Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal multisystem degenerative disorder with minimal available therapeutic. However, some recent studies showed promising results of immunological-based treatment. Here, we aimed to evaluate the efficacy of ibrutinib against ALS-associated abnormalities by targeting inflammation and muscular atrophy. Ibrutinib was administrated orally to SOD1 G93A mice from 6 to 19 weeks for prophylactic administration and 13 to 19 weeks for therapeutic administration. Our results demonstrated that ibrutinib treatment significantly delayed ALS-like symptom onset in the SOD1 G93A mice, as shown by improved survival time and reduced behavioral impairments. Ibrutinib treatment significantly reduced muscular atrophy by increasing muscle/body weight and decreasing muscular necrosis. The ibrutinib treatment also considerably reduced pro-inflammatory cytokine production, IBA-1, and GFAP expression, possibly mediated by mTOR/Akt/Pi3k signaling in the medulla, motor cortex and spinal cord of the ALS mice. In conclusion, our study demonstrated that ibrutinib could delay ALS onset, increase survival time, and reduce ALS progression by targeting inflammation and muscular atrophy via mTOR/Akt/PI3K modulation.
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All data generated or analyzed during this study are included in this published article [and its supplementary information files].
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Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions(2023SHIBS0004).
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This work was supported by Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions No: 2019SHIBS0004; International Cooperation Project(NCT03721302)of Shenzhen Children’s Hospital; Guangdong High-level Hospital Construction Fund; Basic research of Shenzhen Science and Technology Plan Project (General Program: JCYJ20220530155611026).
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C.Z. and W.F. performed the experiments; T.A. did data analysis and wrote the manuscript; Z.P, J.L, and Z.P helped in the investigation. S.L and J.F. endorsed the study, and corresponding authors, reviewed and approved the manuscript and held all the responsibilities related to this manuscript. All authors reviewed and approved the manuscript.
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Zheng, C., Li, W., Ali, T. et al. Ibrutinib Delays ALS Installation and Increases Survival of SOD1G93A Mice by Modulating PI3K/mTOR/Akt Signaling. J Neuroimmune Pharmacol 18, 383–396 (2023). https://doi.org/10.1007/s11481-023-10068-9
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DOI: https://doi.org/10.1007/s11481-023-10068-9