Dissertation > Medicine, health > Pharmacy > Pharmacology

The Effects of Antipsychotics on the Development of Oligodendrocyte and Remyelination in C57B1/6 Mice

Author WangZuoZhi
Tutor XiaoZuo;CaiWenQin
School Third Military Medical University
Course Human Anatomy and Embryology
Keywords Haloperidol Quetiapine Myelin repair Oligodendrocytes Oligodendrocyte precursor cells
Type PhD thesis
Year 2010
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Schizophrenia is a severe mental illness of unknown etiology, global annual incidence rate of 0.4-1%, causing physical, economic and social harmony heavy burden to patients, society and the state. In recent years found that patients with schizophrenia have different levels of white matter abnormalities in schizophrenia research as well as less oligodendrocyte lineage (oligodendrocyte lineage cells, OLs) and myelin pathology change. DNA microarray analysis revealed multiple brain regions of schizophrenia the cortical myelin-associated genes, including significantly down-regulated expression of CNP, MAG, GALC, MOG. Imaging further confirmed that the observed lateral ventricles expand MRI magnetic resonance imaging of patients with schizophrenia, the medial temporal lobe, the superior temporal gyrus cortex, parietal lobe volume reduction with varying degrees of reduction of the corpus callosum, the cerebellum, whole brain or local white matter volume abnormal thalamus and subcortical structures. The above studies prompted the cognitive disorders of schizophrenia may be due to the neurons associated myelin reduction in volume resulting in the above-described structure of the signal transduction disorders. Oligodendrocyte function abnormalities may be one of the causes of schizophrenia, and oligodendrocytes do this after all targets for the treatment of schizophrenia. The etiology of schizophrenia is unknown, the first-line treatment for schizophrenia primarily rely on the use of antipsychotic medication. Atypical antipsychotics, such as haloperidol (haloperidol, HAL), mainly through the inhibition of dopamine D2-like receptor (including D2r, D3r, and D4r) medication. While HAL can effectively improve the positive symptoms of schizophrenia, but can not effectively treat negative symptoms, and can not reverse the course of the disease. In recent years, many atypical antipsychotics, such as quetiapine (Quetiapine is, QUE), olanzapine (Olanzopine, OLA), through two-way regulating neurotransmitter dopamine, serotonin receptor, can significantly improve schizophrenic the negative symptoms of the disease, and some can improve positive symptoms, and can effectively reverse the disease process. Recent series of studies suggest that, as the white matter of the major cellular components oligodendrocytes and antipsychotic drug action potential association exists, but does not, in fact, a clear role of antipsychotic drugs on the development of oligodendrocytes or myelin repair . The study is intended to antipsychotic tools, comparing typical and atypical antipsychotics oligodendrocyte development and thus take advantage of the central nervous system demyelinating model comparing two types of antipsychotics on demyelinating regeneration and repair, as well as the impact of changes in animal behavior, and detect atypical antipsychotics may promote Cellular mechanisms of oligodendrocytes, the glial cells. For oligodendrocytes degeneration of glial cells involved in the pathophysiology of schizophrenia process clarify the the neuropharmacology experimental basis, and to provide new clues to the research and development of drugs for the treatment of central nervous system demyelinating disease. The experiment is divided into the following three parts: Part I: antipsychotics on adult mouse brain oligodendrocytes glial precursor cells (Oligododendrocyte precursor cells, OPCs) by chronic intake of two types of antipsychotic HAL QUE were used to detect the impact of antipsychotics on brain the OLs cells in development, to clarify the different brain regions the OLs distribution, density changes. The main results are as follows: 1. HAL can inhibit the spontaneous activity of the mice in the opening test activity and exploratory behavior in an unfamiliar environment. 2. HAL can promote brain corpus callosum NG2 cells in adult mice. 3. HAL can promote various brain regions of the adult mouse brain (corpus callosum, hippocampus, cortex) of Olig2 OPCs, hyperplasia, and Olig2 protein expression increased. 4. HAL APC, GFAP of CD68 cell number did not change. 5. QUE OLs in the brain of normal mice without any impact. These results suggest that HAL can promote the proliferation of adult mouse brain OPCs and does not cause proliferation of glial cells and prompt of OPCs and schizophrenia pathological mechanisms from another relationship, that OPCs might of the targets of antipsychotic drugs. Part II: the impact of antipsychotics on myelin repair in demyelinating models in this study were observed by murine demyelination model establishing Cuprizone induced, two types of antipsychotic HAL, QUE myelin repair, clear white matter damage in the pathogenesis of schizophrenia, while understanding remyelination of demyelinating disease mechanisms. The main results are as follows: 1. Successful establishing Cuprizone induced demyelinating animal model. 0.2% Cupriozone intake of six weeks, maximum, three weeks after the withdrawal, spontaneous myelin repair demyelinating lesions of the corpus callosum, and almost reached normal levels. The continuous intake for 0.2% cuprizone12 weeks after withdrawal of three weeks still visible lower levels of myelin repair. 2. HAL can postpone the spontaneous repair of myelin. The QUE promote chronic remyelination process. The 3. HAL in acute myelin repair process can contribute to increase life OPCs, OPCs reduce the number of chronic myelin repair HAL. QUE can promote the OPCs hyperplasia in chronic myelin repair. 4. QUE can reduce the recruitment and activation of microglial cells in the myelin repair process. These results suggest that the two types of antipsychotics differ on myelin repair: HAL inhibits the repair and regeneration of myelin, in acute myelin repair promote OPCs hyperplasia, but in chronic myelin repair process to reduce the number of OPCs cells; QUE chronic myelin repair induced increase in the number of the OPCs, the promotion of remyelination. In addition, QUE inhibition of microglial activation and aggregation in myelin injury site. In this study, experimental study Part III: quetiapine regulation of LPS-induced microglial activation by lipopolysaccharide (LPS)-induced microglial N9 cell activation model, observed QUE microglial activation, combination of cell culture, flow cytometry, immunofluorescence cytochemistry explore QUE microglia activation is extremely regulation. The main results are as follows: 1. LPS-induced N9 microglial activation model that LPS does not affect the N9 cell proliferation, but to promote the release of NO leaving cell activation. 2. QUE (10nM) can reduce the LPS activated N9 cells released NO product content, as well as to reduce the amount of the expression of CD11b in the membrane. Thereby inhibit the N9 cell activation. 3. QUE inhibited NFκB activation and displacement into the nucleus. These results suggest that, QUE can inhibit LPS-induced N9 microglial cell activation, and this effect may be achieved by inhibiting the activation of NFκB in microglia. To sum up: in normal mice, HAL can activate the OPCs resting adult mouse brain cells; QUE no apparent effect on normal mice. Inhibit myelin spontaneous repair in demyelinating model, HAL, QUE can promote chronic myelin repair process, its mechanism may be related to the two drugs on the the OPCs different role. Thus, OPCs may the antipsychotic therapeutic targets. , QUE can inhibit the activation of microglia in demyelinating injury site, and may also be one of the reasons QUE promote myelin repair.

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