Fasudil reduces β-amyloid levels and neuronal apoptosis in APP/PS1 transgenic mice via inhibition of the Nogo-A/NgR/RhoA signaling axis

Guo, Minfang; Zhang, Huiyu; Zhang, Peijun; Liu, Xiaoqin; Song, Lijuan; Wei, Wenyue; Wang, Yuyin; Mu, Bing-Tao; Chai, Zhi; Yu, Jie‐Zhong; Ma, Chi

doi:10.31083/j.jin.2020.04.243

Cited by 13 publications

(5 citation statements)

References 35 publications

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“…Fasudil was found to improve cognition in animal models of stroke (Satoh et al, 1996 ), to protect against age-related memory impairment in rats (Huentelman et al, 2009 ), and to improve memory in patients with cerebrovascular dementia (Kamei et al, 1996 ). Fasudil was shown to exert neuroprotective effects by reducing Aβ and tau deposition, oxidative stress and neuronal apoptosis, as well as improving spatial memory and restoring cognitive function in APP/PS1 mice (Elliott et al, 2018 ; Guo et al, 2020 ; Wei et al, 2021 ; Yan et al, 2021 ). Recently, the repurposing potential of fasudil has been supported by evidence showing its effect in reverting neurodegenerative-related phenotype in triple transgenic model of AD (Killick et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Effect of the ROCK inhibitor fasudil on the brain proteomic profile in the tau transgenic mouse model of Alzheimer's disease

Collu,

Yin,

Giunti

et al. 2024

Front. Aging Neurosci.

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IntroductionThe goal of this study is to explore the pharmacological potential of the amyloid-reducing vasodilator fasudil, a selective Ras homolog (Rho)-associated kinases (ROCK) inhibitor, in the P301S tau transgenic mouse model (Line PS19) of neurodegenerative tauopathy and Alzheimer's disease (AD).MethodsWe used LC-MS/MS, ELISA and bioinformatic approaches to investigate the effect of treatment with fasudil on the brain proteomic profile in PS19 tau transgenic mice. We also explored the efficacy of fasudil in reducing tau phosphorylation, and the potential beneficial and/or toxic effects of its administration in mice.ResultsProteomic profiling of mice brains exposed to fasudil revealed the activation of the mitochondrial tricarboxylic acid (TCA) cycle and blood-brain barrier (BBB) gap junction metabolic pathways. We also observed a significant negative correlation between the brain levels of phosphorylated tau (pTau) at residue 396 and both fasudil and its metabolite hydroxyfasudil.ConclusionsOur results provide evidence on the activation of proteins and pathways related to mitochondria and BBB functions by fasudil treatment and support its further development and therapeutic potential for AD.

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Section: Introductionmentioning

confidence: 99%

Effect of the ROCK inhibitor fasudil on the brain proteomic profile in the tau transgenic mouse model of Alzheimer's disease

Collu,

Yin,

Giunti

et al. 2024

Front. Aging Neurosci.

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“…While Nogo-A signaling is mainly associated to myelination and inhibition of synaptic and axonal plasticity in adult mammalian CNS, it has also been found to correlate with numerous homeostatic and pathological mechanisms, such as found in schizophrenia ( 51 ), stroke ( 52 ), beta-amyloid disease ( 53 ), spinal cord injury ( 54 ) and amyotrophic lateral sclerosis ( 55 , 56 ).…”

Section: The Processes Behind Demyelinationmentioning

confidence: 99%

Central nervous system demyelinating diseases: glial cells at the hub of pathology

et al. 2023

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Inflammatory demyelinating diseases (IDDs) are among the main causes of inflammatory and neurodegenerative injury of the central nervous system (CNS) in young adult patients. Of these, multiple sclerosis (MS) is the most frequent and studied, as it affects about a million people in the USA alone. The understanding of the mechanisms underlying their pathology has been advancing, although there are still no highly effective disease-modifying treatments for the progressive symptoms and disability in the late stages of disease. Among these mechanisms, the action of glial cells upon lesion and regeneration has become a prominent research topic, helped not only by the discovery of glia as targets of autoantibodies, but also by their role on CNS homeostasis and neuroinflammation. In the present article, we discuss the participation of glial cells in IDDs, as well as their association with demyelination and synaptic dysfunction throughout the course of the disease and in experimental models, with a focus on MS phenotypes. Further, we discuss the involvement of microglia and astrocytes in lesion formation and organization, remyelination, synaptic induction and pruning through different signaling pathways. We argue that evidence of the several glia-mediated mechanisms in the course of CNS demyelinating diseases supports glial cells as viable targets for therapy development.

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“…To date, fasudil, as well as its analogues, are the most investigated ROCK inhibitors. Many studies have shown that the compound improves memory deficits, significantly reduces Aβ and p-tau protein levels, restores cognitive function, reduces oxidative stress, and decreases neuronal apoptosis in the hippocampus [ 111 , 112 , 113 , 114 ].…”

Section: 5-ht 6 R/rocki/rockii As Multitarget Appr...mentioning

confidence: 99%

Multitargeting the Action of 5-HT6 Serotonin Receptor Ligands by Additional Modulation of Kinases in the Search for a New Therapy for Alzheimer’s Disease: Can It Work from a Molecular Point of View?

Czarnota-Łydka

Kucwaj-Brysz

Pyka

et al. 2022

IJMS

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In view of the unsatisfactory treatment of cognitive disorders, in particular Alzheimer’s disease (AD), the aim of this review was to perform a computer-aided analysis of the state of the art that will help in the search for innovative polypharmacology-based therapeutic approaches to fight against AD. Apart from 20-year unrenewed cholinesterase- or NMDA-based AD therapy, the hope of effectively treating Alzheimer’s disease has been placed on serotonin 5-HT6 receptor (5-HT6R), due to its proven, both for agonists and antagonists, beneficial procognitive effects in animal models; however, research into this treatment has so far not been successfully translated to human patients. Recent lines of evidence strongly emphasize the role of kinases, in particular microtubule affinity-regulating kinase 4 (MARK4), Rho-associated coiled-coil-containing protein kinase I/II (ROCKI/II) and cyclin-dependent kinase 5 (CDK5) in the etiology of AD, pointing to the therapeutic potential of their inhibitors not only against the symptoms, but also the causes of this disease. Thus, finding a drug that acts simultaneously on both 5-HT6R and one of those kinases will provide a potential breakthrough in AD treatment. The pharmacophore- and docking-based comprehensive literature analysis performed herein serves to answer the question of whether the design of these kind of dual agents is possible, and the conclusions turned out to be highly promising.

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Fasudil reduces β-amyloid levels and neuronal apoptosis in APP/PS1 transgenic mice via inhibition of the Nogo-A/NgR/RhoA signaling axis

Cited by 13 publications

References 35 publications

Effect of the ROCK inhibitor fasudil on the brain proteomic profile in the tau transgenic mouse model of Alzheimer's disease

Effect of the ROCK inhibitor fasudil on the brain proteomic profile in the tau transgenic mouse model of Alzheimer's disease

Central nervous system demyelinating diseases: glial cells at the hub of pathology

Multitargeting the Action of 5-HT6 Serotonin Receptor Ligands by Additional Modulation of Kinases in the Search for a New Therapy for Alzheimer’s Disease: Can It Work from a Molecular Point of View?

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