NADPH oxidase 4 inhibition is a complementary therapeutic strategy for spinal muscular atrophy

Frontiers in Cellular Neuroscience

Cellular Neuroscience

Gaelle Bruneteau¹  Assaad A. Eid²  Olivier Biondi³  Laure Weill³  Sabrina Bendris³  Frédéric Charbonnier³  Cynthia Bezier³  Delphine Sapaly³  Zoé Clerc³  Mirella El Khoury⁴  Elias Abi Akar⁴ 

[1] Centre de Recherche en Myologie, UMRS974, Association Institut de Myologie, Sorbonne Université, INSERM, Paris, France;Département de Neurologie, Centre référent SLA, APHP, Hôpital Pitié-Salpêtrière, Paris, France;Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon;Faculty of Basic and Biomedical Sciences, University Paris Cité & Inserm UMR_S1124, Paris, France;Faculty of Basic and Biomedical Sciences, University Paris Cité & Inserm UMR_S1124, Paris, France;Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon;

关键词: Spinal muscular atrophy;    neurodegenerative disorders;    oxidative stress;    NADPH oxidase 4;    GKT137831;    severe type SMA-like mice;    Setanaxib;   

DOI  :  10.3389/fncel.2023.1242828

 received in 2023-06-19, accepted in 2023-08-30,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionSpinal muscular atrophy (SMA) is a fatal neurodegenerative disorder, characterized by motor neuron (MN) degeneration and severe muscular atrophy and caused by Survival of Motor Neuron (SMN) depletion. Therapies aimed at increasing SMN in patients have proven their efficiency in alleviating SMA symptoms but not for all patients. Thus, combinational therapies are warranted. Here, we investigated the involvement of NADPH oxidase 4 (NOX4) in SMA-induced spinal MN death and if the modulation of Nox4 activity could be beneficial for SMA patients.MethodsWe analysed in the spinal cord of severe type SMA-like mice before and at the disease onset, the level of oxidative stress and Nox4 expression. Then, we tested the effect of Nox4 inhibition by GKT137831/Setanaxib, a drug presently in clinical development, by intrathecal injection on MN survival and motor behaviour. Finally, we tested if GKT137831/Setanaxib could act synergistically with FDA-validated SMN-upregulating treatment (nusinersen).ResultsWe show that NOX4 is overexpressed in SMA and its inhibition by GKT137831/Setanaxib protected spinal MN from SMA-induced degeneration. These improvements were associated with a significant increase in lifespan and motor behaviour of the mice. At the molecular level, GKT137831 activated the pro-survival AKT/CREB signaling pathway, leading to an increase in SMN expression in SMA MNs. Most importantly, we found that the per os administration of GKT137831 acted synergistically with a FDA-validated SMN-upregulating treatment.ConclusionThe pharmacological inhibition of NOX4 by GKT137831/Setanaxib is neuroprotector and could represent a complementary therapeutic strategy to fight against SMA.

【 授权许可】

Unknown   
Copyright © 2023 El Khoury, Biondi, Bruneteau, Sapaly, Bendris, Bezier, Clerc, Akar, Weill, Eid and Charbonnier.