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Progesterone alleviates neural behavioral deficits and demyelination with reduced degeneration of oligodendroglial cells in cuprizone-induced mice.

ABSTRACT: Demyelination occurs widely in neurodegenerative diseases. Progesterone has neuroprotective effects, is known to reduce the clinical scores and the inflammatory response. Progesterone also promotes remyelination in experimental autoimmune encephalomyelitis and cuprizone-induced demyelinating brain. However, it still remains unclear whether progesterone can alleviate neural behavioral deficits and demyelination with degeneration of oligodendroglial cells in cuprizone-induced mice. In this study, mice were fed with 0.2% cuprizone to induce demyelination, and treated with progesterone to test its potential protective effect on neural behavioral deficits, demyelination and degeneration of oligodendroglial cells. Our results showed noticeable alleviation of neural behavioral deficits following progesterone treatment as assessed by changes in average body weight, and activity during the open field and Rota-rod tests when compared with the vehicle treated cuprizone group. Progesterone treatment alleviated demyelination as shown by Luxol fast blue staining, MBP immunohistochemical staining, and electron microscopy. There was an obvious decrease in TUNEL and Caspase-3-positive apoptotic cells, and an increase in the number of oligodendroglial cells staining positive for PDGFR?, Olig2, Sox10 and CC-1 antibody in the brains of cuprizone-induced mice after progesterone administration. These results indicate that progesterone can alleviate neural behavioral deficits and demyelination against oligodendroglial cell degeneration in cuprizone-induced mice.

SUBMITTER: Ye JN

PROVIDER: S-EPMC3554738 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Progesterone alleviates neural behavioral deficits and demyelination with reduced degeneration of oligodendroglial cells in cuprizone-induced mice.

Ye Jian-Ning JN Chen Xing-Shu XS Su Le L Liu Yun-Lai YL Cai Qi-Yan QY Zhan Xiao-Li XL Xu Yan Y Zhao Shi-Fu SF Yao Zhong-Xiang ZX

PloS one 20130124 1

Demyelination occurs widely in neurodegenerative diseases. Progesterone has neuroprotective effects, is known to reduce the clinical scores and the inflammatory response. Progesterone also promotes remyelination in experimental autoimmune encephalomyelitis and cuprizone-induced demyelinating brain. However, it still remains unclear whether progesterone can alleviate neural behavioral deficits and demyelination with degeneration of oligodendroglial cells in cuprizone-induced mice. In this study, ...[more]

PMID: 23359803

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Project description:Shi-Zhen-An-Shen decoction (SZASD), a Chinese herbal medicine that is a liquor extracted from plants by boiling, has been reported to be effective in treating schizophrenia. However, the mechanism is unclear. Abnormal demyelination has been implicated in schizophrenia. The aim of this study was to investigate the effect of SZASD on myelin in demyelinated mice exhibiting schizophrenia-like behaviors. Sixty male C57BL/6 mice were randomly divided into six groups (n = 10 per group): (1) control group, (2) cuprizone (CPZ, a copper chelator that induced demyelination, 0.2% w/w)+saline, (3) CPZ+low-dose SZASD (8.65 g·kg-1·d-1), (4) CPZ+medium-dose SZASD (17.29 g·kg-1·d-1), (5) CPZ+high-dose SZASD (25.94 g·kg-1·d-1), and (6) CPZ+quetiapine (QTP, an atypical antipsychotic that served as a positive treatment control, 10 mg·kg-1·d-1). Mice in groups 2-6 were treated with CPZ added to rodent chow for six weeks to induce demyelination. During the last two weeks, these mice were given an oral gavage of sterile saline, SZASD, or quetiapine. Behavioral tests and brain analyses were conducted after the last treatment. The brain expression of myelin basic protein (MBP) and neuregulin-1 (NRG-1) was assessed using immunohistochemistry and Western blots. CPZ induced significant schizophrenia-like behaviors in the mice, including reduced nest-building activity and sensory gating deficits. Hyperlocomotor activity was accompanied by significant reductions in MBP expression in the corpus callosum, hippocampus, and cerebral cortex. However, both QTP and SZASD significantly reversed the schizophrenia-like behaviors and demyelination in CPZ-fed mice. The QTP and medium-dose SZASD resulted in better therapeutic effects compared to the low and high SZASD doses. Reduced NRG-1 expression was observed in CPZ-fed mice compared with controls, but neither QTP nor SZASD showed significant influence on NRG-1 expression in the hippocampus. Together, SZASD showed a therapeutic effect on demyelinated mice, and the improvement of demyelination might not be through the NRG-1 pathway.

Project description:Background:The cuprizone (CPZ) model of multiple sclerosis (MS) was used to identify microRNAs (miRNAs) related to in vivo de- and remyelination. We further investigated the role of miR-146a in miR-146a-deficient (KO) mice: this miRNA is differentially expressed in MS lesions and promotes differentiation of oligodendrocyte precursor cells (OPCs) during remyelination, but its role has not been examined during demyelination. Methods:MicroRNAs were examined by Agilent Mouse miRNA Microarray in the corpus callosum during CPZ-induced demyelination and remyelination. Demyelination, axonal loss, changes in number of oligodendrocytes, OPCs, and macrophages/microglia was compared by histology/immunohistochemistry between KO and WT mice. Differential expression of target genes and proteins of miR-146a was analyzed in the transcriptome (4?×?44K Agilent Whole Mouse Genome Microarray) and proteome (liquid chromatography tandem mass spectrometry) of CPZ-induced de- and remyelination in WT mice. Levels of proinflammatory molecules in the corpus callosum were compared in WT versus KO mice by Meso Scale Discovery multiplex protein analysis. Results:miR-146a was increasingly upregulated during CPZ-induced de- and remyelination. The absence of miR-146a in KO mice protected against demyelination, axonal loss, body weight loss, and atrophy of thymus and spleen. The number of CNP+ oligodendrocytes was increased during demyelination in the miR-146a KO mice, while there was a trend of increased number of NG2+ OPCs in the WT mice. miR-146a target genes, SNAP25 and SMAD4, were downregulated in the proteome of demyelinating corpus callosum in WT mice. Higher levels of SNAP25 were measured by ELISA in the corpus callosum of miR-146a KO mice, but there was no difference between KO and WT mice during demyelination. Multiplex protein analysis of the corpus callosum lysate revealed upregulated TNF-RI, TNF-RII, and CCL2 in the WT mice in contrast to KO mice. The number of Mac3+ and Iba1+ macrophages/microglia was reduced in the demyelinating corpus callosum of the KO mice. Conclusion:During demyelination, absence of miR-146a reduced inflammatory responses, demyelination, axonal loss, the number of infiltrating macrophages, and increased the number of myelinating oligodendrocytes. The number of OPCs was slightly higher in the WT mice during remyelination, indicating a complex role of miR-146a during in vivo de- and remyelination.

Dataset Information

Progesterone alleviates neural behavioral deficits and demyelination with reduced degeneration of oligodendroglial cells in cuprizone-induced mice.

Publications

Progesterone alleviates neural behavioral deficits and demyelination with reduced degeneration of oligodendroglial cells in cuprizone-induced mice.

Similar Datasets

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