The Neuroprotective Effect Of Fluoxetine On Ischemic White Matter Injury

Background:Ischemic cerebrovascular disease has become a common and frequent disease threatening the health and quality of life of middle-aged and elderly people.MBP protein is a specific expression protein of mature oligodendrocytes,an essential protein component for normal formation of oligodendrocytes,and a landmark protein of mature myelin sheath,which plays a role in maintaining the complete structure and stable function of myelin sheath.The expression of MBP in the brain can also indirectly reflect the demination of the brain.After injury of myelin sheath,information transmission dysfunction between neurons,cortex and subcortical white matter can be secondary,resulting in learning,memory ability and emotional dysfunction.Fluoxetine is a new type of selective serotonin reuptake inhibitor(SSRIs)antidepressant,we know that which has been widely used in clinical treatment of depression,anxiety,obsessive-compulsive disorder and other mental diseases.Recent studies have found that fluoxetine has a neuroprotective effect on white matter.Therefore,we hypothesized to establish a mouse model of cerebral white matter ischemia injury,to explore the preprotective effect of fluoxetine on ischemic white matter injury and explore the possible mechanism,so as to explore a new therapeutic target for the biological intervention of cerebral white matter injury repair after cerebral ischemia and hypoxia.Objective:Ischemic cerebrovascular disease has become a common and frequently-occurring disease that threatens the health and quality of life of middle-aged and elderly people.After cerebral ischemia,white matter is very susceptible to ischemia and is often more severely damaged than gray matter.The model of cerebral white matter ischemia injury in mice was established by ligation of bilateral common carotid artery and pretreated with fluoxetine.The object is to investigate the effect of fluoxetine pretreatment on white matter myelin in mice with white matter ischemia injury,and to explore the preprotective effect of fluoxetine preconditioning on ischemic white matter and its possible mechanism,by observing the data indexes of forced swimming experiment,tail suspension experiment,open field experiment and cross maze experiment in mice and the changes of myelin basic protein(MBP)in white matter.Methods:After the bilateral common carotid artery was ligated for 20 min,the ligation line was loosened and the neck wound was sutured to establish a model of cerebral white matter ischemic injury in mice.In this study,60 CD1 male mice were randomly divided into three groups: white matter ischemia model group(model group),sham operation group(sham group),and fluoxetine pretreatment group(treatment group).The treatment group was given fluoxetine 10 mg/kg intraperitoneally injected before operation,and the model group and sham group were intraperitoneally injected with 10 mg/kg of normal saline for 5 weeks.In the 5th week,the model group and treatment group were separated from the common carotid artery through the median cervical incision,the incision skin and subcutaneous tissue,and bilateral common carotid artery ligation was performed with 6-0 surgical line for 20 min,and then the ligation line was released and the incision was sutured.In the sham group,only a median cervical incision was performed,bilateral common carotid arteries were isolated,no ligation was performed,and the skin incision was sutured after 20 min.At the 6th week of the experiment,the mice were subjected to forced swimming test,tail suspension experiment,open field experiment,high cross maze experimental behavior test,and the experimental data indicators were recorded and counted.At the 8th week of the experiment,the mice were anesthetized,blood was taken,heart perfused,and decapitated,and the expression of myelin basic protein(MBP)in the brain was tested by Western blot.Results:1.Forced swimming experiment:the static time of the model group in water was significantly longer than that of the sham group and the treatment group,and the difference was statistically significant(P<0.05);the mice in the treatment group remained motionless in water longer than those in the sham group,and the difference was statistically significant(P<0.05).2.Tail suspension experiment: the suspension time of the model group was significantly longer than that of the sham group and the treatment group(P<0.05).the suspension time of mice in the treatment group was longer than that in the sham group,and the difference was statistically significant(P<0.05).3.Open-field experiment:compared with the sham group,the mice of model group had significantly less movement distance and residence time in the central region,and the difference was statistically significant(P<0.05);there were statistically significant differences between the model group and the treatment group in motor distance and residence time in the central region(P<0.05).4.High cross maze experiment:compared with the sham group and the model group,the mice in the model group and the treatment group had statistically significant differences in the number of entering the open arm,the number of closing arm,the time of opening arm retention,and the time of closing arm retention(P<0.05);there was no statistically significant difference between the sham group and the treatment group in the number of open arm entry,number of closed arm entry,open arm retention time and closed arm retention time(P>0.05).5.Expression of MBP protein in white matter:the expression of MBP in the model group was lower than that in the treatment group and sham group,and the difference was statistically significant(P<0.05);the expression of MBP in the treated group was lower than that in sham group,and the difference was statistically significant(P<0.05).Conclusion:1.Forced swimming,tail-hanging experiment,open-field experiment and high-cross maze experiment showed that mice with white matter ischemic injury showed depression-like and anxiety-like behaviors,and fluoxetine pretreatment could improve depression and anxiety behaviors of mice with white matter ischemic injury.2.The results of MBP western blot showed that the expression of MBP in the white matter of the model group was lower than that in the sham group.After the occurrence of white matter ischemic injury in mice in the treatment group,the expression of white matter MBP in the treatment group increased compared with that in the model group,but decreased compared with that in the sham group,indicating that fluoxetine can improve the content of myelin basic protein,and fluoxetine can protect the white matter of mice with cerebral ischemia by inhibiting the degradation and disappearance of myelin basic protein.