FSD-C10, a Fasudil derivative, promotes neuroregeneration through indirect and direct mechanisms

Lǐ, Yànhuá; Xie, Chong; Zhang, Yuan; Li, Xing; Zhang, Haifei; Wang, Qing; Chai, Zhi; Xiao, Bao‐Guo; Thomé, Rodolfo; Zhang, Guang‐Xian; Ma, Cun‐Gen

doi:10.1038/srep41227

Cited by 16 publications

(8 citation statements)

References 59 publications

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“…A fasudil derivative, FSD-C10, demonstrated better safety profile when compared to fasudil (Xin et al, 2015). FSD-C10 showed therapeutic potential in AD mouse model, possibly through inhibiting the formation of Aβ42 and phosphorylation of tau and promoting the generation of synapseassociated proteins and neurotrophic factors (Li et al, 2017;Gu et al, 2018). Li et al (2016) investigated the molecular mechanism of Xanthoceras sorbifolia extract (XSE)-a traditional medicine used for treating CNS diseases in China-that has recently been shown to have anti-inflammatory, anti-HIV, and anti-tumor properties.…”

Section: Applications Of Rho Gtpase Modulators In Neurogenerative Diseases Admentioning

confidence: 99%

Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases

Guiler

Koehler

Boykin

et al. 2021

Front. Cell. Neurosci.

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Classical Rho GTPases, including RhoA, Rac1, and Cdc42, are members of the Ras small GTPase superfamily and play essential roles in a variety of cellular functions. Rho GTPase signaling can be turned on and off by specific GEFs and GAPs, respectively. These features empower Rho GTPases and their upstream and downstream modulators as targets for scientific research and therapeutic intervention. Specifically, significant therapeutic potential exists for targeting Rho GTPases in neurodegenerative diseases due to their widespread cellular activity and alterations in neural tissues. This study will explore the roles of Rho GTPases in neurodegenerative diseases with focus on the applications of pharmacological modulators in recent discoveries. There have been exciting developments of small molecules, nonsteroidal anti-inflammatory drugs (NSAIDs), and natural products and toxins for each classical Rho GTPase category. A brief overview of each category followed by examples in their applications will be provided. The literature on their roles in various diseases [e.g., Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), Frontotemporal dementia (FTD), and Multiple sclerosis (MS)] highlights the unique and broad implications targeting Rho GTPases for potential therapeutic intervention. Clearly, there is increasing knowledge of therapeutic promise from the discovery of pharmacological modulators of Rho GTPases for managing and treating these conditions. The progress is also accompanied by the recognition of complex Rho GTPase modulation where targeting its signaling can improve some aspects of pathogenesis while exacerbating others in the same disease model. Future directions should emphasize the importance of elucidating how different Rho GTPases work in concert and how they produce such widespread yet different cellular responses during neurodegenerative disease progression.

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Section: Applications Of Rho Gtpase Modulators In Neurogenerative Diseases Admentioning

confidence: 99%

Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases

Guiler

Koehler

Boykin

et al. 2021

Front. Cell. Neurosci.

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“…Consecutive 4 μm or 10 μm sections were taken, and Luxol Fast Blue (LFB) staining and hematoxylin and eosin (H&E) stained slices were analyzed in a blind fashion to assess basic histopathological changes. For immunohistochemistry [13], sections were preincubated for 2 h with the blocking buffer (1% BSA in PBS) and then incubated with one of the following polyclonal and monoclonal primary antibodies: anti-myelin basic protein (Millipore, Billericay, MA), anti-CD4, anti-IFN-γ, anti-IL-17 (BD, NJ, USA), anti-IL-10, and anti-pDrp1 (ser616) (Abcam, Cambridge, UK). As a negative control, additional sections were treated similarly, but the primary antibodies were omitted.…”

Section: Methodsmentioning

confidence: 99%

Mdivi-1, a mitochondrial fission inhibitor, modulates T helper cells and suppresses the development of experimental autoimmune encephalomyelitis

Lǐ

Thomé

et al. 2019

J Neuroinflammation

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Background Unrestrained activation of Th1 and Th17 cells is associated with the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). While inactivation of dynamin-related protein 1 (Drp1), a GTPase that regulates mitochondrial fission, can reduce EAE severity by protecting myelin from demyelination, its effect on immune responses in EAE has not yet been studied. Methods We investigated the effect of Mdivi-1, a small molecule inhibitor of Drp1, on EAE. Clinical scores, inflammation, demyelination and Drp1 activation in the central nervous system (CNS), and T cell responses in both CNS and periphery were determined. Results Mdivi-1 effectively suppressed EAE severity by reducing demyelination and cellular infiltration in the CNS. Mdivi-1 treatment decreased the phosphorylation of Drp1 (ser616) on CD4 + T cells, reduced the numbers of Th1 and Th17 cells, and increased Foxp3 + regulatory T cells in the CNS. Moreover, Mdivi-1 treatment effectively inhibited IFN-γ + , IL-17 + , and GM-CSF + CD4 + T cells, while it induced CD4 + Foxp3 + regulatory T cells in splenocytes by flow cytometry. Conclusions Together, our results demonstrate that Mdivi-1 has therapeutic potential in EAE by modulating the balance between Th1/Th17 and regulatory T cells.

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“…Male C57BL/6J mice were purchased from Vital River Laboratory Animal Technology Co. Ltd. (SCXK 2016‐0011). All mice were housed (five animals per cage) in pathogen‐free conditions in a temperature‐controlled room (25 ± 2°C) with a 12 h–12 h light–dark cycle (Liu et al., , ).…”

Section: Methodsmentioning

confidence: 99%

“…Statistical significance for the other results was analysed using one‐way ANOVA followed by Dunnett's test for statistical analysis. A value of P < 0.05 was considered to be statistically significant (Li et al., ).…”

Section: Methodsmentioning

confidence: 99%

Therapeutic effect of oligomeric proanthocyanidin in cuprizone‐induced demyelination

Wang

Yang

et al. 2019

Experimental Physiology

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New Findings What is the central question of this study?Oligomeric proanthocyanidin has the capacity to alleviate abnormalities in neurological functioning. However, whether oligomeric proanthocyanidin can reduce the progression of demyelination or promote remyelination in demyelinating diseases remains unknown. What is the main finding and its importance?Oligomeric proanthocyanidin can improve cuprizone‐induced demyelination by inhibiting immune cell infiltration, reversing overactivated microglia, decreasing the inflammatory cytokines secreted by inflammatory cells and decreasing the production of myelin oligodendrocyte glycoprotein35–55‐specific antibody in the brain. Abstract Demyelinating diseases of the CNS, including multiple sclerosis, neuromyelitis optica and acute disseminated encephalomylitis, are characterized by recurrent primary demyelination–remyelination and progressive neurodegeneration. In the present study, we investigated the therapeutic effect of oligomeric proanthocyanidin (OPC), the most effective component of grape seed extract, in cuprizone‐fed C57BL/6 mice, a classic demyelination–remyelination model. Our results showed that OPC attenuated abnormal behaviour, reduced demyelination and increased expression of myelin basic protein and expression of O4+ oligodendrocytes in the corpus callosum. Oligomeric proanthocyanidin also reduced the numbers of B and T cells, activated microglia in the corpus callosum and inhibited secretion of inflammatory factors. Furthermore, concentrations of myelin oligodendrocyte glycoprotein‐specific antibodies were significantly reduced in serum and brain homogenates after OPC treatment. Together, these results demonstrate a potent therapeutic effect for OPC in cuprizone‐mediated demyelination and clearly highlight multiple effects of this natural product in attenuating myelin‐specific autoantibodies and the inflammatory microenvironment in the brain.

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FSD-C10, a Fasudil derivative, promotes neuroregeneration through indirect and direct mechanisms

Cited by 16 publications

References 59 publications

Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases

Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases

Mdivi-1, a mitochondrial fission inhibitor, modulates T helper cells and suppresses the development of experimental autoimmune encephalomyelitis

Therapeutic effect of oligomeric proanthocyanidin in cuprizone‐induced demyelination

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