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

Cuprizone (CPZ) 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 (IGF-1) was significantly increased by olanzapine treatment in cuprizone-fed mice as measured by the quantitative real-time polymerase chain reaction (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.