HDAC Inhibitors Induce BDNF Expression and Promote Neurite Outgrowth in Human Neural Progenitor Cells-Derived Neurons.

Amir Bagheri,Claude-Henry Volmar,Seyed Javad Mowla,Claes Wahlestedt,Nancy T Chee,Seyedeh Fatemeh Razavipour,Mohammad Ali Faghihi,Shaun P Brothers,Parham Habibzadeh

doi:10.3390/ijms20051109

Amir Bagheri, Claude-Henry Volmar + Show 7 more

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https://doi.org/10.3390/ijms20051109

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Besides its key role in neural development, brain-derived neurotrophic factor (BDNF) is important for long-term potentiation and neurogenesis, which makes it a critical factor in learning and memory. Due to the important role of BDNF in synaptic function and plasticity, an in-house epigenetic library was screened against human neural progenitor cells (HNPCs) and WS1 human skin fibroblast cells using Cell-to-Ct assay kit to identify the small compounds capable of modulating the BDNF expression. In addition to two well-known hydroxamic acid-based histone deacetylase inhibitors (hb-HDACis), SAHA and TSA, several structurally similar HDAC inhibitors including SB-939, PCI-24781 and JNJ-26481585 with even higher impact on BDNF expression, were discovered in this study. Furthermore, by using well-developed immunohistochemistry assays, the selected compounds were also proved to have neurogenic potential improving the neurite outgrowth in HNPCs-derived neurons. In conclusion, we proved the neurogenic potential of several hb-HDACis, alongside their ability to enhance BDNF expression, which by modulating the neurogenesis and/or compensating for neuronal loss, could be propitious for treatment of neurological disorders.

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Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) are the major neurodegenerative diseases imposing a considerable burden on health care systems worldwide
human neural progenitor cells (HNPCs) and WS1 human skin fibroblast cells were treated in 384-well plates and screened against an in-house epigenetic library with more than 160 compounds at 1 μM concentration (Figure 1)
We subsequently investigated whether the test compounds would be effective on neurite outgrowth in HNPCs-derived neurons (Figure 5)

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Introduction

Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) are the major neurodegenerative diseases imposing a considerable burden on health care systems worldwide. Reduction in histone acetylation is considered to be a common cause of various brain pathologies such as neurodegenerative and neurodevelopmental cognitive disorders [2]. In the wake of studies showing the key role of histone acetylation in memory formation, researchers have investigated the HDACis potential to improve memory formation in diseases characterized by memory loss and cognitive impairments such as AD. HDACis may be beneficial in the treatment of various brain disorders through three potential mechanisms: (1) anti-inflammatory effect via down-regulation of pro-inflammatory factors such as Fas-L and IL-6; (2) anti-neurotoxic effects through down-regulation of neurotoxic proteins such as α-synuclein and β-amyloid; and (3) neuroprotective effect via up-regulation of neuroprotective proteins such as brain-derived neurotrophic factor (BDNF) and the glial cell-derived neurotrophic factor (GDNF) [3,4,5]

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