Widespread cortical demyelination of both hemispheres can be induced by injection of pro-inflammatory cytokines via an implanted catheter in the cortex of MOG-immunized rats

Üçal, Muammer; Haindl, Michaela Tanja; Adzemovic, Milena Z.; Strasser, Johannes; Theisl, Lisa; Zeitelhofer, Manuel; Kraitsy, Klaus; Ropele, Stefan; Schäfer, Ute; Fazekas, Franz; Hochmeister, Sonja

doi:10.1016/j.expneurol.2017.04.014

Cited by 25 publications

(36 citation statements)

References 26 publications

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“…A second key aspect of MS is the presence of CLs which is not reported in the classical EAE model. We were able to induce this key feature in our EAE mouse model, similar to what was reported in an EAE model in common marmoset and rats ( Gardner et al, 2013 ; Merkler et al, 2006 ; Stassart et al, 2016 ; Üçal et al, 2017 ). We induced CLs by the stereotactic injection of TNFα and IFNɣ in the mouse cortex.…”

Section: Discussionsupporting

confidence: 84%

miRNA profile is altered in a modified EAE mouse model of multiple sclerosis featuring cortical lesions

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Guillemot-Legris

Capasso

et al. 2020

eLife

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Cortical lesions represent a hallmark of multiple sclerosis and are proposed as a predictor of disease severity. microRNAs are suggested to be important players in the disease pathogenesis and the experimental autoimmune encephalomyelitis animal model. We implemented a mouse model recapitulating more closely the human pathology as it is characterized by both an autoimmune heterogeneity and the presence of cortical lesions, two parameters missing in experimental autoimmune encephalomyelitis. In our model, mice clustered in two groups displaying high or low clinical scores. Upon cortical cytokine injection, lesions appeared with a specific topography while cortical miRNA profiles were altered. These two features differed according to disease severity. We evidenced changes in miRNA regulators and targets suggesting that miRNA alteration had functional repercussions that could explain the differences in cortical lesions. This model represents a crucial tool for the study of both miRNA involvement and cortical lesion formation in disease pathogenesis.

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Section: Discussionsupporting

confidence: 84%

miRNA profile is altered in a modified EAE mouse model of multiple sclerosis featuring cortical lesions

Orefice

Guillemot-Legris

Capasso

et al. 2020

eLife

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“…All animals underwent intracerebral catheter implantation, as described previously [ 11 ]. After 2 weeks of healing of the blood-brain barrier (BBB), animals were immunized with a recombinant MOG1-125 protein and received antibody treatment (anti-CD20 or isotype control) in two alternative orders: In experiment 1, animals received anti-CD20 (E1, n = 9) or isotype control antibody (C1, n = 4) after MOG immunization.…”

Section: Methodsmentioning

confidence: 99%

“…The integrity of the BBB was verified in previous experiments during establishing and validation of the animal model by lack of fibrin leakage in the tissue after 14 days. This was assessed by immunohistochemistry of the catheter area after different time points after catheter implantation [ 11 ].…”

Section: Methodsmentioning

confidence: 99%

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Anti-CD20 treatment effectively attenuates cortical pathology in a rat model of widespread cortical demyelination

Haindl

Üçal

Klaus

et al. 2021

J Neuroinflammation

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Background Cortical demyelination represents a prominent feature of the multiple sclerosis (MS) brain, especially in (late) progressive stages. We recently developed a new rat model that reassembles critical features of cortical pathology characteristic to progressive types of MS. In persons affected by MS, B-cell depleting anti-CD20 therapy proved successful in the relapsing remitting as well as the early progressive course of MS, with respect to reducing the relapse rate and number of newly formed lesions. However, if the development of cortical pathology can be prevented or at least slowed down is still not clear. The main goal of this study was thus to increase our understanding for the mode of action of B-cells and B-cell directed therapy on cortical lesions in our rat model. Methods For this purpose, we set up two separate experiments, with two different induction modes of B-cell depletion. Brain tissues were analyzed thoroughly using histology. Results We observed a marked reduction of cortical demyelination, microglial activation, astrocytic reaction, and apoptotic cell loss in anti-CD20 antibody treated groups. At the same time, we noted increased neuronal preservation compared to control groups, indicating a favorable impact of anti-CD20 therapy. Conclusion These findings might pave the way for further research on the mode of action of B-cells and therefore help to improve therapeutic options for progressive MS.

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“…After routine embedding in para n, brains, spinal cords and spleens were cut in 1.5 µm sections. For immunohistochemistry (IHC), sections were dewaxed in xylol (Fisher Thermo Scienti c, Schwerte, Germany), rehydrated and steamed for 1 h in citric acid (Merck) for antigen retrieval using a commercial steamer (Adzemovic et al, 2013;Ücal et al, 2017). To avoid unspeci c binding, sections were blocked with 2.5% normal horse serum (Vector Laboratories Burlingame, CA, USA) at room temperature for 20 min, prior to incubation with the primary antibodies at 4°C overnight.…”

Section: Neuropathology Immunohistochemistry and Immuno Uorescencementioning

confidence: 99%

Anti-CD20 Treatment Effectively Attenuates Cortical Pathology in a Rat Model of Widespread Cortical Demyelination

Haindl

Üçal

Klaus

et al. 2021

Preprint

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BackgroundCortical demyelination represents a prominent feature of the multiple sclerosis (MS) brain, especially in (late) progressive stages. We recently developed a new rat model that reassembles critical features of cortical pathology characteristic to progressive types of MS. In persons affected by MS, B-cell depleting anti-CD20 therapy proved successful in the relapsing remitting as well as the early progressive course of MS, with respect to reducing the relapse rate and number of newly formed lesions. However, if the development of cortical pathology can be prevented or at least slowed down is still not clear. The main goal of this study was thus to increase our understanding for the mode of action (MOD) of B-cells and B-cell directed therapy on cortical lesions in our rat model. MethodsFor this purpose, we set up two separate experiments, with two different induction modes of B-cell depletion. Brain tissues were analyzed thoroughly using histology. ResultsWe observed a marked reduction of cortical demyelination, microglial activation, astrocytic reaction and apoptotic cell loss in anti-CD20 antibody treated groups. At the same time, we noted increased neuronal preservation compared to control groups, indicating a favorable impact of anti-CD20 therapy. ConclusionThese findings might pave the way for further research on the MOD of B-cells and therefore help to improve therapeutic options for progressive MS.

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Widespread cortical demyelination of both hemispheres can be induced by injection of pro-inflammatory cytokines via an implanted catheter in the cortex of MOG-immunized rats

Cited by 25 publications

References 26 publications

miRNA profile is altered in a modified EAE mouse model of multiple sclerosis featuring cortical lesions

miRNA profile is altered in a modified EAE mouse model of multiple sclerosis featuring cortical lesions

Anti-CD20 treatment effectively attenuates cortical pathology in a rat model of widespread cortical demyelination

Anti-CD20 Treatment Effectively Attenuates Cortical Pathology in a Rat Model of Widespread Cortical Demyelination

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