CZ-7, a new derivative of Claulansine F, promotes remyelination induced by cuprizone by enhancing myelin debris clearance.

The mechanism of demyelinating diseases is controversial, while demyelination and remyeliantion disorder is the acknowledged etiology and therapeutic target. Untill now, there is no efficient therapy for these diseases. CZ-7, a new derivative of Claulansine F, which has been reported before, were investigated its pro-remyelination effect and its associated mechanism in cuprizone (CPZ)-induced demyelination model. In this study, male C57BL/6 mice were subjected to CPZ (300 mg/kg) through intragastric gavage and were orally administered CZ-7 (20 mg/kg) meanwhile. The results of weight monitoring and behavioral testing showed that CZ-7 can significantly improve behavior dysfunction in the demyelinating mice. Luxol-fast blue (LFB) staining, myelin basic protein (MBP) immunostaining, transmission electron microscopy (TEM) and QPCR results indicated the therapeutic effect of CZ-7 on CPZ mice model. Furthermore, degraded myelin basic protein (dMBP) immunofluorescent staining and oil red O staining showed that CZ-7 contributed to the clearance of degraded myelin debris. More microglia displayed phagocytic shape assembled in corpus callosum (CC) and there was an active process of phagocytosis in microglia after CZ-7 treatment. Immunofluorescent staining and QPCR analysis revealed the M2-polarized phenotype switch of microglia in the process of myelin debris removel, which demostrated the microenvironment improvement of CZ-7. Moreover, immunofluorescent staining of NG2 and O4 demonstated that more oligodendrocyte precursor cells (OPCs) existed in CC after CZ-7 treatment. In conclusion, our results demonstrated CZ-7 has a potential therapeutic effect for MS and other demyelinating diseases through enhancing myelin debris clearance to improve the microenvironment.

Wang SS ，Bi HZ ，Chu SF ，Dong YX ，He WB ，Tian YJ ，Zang YD ，Zhang DM ，Zhang Z ，Chen NH ... -  《-》

Electroacupuncture Promotes Remyelination after Cuprizone Treatment by Enhancing Myelin Debris Clearance.

Zhu K ，Sun J ，Kang Z ，Zou Z ，Wu G ，Wang J ... -  《-》

Fasudil enhances the phagocytosis of myelin debris and the expression of neurotrophic factors in cuprizone-induced demyelinating mice.

Multiple sclerosis (MS) is mainly associated with the neuroinflammation and demyelination in the central nervous system (CNS), in which the failure of remyelination results in persistent neurological dysfunction. Fasudil, a typical Rho kinase inhibitor, has been exhibited beneficial effects on several models of neurodegenerative disorders. In this study, we showed that Fasudil promoted the uptake of myelin debris by microglia via cell experiments and through a cuprizone (CPZ)-induced demyelinating model. In vitro, microglia with phagocytic debris exhibited enhanced expression of brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF), and the conditioned medium promoted the maturation of oligodendrocyte precursor cells (OPCs). Meanwhile, Fasudil upregulated TREM2/DAP12 pathway, which positively regulated the phagocytosis of myelin debris by microglia. Similarly, in vivo, Fasudil intervention enhanced the clearance of myelin debris, upregulated the expression of BDNF and GDNF on microglia, and promoted the formation of Oligo2+/PDGFRα+ OPCs and the maturation of MBP + oligodendrocytes in the brain. Our results showed that Fasudil targeted the phagocytic function of microglia, effectively clearing myelin debris produced during pathological process possibly by upregulating TREM2/DAP12 pathway, accompanied by increased expression of BDNF and GDNF. However, the precise mechanism underlying the effects of Fasudil in promoting phagocytic effects and neurotrophic factors remains to be elucidated.

Ding ZB ，Han QX ，Wang Q ，Song LJ ，Chu GG ，Guo MF ，Chai Z ，Yu JZ ，Xiao BG ，Li XY ，Ma CG ... -  《-》

Deletion of Nox4 enhances remyelination following cuprizone-induced demyelination by increasing phagocytic capacity of microglia and macrophages in mice.

NOX4 is a major reactive oxygen species-producing enzyme that modulates cell stress responses. We here examined the effect of Nox4 deletion on demyelination-remyelination, the most common pathological change in the brain. We used a model of cuprizone (CPZ)-associated demyelination-remyelination in wild-type and Nox4-deficient (Nox4-/- ) mice. While the CPZ-induced demyelination in the corpus callosum after 4 weeks of CPZ intoxication was slightly less pronounced in Nox4-/- mice than that in wild-type mice, remyelination following CPZ withdrawal was significantly enhanced in Nox4-/- mice with an increased accumulation of IBA1-positive microglia/macrophages in the demyelinating corpus callosum. Consistently, locomotor function, as assessed by the beam walking test, was significantly better during the remyelination phase in Nox4-/- mice. Nox4 deletion did not affect autonomous growth of primary-culture oligodendrocyte precursor cells. Although Nox4 expression was higher in cultured macrophages than in microglia, Nox4-/- microglia and macrophages both showed enhanced phagocytic capacity of myelin debris and produced increased amounts of trophic factors upon phagocytosis. The expression of trophic factors was higher, in parallel with the accumulation of IBA1-positive cells, in the corpus callosum in Nox4-/- mice than that in wild-type mice. Nox4 deletion suppressed phagocytosis-induced increase in mitochondrial membrane potential, enhancing phagocytic capacity of macrophages. Treatment with culture medium of Nox4-/- macrophages engulfing myelin debris, but not that of Nox4-/- astrocytes, enhanced cell growth and expression of myelin-associated proteins in cultured oligodendrocyte precursor cells. Collectively, Nox4 deletion promoted remyelination after CPZ-induced demyelination by enhancing microglia/macrophage-mediated clearance of myelin debris and the production of trophic factors leading to oligodendrogenesis.

Yamanaka K ，Nakamura K ，Shibahara T ，Takashima M ，Takaki H ，Hidaka M ，Komori M ，Yoshikawa Y ，Wakisaka Y ，Ago T ，Kitazono T ... -  《-》

Icariin ameliorates the cuprizone-induced acute brain demyelination and modulates the number of oligodendrocytes, microglia and astrocytes in the brain of C57BL/6J mice.

This study aimed at testing the hypothesis that treatment with icariin (ICA, a type of flavonoid) could mitigate the cuprizone (CPZ)-induced acute demyelination in the brain of mice and the potential mechanisms. Female C57BL/6J mice were fed continually with regular rodent chow or the chow supplemented with CPZ (0.2 % w/w) for six weeks to induce acute demyelination. The CPZ-fed mice were treated with vehicle or ICA at 12.5 or 25 mg/kg beginning at three weeks post CPZ feeding daily for three weeks. Their brain tissue sections were stained with oil red O, luxol-fast blue (LFB) and immunohistochemistry to characterize the levels of brain demyelination, myelin basic protein (MBP) and brain-derived neurotrophic factor (BDNF) and the numbers of oligodendrocytes (Ols), oligodendrocyte progenitor cells (OPCs), microglia and astrocytes in mice. Compared with the healthy controls, CPZ feeding caused the brain demyelination by increasing NG2+ OPCs, but decreased oil red O and LFB staining, MBP level and GST-pi+ Ols in the brain corpus callosum region of mice. Furthermore, CPZ feeding decreased the number of BDNF+ cells in the brain cortex and hippocampus regions, but increased microglia in the brain corpus callosum, cortex and caudate putamen, and astrocytes in the corpus callosum regions of mice. Treatment with ICA significantly mitigated or abrogated the toxic demyelination of CPZ by preserving MBP and BDNF proteins and modulating the numbers of Ols, OPCs, microglia and astrocytes in the brain of mice. ICA treatment significantly ameliorated the CPZ-mediated demyelination and modulated the number of Ols, microglia and astrocytes in the brain of mice.

Cong H ，Liang M ，Wang Y ，Chang H ，Du L ，Zhang X ，Yin L ... -  《-》