The Effect Of Lamotrizine On Chronic Inflammatory Response In The Brain Of APP/PS1 Mice And Its Mechanism

Objective This article aims to investigate the effect of lamotrizine on chronic inflammatory response in the brain of APP/PS1 double transgenic mice,and to further explore its possible mechanism,thus providing a valuable reference for clinical drug treatment of Alzheimer's disease and providing important theoretical support and experimental basis for the clinical application and industrialization of LTG in the treatment of Alzheimer's disease.Methods Twenty 4-months-old male APP/PS1 double transgenic positive mice(TG)were divided into two groups,10 in treatment model group(TG+LTG)and 10 in model group(TG).Twenty 4-months-old male wild control mice(WT)were divided into two groups,10 in treatment control group(WT+LTG)and 10 in blank control group(WT).The treament mice were given lamotrigine(30 mg/kg.d)for 3 months.Then,we extracted the brain protein.The expression levels of inflammatory factors IL-1?,IL-10,TNF-? and TGF-? in the brain of each group were detected by ELISA;The expression levels of sodium channel proteins Nav1.1,Nav1.2 and Nav1.6 in the brain of each group was detected by Western Blot;The expression levels of signaling pathway proteins p-PI3K/PI3K?p-AKT/AKT and p-GSK-3?/GSK-3? in the brain of each group was detected by Western Blot.Results 1.Lamotrigine can up-regulate the expression of anti-inflammatory factors and down-regulate the expression of pro-inflammatory factors in the brain of APP/PS1 double transgenic mice.Compared with wild control mice(WT),the expression levels of pro-inflammatory factors IL-1? and TNF-? in the brain of APP/PS1 double transgenic mice(TG)were significantly increased(P<0.001,P<0.001).After treatment with lamotrigine,it decreased significantly(P<0.05,P<0.05);Compared with wild control mice(WT),the expression levels of anti-inflammatory factors IL-10 and TGF-? in the brain of APP/PS1 double transgenic mice(TG)were significantly decreased(P<0.001,P<0.05).After treatment with lamotrigine,it increased significantly(P<0.05,P<0.05).Lamotrigine had no significant effect on the expression levels of inflammatory cytokines IL-1?,IL-10,TNF-? and TGF-? in the brain of wild control mice(WT)(P>0.05).2.Lamotrigine can reduce the expression of Nav1.6 protein in the brain of APP/PS1 double transgenic mice The relative expression level of Nav1.6 protein in the brain of APP/PS1 double transgenic mice(TG)was significantly higher than that in wild control mice(WT)(P<0.001),but decreased after treatment with lamotrigine(P< 0.01).Lamotrigine had no significant effect on the relative expression level of Nav1.6 protein in the brain of wild control mice(WT)(P>0.05).Lamotrigine had no significant effect on the relative expression levels of Nav1.1 and Nav1.2 proteins in the brain of APP/PS1 double transgenic mice(TG)(F=1.468,P=0.295;F=1.383,P=0.316)..3.Lamotrigine can increase the expression levels of PI3 K,AKT and GSK-3? in the brain of APP/PS1 double transgenic mice Lamotrigine treatment can increase the relative expression level of PI3 K protein in the brain of APP/PS1 double transgenic mice(P<0.01).However,lamotrigine had no significant effect on the relative expression level of PI3 K protein in the brain of wild control mice(WT)(P>0.05).The relative expression level of AKT protein in the brain of APP/PS1 double transgenic mice(TG)was significantly lower than that in wild control mice(WT)(P<0.001),but increased after treatment with lamotrigine(P<0.05).Lamotrigine had no significant effect on the relative expression level of AKT protein in the brain of wild control mice(WT)(P>0.05).Lamotrigine treatment can increase the relative expression level of GSK-3? protein in the brain of APP/PS1 double transgenic mice(P<0.01).However,lamotrigine had no significant effect on the relative expression level of GSK-3? protein in the brain of wild control mice(WT)(P>0.05).4.Lamotrigine can increase the expression levels of p-PI3 K,p-AKT and p-GSK-3? in the brain of APP/PS1 double transgenic mice Lamotrigine treatment can increase the relative expression level of p-PI3 K protein in the brain of APP/PS1 double transgenic mice(P<0.05);Compared with wild control mice(WT),the expression levels of p-AKT in the brain of APP/PS1 double transgenic mice(TG)were significantly decreased(P<0.001).After treatment with lamotrigine,it increased significantly(P<0.05);Compared with wild control mice(WT),the expression levels of p-GSK-3? in the brain of APP/PS1 double transgenic mice(TG)were significantly decreased(P<0.001).After treatment with lamotrigine,it increased significantly(P<0.01)Conclusion Lamotrigine may reduce the expression of Nav1.6 protein by activating PI3K/AKT/ GSK-3? signaling pathway,thereby attenuating the chronic inflammatory response in the brain of APP/PS1 double transgenic mice.