Dataset Information

MGCD0103, a selective histone deacetylase inhibitor, coameliorates oligomeric Aβ_25-35 -induced anxiety and cognitive deficits in a mouse model.

ABSTRACT:

Aims

Recently, histone deacetylase (HDAC) inhibitors are considered a possible therapeutic strategy in Alzheimer's disease (AD). However, HDACi treatments exhibit diverse functions with unfavorable effects in AD. Thus, the development of selective HDACi without side effects is urgently needed.

Methods

HDACi, namely, BML210, MGCD0103, PXD101, and Droxinostat, were screened in mouse hippocampal primary cultures incubated with oligomeric Aβ_25-35 (50 μmol/L). MGCD0103 was chosen for in vivo tests and was intraperitoneally injected into C57BL/6J mice (0.5 mg/kg, once per day) for 4 weeks following an intrahippocampal CA1 injection of oligomeric Aβ_25-35 . Brain samples were collected for pathological analyses after the behavioral analyses including open- field test (OFT), elevated plus maze (EPM), Y-maze, and Morris water maze (MWM).

Results

Among the HDACi, MGCD0103 exhibited significant neuroprotection against the Aβ toxicity in primary cultures. MGCD0103 coattenuated cognitive deficits and anxiety against Aβ damage in mice. MGCD0103 further ameliorated pathological features such as the levels of acetylated histone 3 at Lys 9 site (H3K9) and α-tubulin, synaptophysin, Aβ, tau protein phosphorylation, and serotonergic neuron loss against Aβ toxicity. Furthermore, chronic MGCD0103 treatment did not show liver or kidney toxicity in mice.

Conclusions

These results reveal MGCD0103 could be a potential therapeutic agent against AD.

SUBMITTER: Huang HJ

PROVIDER: S-EPMC6488906 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

MGCD0103, a selective histone deacetylase inhibitor, coameliorates oligomeric Aβ<sub>25-35</sub> -induced anxiety and cognitive deficits in a mouse model.

Huang Hei-Jen HJ Huang Hsin-Yu HY Hsieh-Li Hsiu Mei HM

CNS neuroscience & therapeutics 20180705 2

<h4>Aims</h4>Recently, histone deacetylase (HDAC) inhibitors are considered a possible therapeutic strategy in Alzheimer's disease (AD). However, HDACi treatments exhibit diverse functions with unfavorable effects in AD. Thus, the development of selective HDACi without side effects is urgently needed.<h4>Methods</h4>HDACi, namely, BML210, MGCD0103, PXD101, and Droxinostat, were screened in mouse hippocampal primary cultures incubated with oligomeric Aβ<sub>25-35</sub> (50 μmol/L). MGCD0103 was c ...[more]

PMID: 29978554

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Project description:BackgroundAlzheimer's disease (AD) is a common chronic neurodegenerative disease in older people, and there is no specific treatment that can stop or reverse its progression. Neobavaisoflavone (NBIF) is a flavonoid that has been shown to have neuroprotective effects, but its role in AD has not been revealed. The present study investigated the role and mechanism of NBIF on Aβ25-35-induced brain injury.MethodsIn this experiment, the AD mouse model was established by injection of Aβ25-35 peptides (200 μM, icv), and Donepezil (Don, 10 mg/kg/days), NBIF-L (15 mg/kg/days), and NBIF-H (30 mg/kg/days) were administered orally for 4 weeks. Learning memory, hippocampal pathological changes, pathological markers, apoptosis, oxidative stress, inflammation, immune cells were measured in mice. Network pharmacology combined with the GEO database led to the identification of SIRT1, a key target for NBIF intervention in AD, and levels of SIRT1, p-STAT3 and FOXO1 were measured. In addition, the antagonistic activity of SIRT1 transfection silencing against NBIF in Aβ25-35-induced in N9 cells and N2a-APP69 cells was investigated to assess whether the effects caused by NBIF were mediated by SIRT1.ResultsThe results showed that NBIF ameliorated learning memory and hippocampal neuronal damage, reduced pathological markers, apoptosis, oxidative stress and neuroinflammation, and modulated immune cells. SIRT1 is a key target for NBIF intervention in AD, and NBIF upregulates SIRT1 and reduces the expression levels of p-STAT3 and FOXO1. Furthermore, silencing SIRT1 effectively reduced the protective effect of NBIF on Aβ25-35-induced N9 cells and N2a-APP69 cells, which indicated that the protective effect of NBIF on AD is related to SIRT1.ConclusionsNBIF ameliorated Aβ25-35-induced brain injury by inhibiting apoptosis, oxidative stress, and neuroinflammation, which may be mediated through SIRT1 signaling. These findings provide a rationale for NBIF in the treatment of AD and help facilitate the development of clinical therapeutic agents for AD.

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Dataset Information

MGCD0103, a selective histone deacetylase inhibitor, coameliorates oligomeric Aβ_25-35 -induced anxiety and cognitive deficits in a mouse model.

Aims

Methods

Results

Conclusions

Publications

MGCD0103, a selective histone deacetylase inhibitor, coameliorates oligomeric Aβ<sub>25-35</sub> -induced anxiety and cognitive deficits in a mouse model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

MGCD0103, a selective histone deacetylase inhibitor, coameliorates oligomeric Aβ25-35 -induced anxiety and cognitive deficits in a mouse model.

Aims

Methods

Results

Conclusions

Publications

MGCD0103, a selective histone deacetylase inhibitor, coameliorates oligomeric Aβ<sub>25-35</sub> -induced anxiety and cognitive deficits in a mouse model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

MGCD0103, a selective histone deacetylase inhibitor, coameliorates oligomeric Aβ_25-35 -induced anxiety and cognitive deficits in a mouse model.