azd-6244 and fasudil

azd-6244 has been researched along with fasudil* in 1 studies

Other Studies

1 other study(ies) available for azd-6244 and fasudil

ArticleYear
ERK and ROCK functionally interact in a signaling network that is compensationally upregulated in Spinal Muscular Atrophy.
    Neurobiology of disease, 2017, Volume: 108

    Spinal Muscular Atrophy (SMA) is a motoneuron disease caused by low levels of functional survival of motoneuron protein (SMN). Molecular disease mechanisms downstream of functional SMN loss are still largely unknown. Previous studies suggested an involvement of Rho kinase (ROCK) as well as the extracellular signal-regulated kinases (ERK) pathways in the pathomechanism. Both pathways are bi-directionally linked and inhibit each other. Thus, we hypothesize that both pathways regulate SMA pathophysiology in vivo in a combined manner rather than acting separately. Here, we applied the repurposed drugs, selumetinib, an ERK inhibitor, and the ROCK inhibitor fasudil to severe SMA mice. Thereby, separately applied inhibitors as well as a combination enabled us to explore the impact of the ROCK-ERK signaling network on SMA pathophysiology. ROCK inhibition specifically ameliorated the phenotype of selumetinib-treated SMA mice demonstrating an efficient ROCK to ERK crosstalk relevant for the SMA pathophysiology. However, ERK inhibition alone aggravated the condition of SMA mice and reduced the number of motoneurons indicating a compensatory hyper-activation of ERK in motoneurons. Taken together, we identified a regulatory network acting downstream of SMN depletion and upstream of the SMA pathophysiology thus being a future treatment target in combination with SMN dependent strategies.

    Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Benzimidazoles; Cell Death; Cell Line; Cytoplasm; Disease Models, Animal; Disease Progression; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Mice, Transgenic; Motor Neurons; Muscular Atrophy, Spinal; Random Allocation; rho-Associated Kinases; RNA, Small Interfering; Severity of Illness Index; Signal Transduction; Spinal Cord; Up-Regulation

2017