N‐acetylcysteine attenuates the cuprizone‐induced behavioral changes and oligodendrocyte loss in male C57BL/7 mice via its anti‐inflammation actions

Previous animal studies have linked white matter damage to certain schizophrenia‐like behaviors in cuprizone (CPZ)‐exposed mouse. Mitochondrial dysfunction, oxidative stress, neuroinflammation, and oligodendrocyte loss coexist in the brain of such mice. The aim of this study was to examine effects of the antioxidant N‐acetylcysteine (NAC) on CPZ‐induced behavioral changes and concurrent oligodendrocyte loss, oxidative stress, and neuroinflammation in these animals. Male C57BL/6 mice were given intraperitoneal saline or NAC at doses of 100, 200, and 400 mg/kg/day for 2 weeks; animals were fed a CPZ‐containing diet (0.2%, w/w) during days 5–14. During days 15–17, the mice were examined in open‐field, social recognition, and Y‐maze tests (1 test per day). Six mice in each group were then used for biochemical and enzyme‐linked immunosorbent assay analyses, while the remaining animals were used for immunohistochemical and immunofluorescence staining. The mice exposed to CPZ for 10 days showed significantly lower spontaneous alternation in the Y‐maze, lower activity of total superoxide dismutase, and glutathione peroxidase, but higher levels of malondialdehyde in the cerebral cortex and hippocampus, elevated concentrations of interleukin‐1β and tumor necrosis factor‐α in the brain regions mentioned above and caudate putamen, and a decreased number of mature oligodendrocytes, but increased number of microglia in all the brain regions examined. These changes, however, were not seen or effectively alleviated in NAC‐treated mice at all three doses. These results demonstrate that NAC protected mature oligodendrocytes against the toxic effects of CPZ, likely via its antioxidant and anti‐inflammatory actions.