Beneficial Effects of Minocycline on Cuprizone Induced Cortical Demyelination

Skripuletz, Thomas; Miller, Elvira; Moharregh-Khiabani, Darius; Blank, Alexander; Pul, Refik; Gudi, Viktoria; Trebst, Corinna; Stangel, Martin

doi:10.1007/s11064-010-0202-7

Cited by 51 publications

(46 citation statements)

References 43 publications

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“…Taken together with the observation that cuprizone-induced demyelination is attenuated by minocycline, which also reduced Ox42/CD11b-expressing microglia, these studies support the idea that the effects of cuprizone on oligodendroglia may be mediated at least in part through cytokine secretion by activated microglia [258]. In other studies, minocycline also showed beneficial effects in attenuating the myelin damage in both cortex and corpus callosum after 4–6 weeks of cuprizone [259]. When administered simultaneously with cuprizone, minocycline improved motor coordination in the beam walking test, although the differential protection of various myelin-specific proteins was partial and region-dependent.…”

Section: The Prodromal High-risk Phenotype and Onset Of Schizophreniasupporting

confidence: 72%

“…Notably in this study, spontaneous re-expression of the myelin proteins PLP, MBP and 2′,3′-cyclic nucleotide 3′-phosphodiesterase was demonstrated in the corpus callosum without minocycline, but in the cortex, progressive damage by cuprizone continued. Minocycline also did not affect OPC numbers or the extent of astrogliosis [259], suggesting that direct protection of these cells by minocycline was less likely. Besides minocycline, modulation with antipsychotic drugs such as quetiapine and clozapine [260] has also shown enhanced protection or cellular repair in the demyelinated lesions using simultaneous treatment with cuprizone [260] or after cuprizone withdrawal [261].…”

Section: The Prodromal High-risk Phenotype and Onset Of Schizophreniamentioning

confidence: 99%

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Oligodendroglial Alterations and the Role of Microglia in White Matter Injury: Relevance to Schizophrenia

2013

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Schizophrenia is a chronic and debilitating mental illness characterized by a broad range of abnormal behaviors, including delusions and hallucinations, impaired cognitive function, as well as mood disturbances and social withdrawal. Due to the heterogeneous nature of the disease, the causes of schizophrenia are very complex; its etiology is believed to involve multiple brain regions and the connections between them, and includes alterations in both gray and white matter regions. The onset of symptoms varies with age and severity, and there is some debate over a degenerative or developmental etiology. Longitudinal magnetic resonance imaging studies have detected progressive gray matter loss in the first years of disease, suggesting neurodegeneration; but there is also increasing recognition of a temporal association between clinical complications at birth and disease onset that supports a neurodevelopmental origin. Presently, neuronal abnormalities in schizophrenia are better understood than alterations in myelin-producing cells of the brain, the oligodendrocytes, which are the predominant constituents of white matter structures. Proper white matter development and its structural integrity critically impacts brain connectivity, which affects sensorimotor coordination and cognitive ability. Evidence of defective white matter growth and compromised white matter integrity has been found in individuals at high risk of psychosis, and decreased numbers of mature oligodendrocytes are detected in schizophrenia patients. Inflammatory markers, including proinflammatory cytokines and chemokines, are also associated with psychosis. A relationship between risk of psychosis, white matter defects and prenatal inflammation is being established. Animal models of perinatal brain injury are successful in producing white matter damage in the brain, typified by hypomyelination and/or dysmyelination, impaired motor coordination and prepulse inhibition of the acoustic startle reflex, recapitulating structural and functional characteristics observed in schizophrenia. In addition, elevated expression of inflammation-related genes in brain tissue and increased production of cytokines by blood cells from patients with schizophrenia indicate immunological dysfunction and abnormal inflammatory responses, which are also important underlying features in experimental models. Microglia, resident immune defenders of the central nervous system, play important roles in the development and protection of neural cells, but can contribute to injury under pathological conditions. This article discusses oligodendroglial changes in schizophrenia and focuses on microglial activity in the context of the disease, in neonatal brain injury and in various experimental models of white matter damage. These include disorders associated with premature birth, and animal models of perinatal bacterial and viral infection, oxygen deprivation (hypoxia) and excess (hyperoxia), and elevated systemic proinflammatory cytokine levels. We briefly review the effects of treatme...

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Section: The Prodromal High-risk Phenotype and Onset Of Schizophreniasupporting

confidence: 72%

Section: The Prodromal High-risk Phenotype and Onset Of Schizophreniamentioning

confidence: 99%

Oligodendroglial Alterations and the Role of Microglia in White Matter Injury: Relevance to Schizophrenia

2013

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“…We assume that the increased activation of microglia/monocytes and/or astrocytes in the white compared to the gray matter results in a higher lesion expansion. In support of this assumption is the observation that in the cuprizone model, explicit microgliosis is evident in regions of profound demyelination [62], that prevention of demyelination is paralleled by a reduced activation of microglia cells [63][64][65], and that the application of the microglia inhibitor minocycline [66] ameliorates demyelination in the cuprizone model [67]. Similar observations have been reported in the LPC model [68].…”

Section: Discussionsupporting

confidence: 59%

Lesion Expansion in Experimental Demyelination Animal Models and Multiple Sclerosis Lesions

et al. 2015

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Gray matter pathology is an important aspect of multiple sclerosis (MS) pathogenesis and disease progression. In a recent study, we were able to demonstrate that the higher myelin content in the white matter parts of the brain is an important variable in the neuroinflammatory response during demyelinating events. Whether higher white matter myelination contributes to lesion development and progression is not known. Here, we compared lesion size of intra-cortical vs. white matter MS lesions. Furthermore, dynamics of lesion development was compared in the cuprizone and lysophosphatidylcholine models. We provide clear evidence that in the human brain, white matter lesions are significantly increased in size as compared to intra-cortical gray matter lesions. In addition, studies using the cuprizone mouse model revealed that the autonomous progression of white matter lesions is more severe compared to that in the gray matter. Focal demyelination revealed that the application of equal amounts of lysophosphatidylcholine results in more severe demyelination in the white compared to the gray matter. In summary, lesion progression is most intense in myelin-rich white matter regions, irrespective of the initial lesion trigger mechanism. A better understanding of myelin debris-triggered lesion expansion will pave the way for the development of new protective strategies in the future.

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“…62 Likewise, FLA in this study alleviated the astrocytes and microglia proliferation in CPZ-treated mice, in addition to ameliorating oligodendrocyte loss and myelin breakdown. The mechanism for this action of FLA may be related to its ability of cell cycle inhibition as discussed above.…”

Section: Flavopiridol Alleviated Cpz-induced Activation Of Astrocytessupporting

confidence: 50%

Cyclin-dependent kinase inhibitor flavopiridol promotes remyelination in a cuprizone induced demyelination model

Mi¹,

Gao

Liu³

et al. 2016

Cell Cycle

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The cuprizone (CPZ) model has been widely used for the studies of de-and remyelination. The CPZexposed mice show oligodendrocyte precursor cells (OPCs) increase and mature oligodendrocytes decrease, suggesting an imbalance between proliferation and differentiation of OPCs. In the first experiment of this study, we examined the expression of cell cycle related genes in brains of mice following CPZ administration for 5 weeks by means of microarray assay. In addition, we performed a double labeling of BrdU and Ki-67 to calculate cell cycle exit index in the mice. Our results showed that CPZ administration up-regulated the expression of 16 cell cycle related genes, but down-regulated the expression of only one in the prefrontal cortex (PFC) of mice compared to control group. The treatment inhibited potential precursor cells exit from cell cycle. In the second experiment, we evaluated effects of a CDK inhibitor flavopiridol (FLA) on CPZ-induced neuropathological changes and spatial working memory impairment in mice.FLA treatment for one week effectively attenuated the CPZ-induced increases in NG2 positive cells, microglia and astrocytes, alleviated the concurrent mature oligodendrocyte loss and myelin breakdown, and improved spatial working memory deficit in the CPZ-exposed mice. These results suggest that CPZ-induced neuropathological changes involve in dysregulation of cell cycle related genes. The therapeutic effects of FLA on CPZ-exposed mice may be related to its ability of cell cycle inhibition.

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Beneficial Effects of Minocycline on Cuprizone Induced Cortical Demyelination

Cited by 51 publications

References 43 publications

Oligodendroglial Alterations and the Role of Microglia in White Matter Injury: Relevance to Schizophrenia

Oligodendroglial Alterations and the Role of Microglia in White Matter Injury: Relevance to Schizophrenia

Lesion Expansion in Experimental Demyelination Animal Models and Multiple Sclerosis Lesions

Cyclin-dependent kinase inhibitor flavopiridol promotes remyelination in a cuprizone induced demyelination model

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