The Rho kinase inhibitor fasudil attenuates Aβ1–42-induced apoptosis via the ASK1/JNK signal pathway in primary cultures of hippocampal neurons

Gao, Ye; Yan, Yuqing; Fang, Qingli; Zhang, Nianping; Kumar, Gajendra; Zhang, Jihong; Song, Lijuan; Yu, Jie‐Zhong; Zhao, Linhu; Zhang, Han‐Ting; Ma, Cun‐Gen

doi:10.1007/s11011-019-00487-0

Cited by 31 publications

(16 citation statements)

References 76 publications

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“…Inhibition of ROCK by fasudil reverses Aβ 1−42 -induced neuronal apoptosis, intracellular calcium overload, and decreases the mitochondrial membrane potential. Thus, ROCK inhibitors such as fasudil can be conferred as future therapeutic and preventive strategies for neuroinflammatory and neurodegenerative diseases (Gao et al, 2019 ). However, it has not been reported that alteration of gut microbiota by fasudil exhibit cognition-enhancing effect in AD mice.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Rho Kinase by Fasudil Ameliorates Cognition Impairment in APP/PS1 Transgenic Mice via Modulation of Gut Microbiota and Metabolites

Yan

Gao

Fang

et al. 2021

Front. Aging Neurosci.

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Background: Fasudil, a Rho kinase inhibitor, exerts therapeutic effects in a mouse model of Alzheimer's disease (AD), a chronic neurodegenerative disease with progressive loss of memory. However, the mechanisms remain unclear. In addition, the gut microbiota and its metabolites have been implicated in AD.Methods: We examined the effect of fasudil on learning and memory using the Morris water-maze (MWM) test in APPswe/PSEN1dE9 transgenic (APP/PS1) mice (8 months old) treated (i.p.) with fasudil (25 mg/kg/day; ADF) or saline (ADNS) and in age- and gender-matched wild-type (WT) mice. Fecal metagenomics and metabolites were performed to identify novel biomarkers of AD and elucidate the mechanisms of fasudil induced beneficial effects in AD mice.Results: The MWM test showed significant improvement of spatial memory in APP/PS1 mice treated with fasudil as compared to ADNS. The metagenomic analysis revealed the abundance of the dominant phyla in all the three groups, including Bacteroidetes (23.7–44%) and Firmicutes (6.4–26.6%), and the increased relative abundance ratio of Firmicutes/Bacteroidetes in ADNS (59.1%) compared to WT (31.7%). In contrast, the Firmicutes/Bacteroidetes ratio was decreased to the WT level in ADF (32.8%). Lefse analysis of metagenomics identified s_Prevotella_sp_CAG873 as an ADF potential biomarker, while s_Helicobacter_typhlonius and s_Helicobacter_sp_MIT_03-1616 as ADNS potential biomarkers. Metabolite analysis revealed the increment of various metabolites, including glutamate, hypoxanthine, thymine, hexanoyl-CoA, and leukotriene, which were relative to ADNS or ADF microbiota potential biomarkers and mainly involved in the metabolism of nucleotide, lipids and sugars, and the inflammatory pathway.Conclusions: Memory deficit in APP/PS1 mice was correlated with the gut microbiome and metabolite status. Fasudil reversed the abnormal gut microbiota and subsequently regulated the related metabolisms to normal in the AD mice. It is believed that fasudil can be a novel strategy for the treatment of AD via remodeling of the gut microbiota and metabolites. The novel results also provide valuable references for the use of gut microbiota and metabolites as diagnostic biomarkers and/or therapeutic targets in clinical studies of AD.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Rho Kinase by Fasudil Ameliorates Cognition Impairment in APP/PS1 Transgenic Mice via Modulation of Gut Microbiota and Metabolites

Yan

Gao

Fang

et al. 2021

Front. Aging Neurosci.

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“…Moreover, fasudil alone did not restore the mitochondrial function in our study, which conflicts with a recent study showing that fasudil can ameliorate mitochondrial stress via stabilization of the mitochondrial membrane potential in hippocampal neurons. 40 Therefore, the interaction between mitochondria and ROCK in PASMCs may be tissue-and cell-specific. Collectively, these results demonstrated that alleviating DCA-induced alleviation of mitochondrial dysfunction may facilitate the inhibitory effects of fasudil on ROCK signaling in pulmonary arterial smooth muscle under hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Fasudil Dichloroacetate Alleviates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension by Ameliorating Dysfunction of Pulmonary Arterial Smooth Muscle Cells

Liu¹,

Huang²,

Ding³

et al. 2021

DDDT

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Background: Pulmonary arterial hypertension (PAH) is an incurable disease that urgently needs therapeutic approaches. Based on the therapeutic effects of fasudil and dichloroacetate (DCA) on PAH, we aimed to explore the effects and potential mechanism of a new salt, fasudil dichloroacetate (FDCA), in a SU5416 plus hypoxia (SuHx)-induced rat model of PAH. Methods: The rat model of PAH was established by a single subcutaneous injection of SU5416 (20 mg/kg) followed by hypoxia (10% O 2 ) exposure for 3 weeks. FDCA (15, 45, or 135 mg/kg i.g. daily) or the positive control, bosentan (100 mg/kg i.g. daily), were administered from the first day after SU5416 injection. After 3-week hypoxia, hemodynamic parameters, and histological changes of the pulmonary arterial vessels and right ventricle (RV) were assessed. Additionally, in vitro, the effects of FDCA (50 μM), compared with equimolar doses of fasudil, DCA, or fasudil+DCA, on the proliferation, migration, and contraction of human pulmonary arterial smooth muscle cell (PASMC) under hypoxia (1% O 2 ) were evaluated. Results: FDCA dose-dependently attenuated SuHx-induced PAH, with significant reductions in RV systolic pressure, pulmonary artery wall thickness, pulmonary vessel muscularization, perivascular fibrosis, as well as RV hypertrophy and fibrosis. In vitro, FDCA inhibited hypoxia-induced PASMC proliferation, migration, and contraction to a greater degree than fasudil or DCA alone by restoring mitochondrial function, reducing intracellular Ca 2+ , and inhibiting calcium/calmodulin-dependent kinase (Ca 2+ /CaMK) activity as well as Rho-kinase activity. Conclusion: FDCA ameliorates hypoxia-induced PASMC dysfunction by inhibiting both Ca 2+ /CaMK and Rho-kinase signaling pathways, as well as maintaining mitochondrial homeostasis, thus alleviating SuHx-induced PAH.

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“…For example, inhibition of the RhoA/ROCK signaling pathway promotes the apoptosis of human urethral scar fibroblasts[ 38 ], cardiac fibroblasts[ 39 ], and neutrophils[ 40 ]. However, the decrease of apoptosis by RhoA/ROCK inhibition is also found in several cell types, such as nitrergic neurons[ 41 ] and progenitor cells[ 42 ]. RhoA is positively correlated with the expression of α-SMA, a gene involved in liver fibrosis[ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Fasudil prevents liver fibrosis via activating natural killer cells and suppressing hepatic stellate cells

Han

Zhao

et al. 2021

WJG

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BACKGROUND Fasudil, as a Ras homology family member A (RhoA) kinase inhibitor, is used to improve brain microcirculation and promote nerve regeneration clinically. Increasing evidence shows that Rho-kinase inhibition could improve liver fibrosis. AIM To evaluate the anti-fibrotic effects of Fasudil in a mouse model of liver fibrosis induced by thioacetamide (TAA). METHODS C57BL/6 mice were administered TAA once every 3 d for 12 times. At 1 wk after induction with TAA, Fasudil was intraperitoneally injected once a day for 3 wk, followed by hematoxylin and eosin staining, sirius red staining, western blotting, and quantitative polymerase chain reaction (qPCR), and immune cell activation was assayed by fluorescence-activated cell sorting. Furthermore, the effects of Fasudil on hepatic stellate cells and natural killer (NK) cells were assayed in vitro . RESULTS First, we found that TAA-induced liver injury was protected, and the positive area of sirius red staining and type I collagen deposition were significantly decreased by Fasudil treatment. Furthermore, western blot and qPCR assays showed that the levels of alpha smooth muscle actin (α-SMA), matrix metalloproteinase 2 (MMP-2), MMP-9, and transforming growth factor beta 1 (TGF-β1) were inhibited by Fasudil. Moreover, flow cytometry analysis revealed that NK cells were activated by Fasudil treatment in vivo and in vitro . Furthermore, Fasudil directly promoted the apoptosis and inhibited the proliferation of hepatic stellate cells by decreasing α-SMA and TGF-β1. CONCLUSION Fasudil inhibits liver fibrosis by activating NK cells and blocking hepatic stellate cell activation, thereby providing a feasible solution for the clinical treatment of liver fibrosis.

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The Rho kinase inhibitor fasudil attenuates Aβ1–42-induced apoptosis via the ASK1/JNK signal pathway in primary cultures of hippocampal neurons

Cited by 31 publications

References 76 publications

Inhibition of Rho Kinase by Fasudil Ameliorates Cognition Impairment in APP/PS1 Transgenic Mice via Modulation of Gut Microbiota and Metabolites

Inhibition of Rho Kinase by Fasudil Ameliorates Cognition Impairment in APP/PS1 Transgenic Mice via Modulation of Gut Microbiota and Metabolites

Fasudil Dichloroacetate Alleviates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension by Ameliorating Dysfunction of Pulmonary Arterial Smooth Muscle Cells

Fasudil prevents liver fibrosis via activating natural killer cells and suppressing hepatic stellate cells

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