its mechanism is unknown and there are no effective drugs for its treatment.In this study,the effects of Setmelanotide(Set),an agonist of MC4 R,on the improvement of cognitive dysfunction in db/db mice were investigated.Methods: Mice aged 6-8 weeks were divided into 3 groups: db/m group,db/db group and db/db+Set group,in which db/db+Set group was injected subcutaneously with Set(1mg/kg)once a day for 6 weeks.T-CHO,TG,HDL-C and LDL-C kits were used to detect the effect of Set on the level of blood lipid in db/db mice.Morris water maze method and scene fear memory test were used to detect the effects of Set on spatial memory and environmental-related fear memory of db/db mice.HE staining and Nissl staining were used to observe the effects of Set on the morphology and structure of hippocampal CA1,CA2,CA3 and DG of db/db mice.Transmission electron microscopy was used to observe the effects of Set on the morphology and structure of neuron mitochondria and endoplasmic reticulum in hippocampal CA1 region of db/db mice..Results: 1.The results of blood glucose showed that compared with db/m group,blood glucose in db/db group was higher,with statistical difference(P<0.01);Compared with db/db group,blood glucose in db/db+Set group decreased to some extent(P<0.01).The results of body weight showed that: compared with db/m group,the body weight of db/db group was significantly higher,with statistical difference(P<0.01);Compared with the db/db group,the body weight of the db/db+Set group decreased(P<0.01).2.Compared with db/m group,serum TCHO,TG,HDL-C,and LDL-C contents of mice in db/db group were significantly increased,with statistical difference(P<0.01);Compared with db/db group,the contents of TCHO,TG,LDL-C,HDL-C and LDL-C in serum of mice in db/db+Set group decreased,with statistical difference(P<0.01).3.In the positioning navigation experiment,compared with the db/m group,the incubation period of the mice in the db/db group was significantly increased;The incubation period of mice in db/db+Set group was significantly shorter than that in db/db group.In the space exploration experiment,it was found that compared with db/m group,the retention time of db/db group was significantly shorter(P<0.01)in effective area.Compared with db/db group,retention time in db/db+Set group increased,with statistical difference(P<0.05).Scene fear memory test: Compared with db/m group,the percentage of stagnation time in db/db group and db/db+Set group was significantly higher,with statistically significant difference(P < 0.01).However,compared with db/db group,there was no significant change in db/db+Set group and no statistical difference(P > 0.05).4.HE staining and Nisl staining results showed that there were different degrees of cell damage in all regions of the hippocampus of db/db mice,especially in CA2 and DG regions.In db/db+Set mice,cell damage in each region of the hippocampus was alleviated to varying degrees.5.The results of electron microscopy showed that the morphology of mitochondria in the db/m group was long rod or oval,and the number of mitochondria was moderate.The number of mitochondria in the db/db group was significantly reduced,and the number of endoplasmic reticulum was also significantly decreased,and the structural fracture was incomplete.In the db/db+Set group,the number of endoplasmic reticulum and mitochondria were restored to some extent,and the structure was relatively intact.Conclusions: 1.Set can reduce the body weight and blood glucose of db/db mice,and reduce the content of blood lipid in db/db mice;2.Set can improve spatial learning and memory impairment in db/db mice;3.Set may reduce the morphological damage of hippocampal neurons in db/db mice by alleviating the damage of endoplasmic reticulum and mitochondria,thus improving the learning and memory impairment.