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

Creators: Kagitani-Shimono, Kuriko, Mohri, Ikuko, Fujitani, Yasushi, Suzuki, Kinuko, Ozono, Keiichi, Urade, Yoshihiro, Taniike, Masako

File Type: pdf | Filesize: 2.9 MB | Date Added: 2012-09-05 | Date Created: 2005-04-06

Abstract Background Twitcher 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-&#945; (TNF&#945;), pro-inflammatory cytokine, and the progression of this disease and 2) effect of the anti-inflammatory therapy by ibudilast, a phosphodiesterase inhibitor. Methods We quantified the expression level of TNF&#945; and TNF-receptor mRNA in twi/twi using semi-quantitative RT-PCR. The relationship between TNF&#945; 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 TNF&#945; production in the brain. Results We found that TNF&#945;-immunoreactive microglia/macrophages appeared in the twi/twi brain and that the mRNA levels of TNF&#945; and TNF-receptor 1 was increased with the progression of demyelination. The distribution profile of TNF&#945;-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. Conclusion We conclude that anti-inflammatory therapy by a phosphodiesterase inhibitor can be considered as a novel alternative therapy for Krabbe's disease.