The Effects Of Quetiapine On Cognition And White Matter Of C57BL/6 Mice With Chronic Alcohol Exposure

BackgroundCerebral white matter is composed of nerve fibers, controlling the signals between neurons and coordinating functions among brain areas, involved in the formation of emotion, cognition, memory and the visual space function.Chronic alcohol consumption can cause varying degrees of cerebral white matter lesions. Recent studies have shown that the antipsychotics quetiapine promotes oligodendrocytes development and brain white matter remyelination. The study of the effect of quetiapine on white matter damage caused by chronic alcohol consumption will play an important role in the clinical prevention and treatment of alcohol consumption.Objective1. To explore the influence of quetiapine on cognitive function and white matter damage due to chronic alcohol exposure by investigating the effects of quetiapine on learning and memory abilities and myelin morphological structure in the corpus callosum of C57BL/6 mice with chronic alcohol exposure.2. To explore the possible molecular mechanisms that underlying protective effect of quetiapine on cognitive function and white matter damage due to alcohol by determining the expression of myeline basic protein(MBP), myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte transcription factor-2 (Olig2) in the corpus callosum of C57BL/6 mice with chronic alcohol exposure.Methods1. One hundred and forty male C57BL/6 mice were through by Morris water maze experiment no significant one hundred and twenty mice, which were randomly divided into six groups according to random number table:control group, quetiapine control group (10 mg·kg-1·d-1 quetiapine), alcohol group,5 mg·kg-1·d-1 quetiapine plus alcohol group,10 mg·kg-1·d-1 quetiapine plus alcohol group and 15 mg·kg-1·d-1 quetiapine plus alcohol group, with 20 mice in each group. Mice in control group and quetiapine control group were maintained with distilled water and solid diet for 20 weeks.10 mg·kg-1·d-1 quetiapine was dissolved in distilled water for mice of quetiapine control group drinking beginning at the 6th week and continuing to the end of the experiment. Mice of alcohol group and quetiapine plus alcohol groups were maintained with distilled water containing volume fraction of 10% alcohol and solid diet for 20 weeks. Drug with different doses was dissolved in mice drinking for intervention beginning at the 6th week and continuing to the end of the experiment.2. After intervention, Morris water maze experiment was used to test the cognitive function of animals, the rest of the animals were killed and take the brain tissue. Luxol fast blue (LFB) staining and electron microscopy were used to observe morphology of corpus callosum. The protein expression of myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) in the corpus callosum was evaluated with immunofluorescence. The gene transcription of MBP, MOG and oligodendrocyte transcription factor-2 (Olig2)in the corpus callosum of the six groups animals are detected by using reverse transcription polymerase chain reaction (RT-PCR).3. Data analysis were conducted using SPSS 20.0. Test results were presented as (x±s)and analysis using one-way analysis of variance (ANOVA), according to the results of homogeneity of variance test (Levene test)Choose least significant difference (LSD)or the Dunnett T3 for pairwise comparisons between groups. All results were two-sides test, and the size of a test was a=0.05.Results1. Behavior results:Morris water maze test showed that the cognition of mice in each group was different (F=4.702, P=0.002). The test score of mice in alcohol group was significantly decreased compared with that of the control group(P<0.05). The test scores of 5 mg·kg-1·d-1 and 10 mg·kg-1·d-1 quetiapine plus alcohol groups were not significant compared with that of the alcohol group. The test score of 15 mg·kg-1·d-1 quetiapine plus alcohol group was significantly increased compared with that of the alcohol group(P< 0.05). The test score of Quetiapine control group was not significant compared with that of the control group.2. LFB staining and electron microscope results:LFB staining and electron microscope results showed severe myelin damage in the corpus callosum of mice in alcohol group and 5 mg·kg-1·d-1 quetiapine plus alcohol group, while the integrity of the myelin sheath in 10 mg·kg-1·d-1 and 15 mg·kg-1·d-1quetiapine plus alcohol groups improved significantly compared with the alcohol group. Quetiapine control group was not significant compared with that of the control group.3. Immunofluorescence results:In the corpus callosum of each group mice, the expression of MBP and MOG was different (MBP:F=12.237, MOG:F=18.275, P< 0.05).The expression of MBP and MOG in alcohol group was significantly decreased compared to the control group (P<0.05). The expression of MBP, MOG in 5 mg·kg-1·d-1 quetiapine plus alcohol group was not significant compared with the alcohol group.The expression of MBP, MOG of 10 mg·kg-1·d-1 and 15 mg·kg-1·d-1 quetiapine plus alcohol groups were significantly increased compared with the alcohol group (P<0.05). The expression of MBP, MOG in quetiapine control group was not significant compared with the control group.4. RT-PCR results:In the corpus callosum of each group mice, the mRNA expression of MBP, MOG and Olig2 was different (MBP:F=8.592, MOG:F=25.558, Olig2:F=9.652, P<0.05). The mRNA expression of MBP, MOG and Olig2 in alcohol group was significantly decreased compared to the control group (P<0.05). The mRNA expression of MBP, MOG and Olig2 in 5 mg·kg-1·d-1 quetiapine plus alcohol group was not significant compared with the alcohol group. The mRNA expression of MBP, MOG and Olig2 of 10 mg-kg-1·d-1 and 15 mg·kg-1·d-1 quetiapine plus alcohol groups were significantly increased compared with the alcohol group (P<0.05). The mRNA expression of MBP, MOG and Olig2 in quetiapine control group was not significant compared with the control group.Conclusions1. Chronic alcohol exposure can induce white matter myelin damage and cognition impairment in mice.2. Quetiapine treatment may prevent the cognition and brain white matter damage due to chronic alcohol exposure in mice.3. The effects of Quetiapine on the expression of MBP, MOG, Olig2 may be one of the molecular mechanisms that quetiapine played the role of underlying protection to white matter myelin and cognition.