Article

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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    • "These results are in accordance with those reported in recent studies in which cuprizone intoxication for 4 weeks decreased the concentration of tNAA in corpus collasum (Praet et al., 2015), and 6 weeks cuprizone treatment decreased the concentrations of both NAA and tNAA in the caudoputamen, but not in the thalamus and midbrain (Yan et al., 2015). Moreover, cuprizone intoxication for 7 days decreased concentrations of NAA, tNAA, tCr and tCho in a bigger VOI mainly consisting of the dorsal hippocampus and thalamus (Xuan et al., 2014) although it was shown to cause no demyelination in mice (Tezuka et al., 2013; Zhang et al., 2014). The results of the present study and all the three previous studies suggest: 1) cuprizone-induced neurochemical changes in the brain are region specific, coinciding with the cuprizone-induced region specific demyelination as observed in our previous study (Yang et al., 2009); 2) cuprizone intoxication may compromise neuronal functioning even before demyelination and this neuronal dysfunction may be visualized as decreases in NAA and/or tNAA detected by 1 H-MRS. "
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