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Kagitani‐Shimono, Kuriko; Mohri, Ikuko; Fujitani, Yasushi; Suzuki, Kinuko; Ozono, Keiichi; Urade, Yoshihiro; Taniike, Masako

doi:10.1186/1742-2094-2-10

Cited by 44 publications

(10 citation statements)

References 44 publications

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“…Indeed, in our study, removal of the upregulated expressions of antigen presentation-related molecules such as CD11c (dendritic cell marker), MHC II, and CD80 and CD86 (costimulatory molecules for antigen presentation) was associated with the worsened pathology in twi+op mice, suggesting that the antigen presentation event is not a major contributing factor in the demyelinating pathology of GLD. Treatment of twi mice with ibudilast, a phosphodiesterase inhibitor which has been proven to suppress glial cell activation decreased the number of apoptotic OL and reduced demyelination (Kagitani-Shimono et al, 2005). Mohri et al (Mohri et al, 2006) have demonstrated reduced demyelination and some improved clinical signs in twi mice by blocking the pathway between an inflammatory mediator, prostaglandin D2 produced by microglia, and its receptors on astrocytes using gene targeting and pharmacological approaches.…”

Section: Discussionmentioning

confidence: 99%

Macrophages Counteract Demyelination in a Mouse Model of Globoid Cell Leukodystrophy

Kondo

Adams²,

Vanier³

et al. 2011

J. Neurosci.

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Whether microglia and macrophages are beneficial or harmful in many neurological disorders including demyelinating diseases such as multiple sclerosis and the leukodystrophies is currently under debate. Answering this question is of special interest in globoid cell leukodystrophy (GLD), a genetic fatal demyelinating disease, because its rapidly progressive demyelination in the nervous system is accompanied by characteristic accumulation of numerous globoid macrophages. Therefore we cross-bred the twitcher (twi) mouse, a bona-fide model of GLD, with the macrophage-deficient osteopetrotic mutant and studied the resultant macrophage-deficient twitcher (twi+op) mouse. The twi+op mouse had few microglia and macrophages in the white matter and, interestingly, showed a more severe clinical phenotype compared to the twi mouse. The number of non-myelinated axons in the spinal cord was significantly higher in twi+op mice than in twi mice at 45 days old. The difference appeared to be due to impaired remyelination in twi+op mice, rather than accelerated demyelination. Quantitative reverse transcription PCR and immunohistochemical studies revealed that the recruitment of oligodendrocyte progenitor cells in response to demyelination was compromised in twi+op mice. Increased myelin debris in the white matter parenchyma of twi+op mice suggested that phagocytosis by macrophages may play an important role in promoting remyelination. Macrophage markers for both protective and destructive phenotypes were significantly upregulated in the spinal cord of twi mice, but were close to normal in twi+op mice due to the reduced macrophage number. The overall effects of macrophages in GLD appear to be beneficial to myelin by promoting myelin repair.

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Section: Discussionmentioning

confidence: 99%

Macrophages Counteract Demyelination in a Mouse Model of Globoid Cell Leukodystrophy

Kondo

Adams²,

Vanier³

et al. 2011

J. Neurosci.

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“…or saline and killed 2 weeks later. The doses of doxorubicin and ibudilast were determined with reference to previous studies (Kagitani-Shimono et al, 2005;Poland, Hahn, Knapp, Beardsley, & Bowers, 2016;Shimauchi et al, 2017). Mice were killed by cervical dislocation, and tissues were removed and processed for histological examination or frozen for further analysis.…”

Section: Animal Modelmentioning

confidence: 99%

Ibudilast attenuates doxorubicin‐induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes

Nishiyama

Numaga‐Tomita

Fujimoto

et al. 2019

British J Pharmacology

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Background and Purpose Doxorubicin is a highly effective anticancer agent but eventually induces cardiotoxicity associated with increased production of ROS. We previously reported that a pathological protein interaction between TRPC3 channels and NADPH oxidase 2 (Nox2) contributed to doxorubicin‐induced cardiac atrophy in mice. Here we have investigated the effects of ibudilast, a drug already approved for clinical use and known to block doxorubicin‐induced cytotoxicity, on the TRPC3‐Nox2 complex. We specifically sought evidence that this drug attenuated doxorubicin‐induced systemic tissue wasting in mice. Experimental Approach We used the RAW264.7 macrophage cell line to screen 1,271 clinically approved chemical compounds, evaluating functional interactions between TRPC3 channels and Nox2, by measuring Nox2 protein stability and ROS production, with and without exposure to doxorubicin. In male C57BL/6 mice, samples of cardiac and gastrocnemius muscle were taken and analysed with morphometric, immunohistochemical, RT‐PCR and western blot methods. In the passive smoking model, cells were exposed to DMEM containing cigarette sidestream smoke. Key Results Ibudilast, an anti‐asthmatic drug, attenuated ROS‐mediated muscle toxicity induced by doxorubicin treatment or passive smoking, by inhibiting the functional interactions between TRPC3 channels and Nox2, without reducing TRPC3 channel activity. Conclusions and Implications These results indicate a common mechanism underlying induction of systemic tissue wasting by doxorubicin. They also suggest that ibudilast could be repurposed to prevent muscle toxicity caused by anticancer drugs or passive smoking.

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“…Recent studies have demonstrated that enzyme replacement therapy (ERT) [26, 27], substrate reduction therapy (SRT) [28], vector therapy [29–31], and anti-inflammatory agents [32] improve the twitcher mouse pathology and modestly prolong lifespan. However, these therapeutic approaches are only partially successful even when combined with BMT [22, 29].…”

Section: Introductionmentioning

confidence: 99%

Multipotent Stromal Cells Alleviate Inflammation, Neuropathology, and Symptoms Associated with Globoid Cell Leukodystrophy in the Twitcher Mouse

et al. 2013

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Globoid cell leukodystrophy (GLD) is a common neurodegenerative lysosomal storage disorder caused by a deficiency in galactocerebrosidase (GALC), an enzyme that cleaves galactocerebroside during myelination. Bone marrow transplantation has shown promise when administered to late-onset GLD patients. However, the side effects (e.g., graft versus host disease), harsh conditioning regimens (e.g., myelosuppression), and variable therapeutic effects make this an unsuitable option for infantile GLD patients. We previously reported modest improvements in the twitcher mouse model of GLD after intracerebroventricular (ICV) injections of a low dose of multipotent stromal cells (MSCs). Goals of this study were to improve bone marrow-derived MSC (BMSC) therapy for GLD by increasing the cell dosage and comparing cell type (e.g., transduced v. native), treatment timing (e.g., single v. weekly), and administration route (e.g., ICV v. intraperitoneal). Neonatal twitcher mice received (1) 2×105 BMSCs by ICV injection, (2) 1×106 BMSCs by intraperitoneal (IP) injection, (3) weekly IP injections of 1×106 BMSCs, or (4) 1×106 lentiviral-transduced BMSCs overexpressing GALC (GALC-BMSC) by IP injection. All treated mice lived longer than untreated mice. However, the mice receiving peripheral MSC therapy had improved motor function (e.g., hind limb strength and rearing ability), twitching symptoms, and weight compared to both the untreated and ICV-treated mice. Inflammatory cell, globoid cell, and apoptotic cell levels in the sciatic nerves were significantly decreased as a result of the GALC-BMSC or weekly IP injections. The results of this study indicate a promising future for peripheral MSC therapy as a non-invasive, adjunct therapy for patients affected with GLD.

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Cited by 44 publications

References 44 publications

Macrophages Counteract Demyelination in a Mouse Model of Globoid Cell Leukodystrophy

Macrophages Counteract Demyelination in a Mouse Model of Globoid Cell Leukodystrophy

Ibudilast attenuates doxorubicin‐induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes

Multipotent Stromal Cells Alleviate Inflammation, Neuropathology, and Symptoms Associated with Globoid Cell Leukodystrophy in the Twitcher Mouse

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