Brain region-specific enhancement of remyelination and prevention of demyelination by the CSF1R kinase inhibitor BLZ945

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system (CNS). While multiple effective immunomodulatory therapies for MS exist today, they lack the scope of promoting CNS repair, in particular remyelination. Microglia play a pivotal role in regulating myelination processes, and the colony-stimulating factor 1 (CSF-1) pathway is a key regulator for microglia differentiation and survival. Here, we investigated the effects of the CSF-1 receptor kinase inhibitor, BLZ945, on central myelination processes in the 5-week murine cuprizone model by non-invasive and longitudinal magnetic resonance imaging (MRI) and histology. Therapeutic 2-week BLZ945 treatment caused a brain region-specific enhancement of remyelination in the striatum/cortex, which was absent in the corpus callosum/external capsule. This beneficial effect correlated positively with microglia reduction, increased oligodendrocytes and astrogliosis. Prophylactic BLZ945 treatment prevented excessive demyelination in the corpus callosum by reducing microglia and increasing oligondendrocytes. In the external capsule oligodendrocytes were depleted but not microglia and a buildup of myelin debris and axonal damage was observed. A similar microglial dysfunction in the external capsule with an increase of myelin debris was obvious in triggering receptor expressed on myeloid cells 2 (TREM2) knock-out mice treated with cuprizone. Finally, therapeutic BLZ945 treatment did not change the disease course in experimental autoimmune encephalomyelitis mice, a peripherally driven neuroinflammation model. Taken together, our data suggest that a short-term therapeutic inhibition of the CSF-1 receptor pathway by BLZ945 in the murine cuprizone model enhances central remyelination by modulating neuroinflammation. Thus, microglia-modulating therapies could be considered clinically for promoting myelination in combination with standard-of-care treatments in MS patients.

Electronic supplementary material

The online version of this article (10.1186/s40478-018-0510-8) contains supplementary material, which is available to authorized users.

Related collections

Most cited references 28

Record: found
Abstract: found
Article: not found

RARE imaging: a fast imaging method for clinical MR.

J. Hennig, A Nauerth, H Friedburg (1986)

Based on the principles of echo imaging, we present a method to acquire sufficient data for a 256 X 256 image in from 2 to 40 s. The image contrast is dominated by the transverse relaxation time T2. Sampling all projections for 2D FT image reconstruction in one (or a few) echo trains leads to image artifacts due to the different T2 weighting of the echo. These artifacts cannot be described by a simple smearing out of the image in the phase direction. Proper distribution of the phase-encoding steps on the echoes can be used to minimize artifacts and even lead to resolution enhancement. In spite of the short data acquisition times, the signal amplitudes of structures with long T2 are nearly the same as those in a conventional 2D FT experiment. Our method, therefore, is an ideal screening technique for lesions with long T2.

0 comments Cited 256 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

The cuprizone animal model: new insights into an old story.

Markus Kipp, Jon Dang, T. Clarner … (2009)

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease that affects the central nervous system and represents the most common neurological disorder in young adults in the Western hemisphere. There are several well-characterized experimental animal models that allow studying potential mechanisms of MS pathology. While experimental allergic encephalomyelitis is one of the most frequently used models to investigate MS pathology and therapeutic interventions, the cuprizone model reflects a toxic experimental model. Cuprizone-induced demyelination in animals is accepted for studying MS-related lesions and is characterized by degeneration of oligodendrocytes rather than by a direct attack on the myelin sheet. The present article reviews recent data concerning the cuprizone model and its relevance for MS. Particular focus is given to the concordance and difference between human MS patterns (types I-IV lesions) and cuprizone-induced histopathology, including a detailed description of the sensitive brain regions extending the observations to different white and grey matter structures. Similarities between pattern III lesions and cuprizone-induced demyelination and dissimilarities, such as inflamed blood vessels or the presence of CD3+ T cells, are outlined. We also aim to distinguish acute and chronic demyelination under cuprizone including processes such as spontaneous remyelination during acute demyelination. Finally, we point at strain and gender differences in this animal model and highlight the contribution of some growth factors and cytokines during and after cuprizone intoxication, including LIF, IGF-1, and PDGFalpha.

0 comments Cited 137 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination.

Thomas Skripuletz, Diane Hackstette, Katharina C Bauer … (2013)

Recent evidence suggests that astrocytes play an important role in regulating de- and remyelination in multiple sclerosis. The role of astrocytes is controversial, and both beneficial as well as detrimental effects are being discussed. We performed loss-of-function studies based on astrocyte depletion in a cuprizone-induced rodent model of demyelination. This led to strong astrogliosis accompanied by microgliosis and demyelination in C57BL/6 wild-type mice. Ablation of astrocytes in glial fibrillary acidic protein-thymidine kinase transgenic mice was associated with a failure of damaged myelin removal and a consecutive delay in remyelination. Despite oligodendrocyte death, myelin was still present, but ultrastructual investigations showed that the myelin structure was loosened and this damaged myelin did not protect axons. These alterations were associated with a decrease in microglial activation. Thus, our results show that astrocyte loss does not prevent myelin damage, but clearance of damaged myelin through recruitment of microglia is impaired. Further studies suggest that this process is regulated by the chemokine CXCL10. As a consequence of the delayed removal of myelin debris, remyelination and oligodendrocyte precursor cell proliferation were impaired. Experiments omitting the influence of myelin debris demonstrated an additional beneficial effect of astrocytes on oligodendrocyte regeneration during remyelination. In conclusion, these data demonstrate for the first time in vivo that astrocytes provide the signal environment that forms the basis for the recruitment of microglia to clear myelin debris, a process required for subsequent repair mechanisms. This is of great importance to understanding regenerative processes in demyelinating diseases such as multiple sclerosis.

0 comments Cited 135 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Derya R. Shimshek: +41795435384 , derya.shimshek@novartis.com

Journal

Journal ID (nlm-ta): Acta Neuropathol Commun

Journal ID (iso-abbrev): Acta Neuropathol Commun

Title: Acta Neuropathologica Communications

Publisher: BioMed Central (London )

ISSN (Electronic): 2051-5960

Publication date (Electronic): 15 February 2018

Publication date PMC-release: 15 February 2018

Publication date Collection: 2018

Volume: 6

Electronic Location Identifier: 9

Affiliations

[1 ]ISNI 0000 0001 1515 9979, GRID grid.419481.1, Musculoskeletal Diseases Area, , Novartis Institutes for BioMedical Research, ; 4002 Basel, Switzerland

[2 ]ISNI 0000 0001 1515 9979, GRID grid.419481.1, Neuroscience, , Novartis Institutes for BioMedical Research, ; 4002 Basel, Switzerland

[3 ]ISNI 0000 0001 1515 9979, GRID grid.419481.1, Autoimmunity, Transplantation and Inflammation, , Novartis Institutes for BioMedical Research, ; 4002 Basel, Switzerland

[4 ]ISNI 0000 0001 1515 9979, GRID grid.419481.1, Global Scientific Operations, , Novartis Institutes for BioMedical Research, ; 4002 Basel, Switzerland

[5 ]ISNI 0000 0001 1515 9979, GRID grid.419481.1, PK Sciences, , Novartis Institutes for BioMedical Research, ; 4002 Basel, Switzerland

[6 ]ISNI 0000 0001 1515 9979, GRID grid.419481.1, Preclinical Safety, , Novartis Institutes for BioMedical Research, ; 4002 Basel, Switzerland

[7 ]Present address: Incyte, 1801 Augustine Cut-off, Wilmington, DE 19803 USA

Article

Publisher ID: 510

DOI: 10.1186/s40478-018-0510-8

PMC ID: 5815182

PubMed ID: 29448957

SO-VID: 57018aa1-41cd-4134-ae42-d399bd41ca38

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 26 January 2018

Date accepted : 26 January 2018

Custom metadata

Keywords: neuroinflammation,microglia,astrocyte,cuprizone,myelination,multiple sclerosis,oligodendrocyte,csf1r kinase,blz945,trem2

Data availability:

Keywords: neuroinflammation, microglia, astrocyte, cuprizone, myelination, multiple sclerosis, oligodendrocyte, csf1r kinase, blz945, trem2

Brain region-specific enhancement of remyelination and prevention of demyelination by the CSF1R kinase inhibitor BLZ945

Read this article at

Abstract

Electronic supplementary material

Related collections

Tobacco Prevention & Cessation

Most cited references 28

RARE imaging: a fast imaging method for clinical MR.

The cuprizone animal model: new insights into an old story.

Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination.

Author and article information

Contributors

Journal

Affiliations

Article

History

Categories

Custom metadata

Comments

Comment on this article

Similar content 430

Cited by 54

Most referenced authors 662