| Schizophrenia is one kind of devastating mental disorder of unknown etiology that affects approximately 0.4-0.6% of general population per year. The impacts may include the psychological, social and financial resources of the patient, family and large community.Recent study results showed that the abnormality of white matter and pathological changes of oligodendrocyte lineage cells and myelination existed in several brain areas of schizophrenia. DNA microarray analyses have been performed in post-mortem brain regions of patients and healthy individuals to investigate the down-regulation of myelin-related genes, including CNP, MAG, GALC, and MOG. Further evidence for the role of oligodendrocytes and myelin in schizophrenia is obtained from imaging studies. Magnetic resonance imaging (MRI) findings in patients diagnosed with schizophrenia include lateral ventricle enlargement, medial temporal lobe volume reduction, neocortical superior temporal gyrus volume reduction, parietal lobe abnormalities, global and regional reduction in white matter volume, such as corpus callosum, and subcortical abnormalities affecting the basal ganglia, thalamus and cerebellum. These findings reveal congnitive dysfunction of schizophrenia possibly result from disconnection in both local neural circuitries that spanning several brain areas. It is assumed that the oligodendrocyte may be one of the therapeutic targets in the treatment of the patients with of schizophrenia.Based on the limited understanding on etiology of schizophrenia, the first line psychiatric treatment for schizophrenia is antipsychotic medication. The typical antipsychotic drugs, such as haloperidol, are dopamine D2-like subfamily receptor (D2r, D3r and D4r) antagonists. Although typical antipsychotic drugs can reduce the positive symptoms of psychosis, they fail neither to significantly ameliorate the negative symptoms, nor reverse the progress of mental disorder. Currently available atypical antipsychotic drugs, such as quetiapine, clozapine, olanzapine, can improve both positive and negative symptoms. These drugs can therefore prevent aggravation of psychotic symptoms, by modulating multiple neurotransmitter receptors, including dopamine receptor, 5-HT receptor.Recently, a series of studies suggest that a potential relationship between oligodendroglia, the main component of white matter regions of the brain and schizophrenia. aIt is, however, still not clear about the effect of antipsychotics treatmen on oligodendrocyte/myelin in brain.In this study, we have investigated the effect of antipsychotic on oligodendrocyte linage in brain of mice, and the remyelination in cuprizone-induced demyelin model, by using two kind of antipsychotic in comparison. The results presented in this paper may provide us a new insight into the degeneration of oligodendrocyte, which may involve in the pathophysiology of schizonphrenia, and reveal a new clue to pharmaprojects for demyelianaton disease in central neural system.This investigation is composed of three parts:Part 1: The effect of antipsychotic on OPCs in brain of adult miceYoung adult C57Bl/6 mice were given antipsychotic treatment in their drinking water for three or six weeks. Based on the investigations of the effect of two kind of antipsychotic on the development of oligodendrocyte lineage, we found that:1. HAL decreases the locomotion of animal in open-field test.2. HAL increases the number of NG2-expression cells in the corpus callosum.3. haloperidol increases the number of Olig2-expressiong cells and the amount of Olig2 protein4. haloperidol treatment has no effect on the maturation of OLs, and also has no effect on the numbers of GFAP+ and CD68+ cells in the brain.5. QUE has no effect on the oligodendrocyte lineage in brain of healthy adult mice.The first part revealed that chronic haloperidol treatment activates quiescent OPCs in adult mouse brain in the absence of gliosis. OPCs are potential targets of antipsychotic medication.Part 2: The effect of antipsychotic on the remyelination of cuprizone-induced demyelin model.To establish the cuprizone-induced demyelination animal model and to investigate the effect of two kind of antipsychotic haloperidol, quetiapine on remyelination, the studies plan to clarify the role of dysfunction of white matter in pathophysiology of schizonphrenia, and to investigate the molecular mechinsm of remyelination in demyelin diseases. The findings are as follows:1. The establishment cuprizone-induced demyelination model, using a diet supplemented with 0.2% cuprizone. The loss of myelin is more pronounced in mice fed the cuprizone diet at 6 weeks. There is spontaneous remyeliantion fowllowing the subsequent 3 weeks when mice are fed normal chow. For the prolonged administration of cuprizone for 12 weeks, the extent of remyelination turns to be very limited when mice change to normal chow.2. Haloperidol can delay the progress of spontaneous remyeliantion; quetiapine can promote the progress of spontaneous remyeliantion in chronic demyelination model.3. In acute demyeliantion model, haloperidol can increase the number of Olig2-expression cells, but decrease the number of this type of cells in chronic demyelination model. Quetiapine can increase the the number of Olig2-expression cells in chronic demyelination model.4. Quetiapine can reduce the recruitment and activation of microglia/macrophage in lesion location of demyeliantion.The second part revealed that we established the cuprizone-induced demyeliantion animal model successfully. Different kinds of antipsychotic play different roles in remyelination: Haloperidol can inhibit the remyelination while quetiapine can promote the progress of remyelination. Haloperidol can increase the number of oligodendrocyge precursor cells (OPCs) in acute demyelination, but decrease this type of cell in chronic demyelination. Quetiapine can increase the OPCs in chronic demyeliantion progress. Additionally, quetiapine can inhibit the recruitment and activation of microglia/macrophage in lesion location of demyeliantion.Part 3: Quetiapine can reduce LPS-induced activation of microglia.This study use lipopolysaccharide (LPS)-activated mouse microglial cell line N9 as an in vitro model to mimic microglia activation seen in mouse. The effects of quetiapine on the LPS-stimulate N9 cells were investigated. The findings are as followings:1. Cell culture and identification of N9 cell. To choose the antibody CD11b to identification N9 cells and count the positive cells, more than 95% N9 cell can be marked with CD11b.2. The establishement of LPS-activated N9 cells model. LPS do not affect the cell viability of N9 cell. However, the release of NO by LPS-stimulated N9 cells resulted in significant increase, which proves the successful establishment of LPS-activated N9 cells.3. Quetiapine can reduce the activation of LPS-stimulated N9 cells. Quetiapine can decrease the NO production induced by LPS-stimulated N9 cells, and decrease the expression amount of CD11b in cell membrane.4. Quetiapine can inhibit the activation of NFκB and prevent the immigration of NFκB to nuclear.The third part revealed that we established the LPS-activated N9 cells model successfully. Quetiapine can inhibit the activation of LPS-stimulated N9 cells. Quetiapine may regulat the activation of NFκB to inhibit the activation of N9 cells.In summary, this study demonstrated that chronic haloperidol treatment activates quiescent OPCs in the brain of normal adult mouse. Haloperidol can delay the progress of spontaneous remyeliantion while quetiapine can promote the progress of spontaneous remyeliantion in chronic demyelination model. The mechanism may be due to the different effects of these two kinds of antipsychotic on OPCs. Therefore, OPCs is a potential target of antipsychotic medication. Additionally, quetiapine can inhibit the recruitments and activation of microglia/macrophage in lesion location of demyeliantion through regulating the activation of NFκB. This may be one of the mechanisms underlying the effect of quetiapine in promotion of remyelination.
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