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Olanzapine ameliorates neuropathological changes and increases IGF-1 expression in frontal cortex of C57BL/6 mice exposed to cuprizone

Psychiatry Research 05/2014; 216(3). DOI: 10.1016/j.psychres.2014.02.019

ABSTRACT Cuprizone-induced demyelinating mouse has been used as an animal model to examine the assumed roles of altered oligodendrocytes in the pathophysiology and treatment of schizophrenia. The objectives of this study were to examine the effect of olanzapine, an atypical antipsychotic, on cuprizone-induced neuropathological changes in the frontal cortex of C57BL/6 mice, and to explore the underlying mechanism for the possible protective effects. The effects of six-week olanzapine (10 mg/kg/day) treatments on neuropathological changes were examined by immunohistochemistry and Western-blot analyses. Olanzapine treatment for six weeks effectively decreased the breakdown of myelin and oligodendrocytes loss of cuprizone-fed mice. Reactive cellular changes, including astrocyte gliosis, microglia accumulation and increased activation of oligodendrocyte progenitor cells, were also attenuated by olanzapine. However, the cortical expression level of insulin-like growth factor 1 was significantly increased by olanzapine treatment in cuprizone-fed mice as measured by quantitative real-time PCR method. Olanzapine treatment in control mice consuming normal food had no effect on all above measures. These results provide the first in vivo evidence for the protective effects of olanzapine on cuprizone-induced neuropathological changes and suggest that up-regulated insulin-like growth factor 1 may contribute to the protective effects of this antipsychotic.

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    ABSTRACT: The cuprizone (CPZ)-induced toxic demyelinating model, characterized by the degeneration of oligodendrocytes, has been utilized to study multiple sclerosis-related lesions. The present study was designed to determine the effect of epimedium flavonoids (EF), the main component extracted from Epimedium sagittatum, on CPZ-induced neuropathological changes in the corpus callosum of C57BL/6 mice. Once we determined an EF-based protective effect on the corpus callosum, we sought to explore the underlying mechanism of this protection. To induce demyelination, 8-week-old mice were fed with 0.2 % CPZ for a maximum period of 6 weeks. EF treatment for a period of 3 weeks effectively decreased the breakdown of myelin, OL loss, and oligodendrocyte precursor cell accumulation in CPZ-fed mice. In addition, EF administration significantly increased the cortical expression level of insulin-like growth factor 1 (IGF-1). This study provides the first in vivo evidence of EF-based protection against CPZ-induced neuropathological changes. Furthermore, our study suggests that upregulated IGF-1 may play a role in this protection.
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