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1.
J Neuroimmunol ; 346: 577284, 2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32652366

RESUMO

Emerging evidence suggests an association of Alzheimer's Disease (AD) with microglial and astrocytic dysregulation. Recent studies have proposed that activated microglia can transform astrocytes to a neurotoxic A1 phenotype, which has been shown to be involved in the promotion of neuronal damage in several neurodegenerative diseases, including AD. In the present study, we observed an obvious microglial activation and A1-specific astrocyte response in the brain tissue of APP/PS1 Tg mice. Fasudil treatment improved the cognitive deficits of APP/PS1 Tg mice, inhibited microglial activation and promoted their transformation to an anti-inflammatory phenotype, and further shifted astrocytes from an A1 to an A2 phenotype. Our experiments suggest Fasudil exerted these functions by inhibing the expression of TLR4, MyD88, and NF-κB, which are key mediators of inflammation. Using in vitro experiments, we further validated in vivo findings. Our cell experiments indicated that Fasudil induces a shift of inflammatory microglia towards an anti-inflammatory phenotype. LPS-induced microglia-conditioned medium promotes A1 astrocytic polarization, but Fasudil treatment resulted in a direct transformation of A1 astrocytes to A2. To summarize, our results show that Fasudil inhibits the neurotoxic activation of microglia and shifts astrocytes towards a neuroprotective A2 phenotype, representing a promising candidate for AD treatment.

2.
Exp Ther Med ; 16(5): 3929-3938, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30344671

RESUMO

Fasudil, a Rho kinase (ROCK) inhibitor, effectively inhibits disease severity in a mouse model of Alzheimer's disease (AD). However, given its significant limitations, including a relatively narrow safety window and poor oral bioavailability, Fasudil is not suitable for long-term use. Thus, screening for ROCK inhibitor(s) that are more efficient, safer, can be used orally and suitable for long-term use in the treatment of neurodegenerative disorders is required. The main purpose of the present study is to explore whether FSD-C10, a novel ROCK inhibitor, has therapeutic potential in amyloid precursor protein/presenilin-1 transgenic (APP/PS1 Tg) mice, and to determine possible mechanisms of its action. The results showed that FSD-C10 effectively improved learning and memory impairment, accompanied by reduced expression of amyloid-ß 1-42 (Aß1-42), Tau protein phosphorylation (P-tau) and ß-site APP-cleaving enzyme in the hippocampus and cortex area of brain. In addition, FSD-C10 administration boosted the expression of synapse-associated proteins, such as postynaptic density protein 95, synaptophsin, α-amino 3-hydroxy-5-methyl-4-isoxa-zolep-propionate receptor and neurotrophic factors, e,g., brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. Taken together, our results demonstrate that FSD-C10 has therapeutic potential in the AD mouse model, possibly through inhibiting the formation of Aß1-42 and P-tau, and promoting the generation of synapse-associated proteins and neurotrophic factors.

3.
CNS Neurol Disord Drug Targets ; 16(2): 199-209, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27401064

RESUMO

INTRODUCTION: Therapeutic strategies targeting Alzheimer's disease-related molecule ß- amyloid (Aß), Tau protein and ß-site amyloid precursor protein cleaving enzyme (BACE) have been recently explored. However, the treatment effect for single target is not ideal. Based on multiaspect roles of Rho kinase inhibitor Fasudil on neuroprotection, neurorepair and immunomodulation, we observed therapeutic potential of Fasudil and explored possible mechanisms in amyloid precursor protein/ presenilin-1 transgenic (APP/PS1 Tg) mice, an animal model of Alzheimer's disease. METHODS: APP/PS1 Tg mice were treated with Fasudil (25 mg/kg/day) for 2 months by intraperitoneal injection. Mouse behavior tests were recorded every day. The expression of Aß deposition, Tau protein phosphorylation, BACE and postsynaptic density 95 (PSD-95) in hippocampus was assayed. The levels in the brain of Toll-like receptors (TLRs)-nuclear factor kappa B/p65(NF-κB/p65)- myeloid differentiation primary response gene 88 (MyD88) inflammatory cytokine axis were measured. RESULTS: Fasudil treatment ameliorated learning and memory deficits, accompanied by reduced Aß deposition, Tau protein phosphorylation, and BACE expression, as well as increased PSD-95 expression in hippocampus. Fasudil intervention also inhibited TLR-2/4, p-NF-κB/p65, MyD88, interleukin-1beta, interleukin-6 and tumor necrosis factor-α for TLRs-NF-κB-MyD88 inflammatory cytokine axis and the induction of interleukin-10. CONCLUSION: Fasudil exhibited multitarget therapeutic effect in APP/PS1 Tg mice. The study provides preclinical evidence that Fasudil treatment ameliorated memory deficits in APP/PS1 Tg mice, accompanied by the reduction of Aß deposition and Tau protein phosphorylation, the decrease of BACE and the increase of PSD-95, as well as inhibition of TLRs-NF-κB-MyD88 inflammatory cytokine axis. However, these results still need to be repeated and confirmed before clinical application.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Doença de Alzheimer/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Citocinas/metabolismo , Proteína 4 Homóloga a Disks-Large/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Camundongos Transgênicos , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/fisiologia , Fosforilação/efeitos dos fármacos , Presenilina-1/genética , Presenilina-1/metabolismo , Aprendizagem Espacial/efeitos dos fármacos , Aprendizagem Espacial/fisiologia , Proteínas tau/metabolismo
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