Rho Kinase Inhibitor Fasudil Protects against<i>β</i>-Amyloid-Induced Hippocampal Neurodegeneration in Rats

Yun, Seok-Kweon; Chen, Xu; Wang, Liyan; Gao, Wei; Zhu, Mingqing

doi:10.1111/cns.12116

Cited by 85 publications

(60 citation statements)

References 27 publications

(35 reference statements)

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“…Interestingly, although no effective therapy is known to combat the progression of AD, studies in animal models provide strong evidence that maintaining dendritic network integrity may ease the symptoms and slow down disease progression (3,42). Furthermore, Rock2 levels increase in the very early stages of AD and remain elevated throughout the course of the disease (43), and Rock2 inhibition reduces amyloid-β levels (43,44) and attenuates amyloid-β-induced neurodegeneration (45). Therefore, the reduction in dendrite disruption, and the improvement in learning and memory observed after fasudil administration to Cdh1 cKO mice, further supports the notion that this clinically approved Rock inhibitor drug should be considered as a drug to treat AD.…”

Section: Discussionmentioning

confidence: 99%

APC/C ^Cdh1 -Rock2 pathway controls dendritic integrity and memory

Bobo-Jiménez

Delgado‐Esteban

Angibaud

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Disruption of neuronal morphology contributes to the pathology of neurodegenerative disorders such as Alzheimer's disease (AD). However, the underlying molecular mechanisms are unknown. Here, we show that postnatal deletion of Cdh1, a cofactor of the anaphasepromoting complex/cyclosome (APC/C) ubiquitin ligase in neurons [Cdh1 conditional knockout (cKO)], disrupts dendrite arborization and causes dendritic spine and synapse loss in the cortex and hippocampus, concomitant with memory impairment and neurodegeneration, in adult mice. We found that the dendrite destabilizer Rho protein kinase 2 (Rock2), which accumulates in the brain of AD patients, is an APC/C Cdh1 substrate in vivo and that Rock2 protein and activity increased in the cortex and hippocampus of Cdh1 cKO mice. In these animals, inhibition of Rock activity, using the clinically approved drug fasudil, prevented dendritic network disorganization, memory loss, and neurodegeneration. Thus, APC/C Cdh1 -mediated degradation of Rock2 maintains the dendritic network, memory formation, and neuronal survival, suggesting that pharmacological inhibition of aberrantly accumulated Rock2 may be a suitable therapeutic strategy against neurodegeneration.APC/C Cdh1 | Rock | dendrite | memory | neurodegeneration

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Section: Discussionmentioning

confidence: 99%

APC/C ^Cdh1 -Rock2 pathway controls dendritic integrity and memory

Bobo-Jiménez

Delgado‐Esteban

Angibaud

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Notably, microglia were activated after LPS exposure in the current study, which could be prevented by CysLT 1 R knockdown or blockade. It has been reported that CysLT 1 R expression was predominantly observed in microglia, astrocytes and some oligodendroglial cells [46] , and inhibition of NF-κB transcriptional activity in the microglial nucleus suppresses pro-inflammatory cytokine expression [47,48] . Therefore, we speculate that LPS-induced neuroinflammation could be involved in microglia activation via CysLT 1 R-mediated NF-κB signaling.…”

Section: Discussionmentioning

confidence: 99%

Hippocampal CysLT1R knockdown or blockade represses LPS-induced depressive behaviors and neuroinflammatory response in mice

et al. 2017

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Evidence suggests that neuroinflammation is involved in depression and that the cysteinyl leukotriene receptor 1 (CysLT 1 R) plays a potential pathophysiological role in several types of CNS disorders. Our previous study has shown that knockdown of hippocampal CysLT 1 R in mice prevents the depressive-like phenotype and neuroinflammation induced by chronic mild stress (CMS). Here, we examined the effects of hippocampal CysLT 1 R knockdown and CysLT 1 R blockade on LPS-induced depressive-like behavior in mice. We found that injection of LPS (0.5 mg/kg, ip) caused marked increase in hippocampal CysLT 1 R expression, which was reversed by pretreatment with fluoxetine (20 mg·kg -1 ·d -1 for 7 d, ig). Knockdown of hippocampal CysLT 1 R or blockade of CysLT 1 R by pretreatment with pranlukast (0.5 mg/kg, ip) significantly suppressed LPS-induced depressive behaviors, as evidenced by decreases in mouse immobility time in the forced swimming test (FST) and tail suspension test (TST) and latency to feed in the novelty-suppressed feeding (NSF) test. Moreover, both CysLT 1 R knockdown and CysLT 1 R blockade markedly prevented LPS-induced neuroinflammation, as shown by the suppressed activation of microglia and NF-κB signaling as well as the hippocampal levels of TNF-α and IL-1β in mice. Our results suggest that CysLT 1 R may be involved in LPS-induced depressive-like behaviors and neuroinflammation, and that downregulation of CysLT 1 R could be a novel and potential therapeutic strategy for the treatment of depression, at least partially due to its role in neuroinflammation.

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“…In murine models of Alzheimer disease, treatment with ROCK inhibitors reduces the level of toxic b-amyloid peptide (Zhou et al, 2003), promotes elongation of dendrite arbors (Couch et al, 2010), and improves learning dysfunction (Hou et al, 2012). Furthermore, the ROCK inhibitor fasudil reduces cognitive impairment and hippocampal neurodegeneration induced by b-amyloid peptide by suppressing the inflammatory response (Song et al, 2013). The anti-inflammatory, neuroprotective, and neuroregeneration-stimulating activities of ROCK inhibitors can be an added value in this pathologic context (Mueller et al, 2005).…”

Section: B Clinical Evaluation and Potential Applications Of Rho-assmentioning

confidence: 99%

Rho Kinases in Health and Disease: From Basic Science to Translational Research

Loirand¹

2015

Pharmacol Rev

149

128

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Rho Kinase Inhibitor Fasudil Protects againstβ-Amyloid-Induced Hippocampal Neurodegeneration in Rats

Abstract: Fasudil can protect against Aβ-induced hippocampal neurodegeneration by suppressing inflammatory response, suggesting that fasudil might be a promising agent for the prevention and treatment of inflammation-related diseases, such as AD.

Cited by 85 publications

References 27 publications

APC/C ^Cdh1 -Rock2 pathway controls dendritic integrity and memory

APC/C ^Cdh1 -Rock2 pathway controls dendritic integrity and memory

Hippocampal CysLT1R knockdown or blockade represses LPS-induced depressive behaviors and neuroinflammatory response in mice

Rho Kinases in Health and Disease: From Basic Science to Translational Research

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Rho Kinase Inhibitor Fasudil Protects againstβ-Amyloid-Induced Hippocampal Neurodegeneration in Rats

Abstract: Fasudil can protect against Aβ-induced hippocampal neurodegeneration by suppressing inflammatory response, suggesting that fasudil might be a promising agent for the prevention and treatment of inflammation-related diseases, such as AD.

Cited by 85 publications

References 27 publications

APC/C Cdh1 -Rock2 pathway controls dendritic integrity and memory

APC/C Cdh1 -Rock2 pathway controls dendritic integrity and memory

Hippocampal CysLT1R knockdown or blockade represses LPS-induced depressive behaviors and neuroinflammatory response in mice

Rho Kinases in Health and Disease: From Basic Science to Translational Research

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Product

Resources

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APC/C ^Cdh1 -Rock2 pathway controls dendritic integrity and memory

APC/C ^Cdh1 -Rock2 pathway controls dendritic integrity and memory