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Anti-inflammatory therapy by ibudilast, a phosphodiesterase inhibitor, in demyelination of twitcher, a genetic demyelination model

Authors
  • Kagitani-Shimono, Kuriko1, 2, 3
  • Mohri, Ikuko1, 2
  • Fujitani, Yasushi2
  • Suzuki, Kinuko3
  • Ozono, Keiichi1
  • Urade, Yoshihiro2
  • Taniike, Masako1
  • 1 Osaka University Graduate School of Medicine, Department of Developmental Medicine (Pediatrics), 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan , Suita, Osaka
  • 2 Osaka Bioscience Institute, Department of Molecular Behavioral Biology, 6-2-4, Furuedai, Suita, Osaka, 565-0874, Japan , Suita, Osaka
  • 3 University of North Carolina at Chapel Hill, Department of Pathology and Laboratory Medicine, 919 Brinkhous-Bullitt Bldg, Chapel Hill, NC, 27599-7525, USA , Chapel Hill
Type
Published Article
Journal
Journal of Neuroinflammation
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Apr 06, 2005
Volume
2
Issue
1
Identifiers
DOI: 10.1186/1742-2094-2-10
Source
Springer Nature
Keywords
License
Yellow

Abstract

BackgroundTwitcher mouse (twi/twi) 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 twi/twi 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.MethodsWe quantified the expression level of TNFα and TNF-receptor mRNA in twi/twi 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 twi/twi with a daily intraperitoneal injection of ibudilast (10 mg/kg), which suppress TNFα production in the brain.ResultsWe found that TNFα-immunoreactive microglia/macrophages appeared in the twi/twi 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 twi/twi brain. When twi/twi 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.ConclusionWe conclude that anti-inflammatory therapy by a phosphodiesterase inhibitor can be considered as a novel alternative therapy for Krabbe's disease.

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