Laquinimod ameliorates secondary brain inflammation

Nedelcu, Julia; Reinbach, Christin; Riedler, Philipp; Brendel, Matthias; Rominger, Axel; Kaye, Joel; Behrangi, Newshan; Zhan, Jiangshan; Schmitz, Christoph; Kipp, Markus

doi:10.1016/j.nbd.2019.104675

Cited by 13 publications

(17 citation statements)

References 51 publications

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“…In the mouse EAE model, both preventive and therapeutic LQ treatment changed γ-aminobutyric acid (GABA)ergic synaptic transmission, while only preventive LQ affected glutamatergic synaptic transmission as well, resulting in reduced glutamatergic excitotoxicity [269]. In line with this, LQ reduced the number of APP-positive axons, specifically of vesicular glutamate transporter 1 (VGLUT1)-positive glutamatergic neurons, and reduced the number of SYP-positive axonal spheroids in cuprizone-fed mice [265]. The neuronal output of the inner layer and b-wave amplitudes, as well as the callosal axon conduction and axonal refractoriness [266] also improved following the LQ treatment.…”

Section: Neuronsmentioning

confidence: 84%

“…LQ also decreased the number of MAC-3-and CD45-positive microglia cells in cuprizone mice, EAE mice and mouse TLR4-knockout and myeloid differentiation primary response 88 (MyD88)-knockout demyelination models [261,[265][266][267][268][269]. Moreover, LQ increased the protein level of the pro-inflammatory microglia marker translocator protein (TSPO) [267] in the CNS of cuprizone-exposed mice [265]. Nevertheless, an increase in TSPO in microglia cells is not necessarily associated with neurodegeneration [270].…”

Section: Microgliamentioning

confidence: 98%

“…In rodent models, for both the acute and chronic type of EAE, as well as in rodent models in which non-immunological demyelination is induced in the CNS, optic nerve or retina, LQ reduced the density of IBA1-positive M1 microglia [261][262][263][264][265]. In EAE mice, mRNA and protein expression levels of IBA1, transmembrane protein 119 (TMEM119) and CD68 were also reduced by LQ [261].…”

Section: Microgliamentioning

confidence: 99%

“…Reactive gliosis, characterized among others by an increase in the number of GFAP-and vimentin (VIM)-positive cells, was reduced following the LQ treatment of cuprizone mice [265,268] and in the EAE-induced mouse demyelination model [261,262,266] with again no effect in AhR-knockout EAE mice [262]. One study has reported that LQ did not affect reactive astrocytes in EAE mice [269].…”

Section: Astrocytesmentioning

confidence: 99%

“…Several neuronal parameters appear to be positively affected by LQ treatment. Multiple studies have shown that in rodents, LQ reduces the axonal injury inflicted by EAE [262,263,266,269] and cuprizone [264,265,267,268], and after TBI [271] and neurodegeneration in the mouse R6/2 HD model [275] and genetically induced demyelination models [267]. Again, no effect was found on the number of APP-positive axons in LQ-treated AhR-knockout mice [262].…”

Section: Neuronsmentioning

confidence: 99%

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Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

Kleijn

Martens

2020

IJMS

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Multiple sclerosis (MS) is characterized by peripheral and central inflammatory features, as well as demyelination and neurodegeneration. The available Food and Drug Administration (FDA)-approved drugs for MS have been designed to suppress the peripheral immune system. In addition, however, the effects of these drugs may be partially attributed to their influence on glial cells and neurons of the central nervous system (CNS). We here describe the molecular effects of the traditional and more recent FDA-approved MS drugs Fingolimod, Dimethyl Fumarate, Glatiramer Acetate, Interferon-β, Teriflunomide, Laquinimod, Natalizumab, Alemtuzumab and Ocrelizumab on microglia, astrocytes, neurons and oligodendrocytes. Furthermore, we point to a possible common molecular effect of these drugs, namely a key role for NFκB signaling, causing a switch from pro-inflammatory microglia and astrocytes to anti-inflammatory phenotypes of these CNS cell types that recently emerged as central players in MS pathogenesis. This notion argues for the need to further explore the molecular mechanisms underlying MS drug action.

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Section: Neuronsmentioning

confidence: 84%

Section: Microgliamentioning

confidence: 98%

Section: Microgliamentioning

confidence: 99%

Section: Astrocytesmentioning

confidence: 99%

Section: Neuronsmentioning

confidence: 99%

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Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

Kleijn

Martens

2020

IJMS

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Cuprizone‐induced demyelination triggers a CD8‐pronounced T cell recruitment

Kaddatz

Joost

Nedelcu

et al. 2020

Glia

Self Cite

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The loss of myelinating oligodendrocytes is a key characteristic of many neurological diseases, including Multiple Sclerosis (MS). In progressive MS, where effective treatment options are limited, peripheral immune cells can be found at the site of demyelination and are suggested to play a functional role during disease progression. In this study, we hypothesize that metabolic oligodendrocyte injury, caused by feeding the copper chelator cuprizone, is a potent trigger for peripheral immune cell recruitment into the central nervous system (CNS). We used immunohistochemistry and flow cytometry to evaluate the composition, density, and activation status of infiltrating T lymphocytes in cuprizone‐intoxicated mice and post‐mortem progressive MS tissues. Our results demonstrate a predominance of CD8+ T cells along with high proliferation rates and cytotoxic granule expression, indicating an antigenic and pro‐inflammatory milieu in the CNS of cuprizone‐intoxicated mice. Numbers of recruited T cells and the composition of lymphocytic infiltrates in cuprizone‐intoxicated mice were found to be comparable to those found in progressive MS lesions. Finally, amelioration of the cuprizone‐induced pathology by treating mice with laquinimod significantly reduces the number of recruited T cells. Overall, this study provides strong evidence that toxic demyelination is a sufficient trigger for T cells to infiltrate the demyelinated CNS. Further investigation of the mode of action and functional consequence of T cell recruitment might offer promising new therapeutic approaches for progressive MS.

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TSPO imaging in animal models of brain diseases

Camp

Lavisse

Roost

et al. 2021

Eur J Nucl Med Mol Imaging

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Over the last 30 years, the 18-kDa TSPO protein has been considered as the PET imaging biomarker of reference to measure increased neuroinflammation. Generally assumed to image activated microglia, TSPO has also been detected in endothelial cells and activated astrocytes. Here, we provide an exhaustive overview of the recent literature on the TSPO-PET imaging (i) in the search and development of new TSPO tracers and (ii) in the understanding of acute and chronic neuroinflammation in animal models of neurological disorders. Generally, studies testing new TSPO radiotracers against the prototypic [11C]-R-PK11195 or more recent competitors use models of acute focal neuroinflammation (e.g. stroke or lipopolysaccharide injection). These studies have led to the development of over 60 new tracers during the last 15 years. These studies highlighted that interpretation of TSPO-PET is easier in acute models of focal lesions, whereas in chronic models with lower or diffuse microglial activation, such as models of Alzheimer’s disease or Parkinson’s disease, TSPO quantification for detection of neuroinflammation is more challenging, mirroring what is observed in clinic. Moreover, technical limitations of preclinical scanners provide a drawback when studying modest neuroinflammation in small brains (e.g. in mice). Overall, this review underlines the value of TSPO imaging to study the time course or response to treatment of neuroinflammation in acute or chronic models of diseases. As such, TSPO remains the gold standard biomarker reference for neuroinflammation, waiting for new radioligands for other, more specific targets for neuroinflammatory processes and/or immune cells to emerge.

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Laquinimod ameliorates secondary brain inflammation

Cited by 13 publications

References 51 publications

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

Cuprizone‐induced demyelination triggers a CD8‐pronounced T cell recruitment

TSPO imaging in animal models of brain diseases

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