Histone Deacetylase (HDAC) Inhibitors - emerging roles in neuronal memory, learning, synaptic plasticity and neural regeneration

Ganai, Shabir Ahmad; Ramadoss, Mahalakshmi; Vijayalakshmi, M.

doi:10.2174/1570159x13666151021111609

Cited by 115 publications

(51 citation statements)

References 141 publications

(132 reference statements)

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“…It is also reported that inhibition of HDAC3 could induce cell autophagy in human glioma cells [ 29 ], and apoptosis in cholangiocarcinoma [ 30 ]. Besides their utilization as targets in cancer therapy, class I HDACs have gained considerable attention as targets in the search for treatments for degenerative neurological diseases, such as Alzheimer’s and Huntington’s disease [ 20 , 31 , 32 , 33 , 34 ], chronic inflammatory diseases, like asthma and COPD [ 35 , 36 , 37 , 38 ], viral infections [ 39 ], especially for human immunodeficiency virus (HIV) [ 40 , 41 , 42 ], and diabetes [ 22 , 43 , 44 , 45 ]. HDAC3, in particular, is an interesting target in Alzheimer’s disease [ 31 , 46 ], since it is reported that HDAC3 plays an important role in maintaining long-term memory for object location [ 47 ].…”

Section: Resultsmentioning

confidence: 99%

The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors

Cao

Zwinderman

2018

Molecules

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Histone deacetylases (HDACs) are epigenetic drug targets that have gained major scientific attention. Inhibition of these important regulatory enzymes is used to treat cancer, and has the potential to treat a host of other diseases. However, currently marketed HDAC inhibitors lack selectivity for the various HDAC isoenzymes. Several studies have shown that HDAC3, in particular, plays an important role in inflammation and degenerative neurological diseases, but the development of selective HDAC3 inhibitors has been challenging. This review provides an up-to-date overview of selective HDAC3 inhibitors, and aims to support the development of novel HDAC3 inhibitors in the future.

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Section: Resultsmentioning

confidence: 99%

The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors

Cao

Zwinderman

2018

Molecules

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“…HDACs are critical regulator of gene expression and HDAC inhibitors are clinically approved drugs for cancer treatment [ 131 ]. More recently, HDAC inhibitors are also explored for other conditions including neurological disorders and neurodegenerative diseases [ 132 ]. There is increasing evidence that VPA has neuroprotective properties and recent studies have shown some promising results in several animal models of neurodegenerative diseases including glaucoma, Alzheimer’s disease and Parkinson’s disease [ 91 , 133 , 134 , 135 ].…”

Section: Valproic Acid Upregulates Glial Bdnf and Ngf Leading To mentioning

confidence: 99%

Neuroprotection, Growth Factors and BDNF-TrkB Signalling in Retinal Degeneration

Kimura

Namekata

Guo

et al. 2016

IJMS

158

121

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Neurotrophic factors play key roles in the development and survival of neurons. The potent neuroprotective effects of neurotrophic factors, including brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell-line derived neurotrophic factor (GDNF) and nerve growth factor (NGF), suggest that they are good therapeutic candidates for neurodegenerative diseases. Glaucoma is a neurodegenerative disease of the eye that causes irreversible blindness. It is characterized by damage to the optic nerve, usually due to high intraocular pressure (IOP), and progressive degeneration of retinal neurons called retinal ganglion cells (RGCs). Current therapy for glaucoma focuses on reduction of IOP, but neuroprotection may also be beneficial. BDNF is a powerful neuroprotective agent especially for RGCs. Exogenous application of BDNF to the retina and increased BDNF expression in retinal neurons using viral vector systems are both effective in protecting RGCs from damage. Furthermore, induction of BDNF expression by agents such as valproic acid has also been beneficial in promoting RGC survival. In this review, we discuss the therapeutic potential of neurotrophic factors in retinal diseases and focus on the differential roles of glial and neuronal TrkB in neuroprotection. We also discuss the role of neurotrophic factors in neuroregeneration.

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“…The cellular imbalance between HAT and HDAC activity alters acetylation homeostasis causing transcriptional dysregulation which in turn provides impetus to neurodegenerative signaling (Saha and Pahan, 2006 ). Aberrant expression of HDACs has been implicated in neurologic pathologies (Ganai et al, 2016 ). For instance, HDAC6 overexpression has been reported to inhibit nerve growth by deacetylating tubulin protein (Rivieccio et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

Combinatorial In Silico Strategy towards Identifying Potential Hotspots during Inhibition of Structurally Identical HDAC1 and HDAC2 Enzymes for Effective Chemotherapy against Neurological Disorders

Ganai

Abdullah

Rashid

et al. 2017

Front. Mol. Neurosci.

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Histone deacetylases (HDACs) regulate epigenetic gene expression programs by modulating chromatin architecture and are required for neuronal development. Dysregulation of HDACs and aberrant chromatin acetylation homeostasis have been implicated in various diseases ranging from cancer to neurodegenerative disorders. Histone deacetylase inhibitors (HDACi), the small molecules interfering HDACs have shown enhanced acetylation of the genome and are gaining great attention as potent drugs for treating cancer and neurodegeneration. HDAC2 overexpression has implications in decreasing dendrite spine density, synaptic plasticity and in triggering neurodegenerative signaling. Pharmacological intervention against HDAC2 though promising also targets neuroprotective HDAC1 due to high sequence identity (94%) with former in catalytic domain, culminating in debilitating off-target effects and creating hindrance in the defined intervention. This emphasizes the need of designing HDAC2-selective inhibitors to overcome these vicious effects and for escalating the therapeutic efficacy. Here we report a top-down combinatorial in silico approach for identifying the structural variants that are substantial for interactions against HDAC1 and HDAC2 enzymes. We used extra-precision (XP)-molecular docking, Molecular Mechanics Generalized Born Surface Area (MMGBSA) for predicting affinity of inhibitors against the HDAC1 and HDAC2 enzymes. Importantly, we employed a novel in silico strategy of coupling the state-of-the-art molecular dynamics simulation (MDS) to energetically-optimized structure based pharmacophores (e-Pharmacophores) method via MDS trajectory clustering for hypothesizing the e-Pharmacophore models. Further, we performed e-Pharmacophores based virtual screening against phase database containing millions of compounds. We validated the data by performing the molecular docking and MM-GBSA studies for the selected hits among the retrieved ones. Our studies attributed inhibitor potency to the ability of forming multiple interactions and infirm potency to least interactions. Moreover, our studies delineated that a single HDAC inhibitor portrays differential features against HDAC1 and HDAC2 enzymes. The high affinity and selective HDAC2 inhibitors retrieved through e-Pharmacophores based virtual screening will play a critical role in ameliorating neurodegenerative signaling without hampering the neuroprotective isoform (HDAC1).

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Histone Deacetylase (HDAC) Inhibitors - emerging roles in neuronal memory, learning, synaptic plasticity and neural regeneration

Cited by 115 publications

References 141 publications

The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors

The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors

Neuroprotection, Growth Factors and BDNF-TrkB Signalling in Retinal Degeneration

Combinatorial In Silico Strategy towards Identifying Potential Hotspots during Inhibition of Structurally Identical HDAC1 and HDAC2 Enzymes for Effective Chemotherapy against Neurological Disorders

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