Anti-inflammatory therapy by ibudilast, a phosphodiesterase inhibitor, in demyelination of twitcher, a genetic demyelination model
<p>Abstract</p> <p>Background</p> <p>Twitcher mouse (<it>twi/twi</it>) is an authentic murine model of Krabbe's disease. Accumulation of psychosine, resulting in apoptosis of oligodendrocytes and subsequent demyelination, is a cardinal event to the path...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2005-04-01
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| Series: | Journal of Neuroinflammation |
| Online Access: | http://www.jneuroinflammation.com/content/2/1/10 |
| _version_ | 1828405715551649792 |
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| author | Suzuki Kinuko Fujitani Yasushi Mohri Ikuko Kagitani-Shimono Kuriko Ozono Keiichi Urade Yoshihiro Taniike Masako |
| author_facet | Suzuki Kinuko Fujitani Yasushi Mohri Ikuko Kagitani-Shimono Kuriko Ozono Keiichi Urade Yoshihiro Taniike Masako |
| author_sort | Suzuki Kinuko |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Twitcher mouse (<it>twi/twi</it>) is an authentic murine model of Krabbe's disease. Accumulation of psychosine, resulting in apoptosis of oligodendrocytes and subsequent demyelination, is a cardinal event to the pathogenesis of this disease. Moreover, recruitment of inflammatory cells plays a significant role in the pathological process in the <it>twi/twi </it>central and peripheral nervous systems. In this study, we investigated the 1) the relationship between tumor necrosis factor-α (TNFα), pro-inflammatory cytokine, and the progression of this disease and 2) effect of the anti-inflammatory therapy by ibudilast, a phosphodiesterase inhibitor.</p> <p>Methods</p> <p>We quantified the expression level of TNFα and TNF-receptor mRNA in <it>twi/twi </it>using semi-quantitative RT-PCR. The relationship between TNFα expression, apoptosis of oligodendrocytes and demyelination was studied with immunohistochemistry and TUNEL method. We then treated <it>twi/twi </it>with a daily intraperitoneal injection of ibudilast (10 mg/kg), which suppress TNFα production in the brain.</p> <p>Results</p> <p>We found that TNFα-immunoreactive microglia/macrophages appeared in the <it>twi/twi </it>brain and that the mRNA levels of TNFα and TNF-receptor 1 was increased with the progression of demyelination. The distribution profile of TNFα-immunoreactive microglia/macrophages overlapped that of TUNEL-positive oligodendrocytes in the <it>twi/twi </it>brain. When <it>twi/twi </it>was treated with ibudilast from PND30, the number of oligodendrocytes undergoing apoptosis was markedly reduced and demyelination was milder. Obvious improvement of clinical symptom was noted in two of five. The failure of constant clinical improvement by ibudilast may result from hepatotoxicity and/or the inhibition of proliferation of NG2-positive oligodendrocyte precursors.</p> <p>Conclusion</p> <p>We conclude that anti-inflammatory therapy by a phosphodiesterase inhibitor can be considered as a novel alternative therapy for Krabbe's disease.</p> |
| first_indexed | 2024-12-10T10:58:09Z |
| format | Article |
| id | doaj.art-fc090cdf70b04b5bbd0058317a83fafb |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-10T10:58:09Z |
| publishDate | 2005-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-fc090cdf70b04b5bbd0058317a83fafb2022-12-22T01:51:47ZengBMCJournal of Neuroinflammation1742-20942005-04-01211010.1186/1742-2094-2-10Anti-inflammatory therapy by ibudilast, a phosphodiesterase inhibitor, in demyelination of twitcher, a genetic demyelination modelSuzuki KinukoFujitani YasushiMohri IkukoKagitani-Shimono KurikoOzono KeiichiUrade YoshihiroTaniike Masako<p>Abstract</p> <p>Background</p> <p>Twitcher mouse (<it>twi/twi</it>) is an authentic murine model of Krabbe's disease. Accumulation of psychosine, resulting in apoptosis of oligodendrocytes and subsequent demyelination, is a cardinal event to the pathogenesis of this disease. Moreover, recruitment of inflammatory cells plays a significant role in the pathological process in the <it>twi/twi </it>central and peripheral nervous systems. In this study, we investigated the 1) the relationship between tumor necrosis factor-α (TNFα), pro-inflammatory cytokine, and the progression of this disease and 2) effect of the anti-inflammatory therapy by ibudilast, a phosphodiesterase inhibitor.</p> <p>Methods</p> <p>We quantified the expression level of TNFα and TNF-receptor mRNA in <it>twi/twi </it>using semi-quantitative RT-PCR. The relationship between TNFα expression, apoptosis of oligodendrocytes and demyelination was studied with immunohistochemistry and TUNEL method. We then treated <it>twi/twi </it>with a daily intraperitoneal injection of ibudilast (10 mg/kg), which suppress TNFα production in the brain.</p> <p>Results</p> <p>We found that TNFα-immunoreactive microglia/macrophages appeared in the <it>twi/twi </it>brain and that the mRNA levels of TNFα and TNF-receptor 1 was increased with the progression of demyelination. The distribution profile of TNFα-immunoreactive microglia/macrophages overlapped that of TUNEL-positive oligodendrocytes in the <it>twi/twi </it>brain. When <it>twi/twi </it>was treated with ibudilast from PND30, the number of oligodendrocytes undergoing apoptosis was markedly reduced and demyelination was milder. Obvious improvement of clinical symptom was noted in two of five. The failure of constant clinical improvement by ibudilast may result from hepatotoxicity and/or the inhibition of proliferation of NG2-positive oligodendrocyte precursors.</p> <p>Conclusion</p> <p>We conclude that anti-inflammatory therapy by a phosphodiesterase inhibitor can be considered as a novel alternative therapy for Krabbe's disease.</p>http://www.jneuroinflammation.com/content/2/1/10 |
| spellingShingle | Suzuki Kinuko Fujitani Yasushi Mohri Ikuko Kagitani-Shimono Kuriko Ozono Keiichi Urade Yoshihiro Taniike Masako Anti-inflammatory therapy by ibudilast, a phosphodiesterase inhibitor, in demyelination of twitcher, a genetic demyelination model Journal of Neuroinflammation |
| title | Anti-inflammatory therapy by ibudilast, a phosphodiesterase inhibitor, in demyelination of twitcher, a genetic demyelination model |
| title_full | Anti-inflammatory therapy by ibudilast, a phosphodiesterase inhibitor, in demyelination of twitcher, a genetic demyelination model |
| title_fullStr | Anti-inflammatory therapy by ibudilast, a phosphodiesterase inhibitor, in demyelination of twitcher, a genetic demyelination model |
| title_full_unstemmed | Anti-inflammatory therapy by ibudilast, a phosphodiesterase inhibitor, in demyelination of twitcher, a genetic demyelination model |
| title_short | Anti-inflammatory therapy by ibudilast, a phosphodiesterase inhibitor, in demyelination of twitcher, a genetic demyelination model |
| title_sort | anti inflammatory therapy by ibudilast a phosphodiesterase inhibitor in demyelination of twitcher a genetic demyelination model |
| url | http://www.jneuroinflammation.com/content/2/1/10 |
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