Histone Deacetylase Inhibitors as Therapeutic Agents for Acute Central Nervous System Injuries

Shein, Na’ama A.; Shohami, Esther

doi:10.2119/molmed.2011.00038

Cited by 72 publications

(40 citation statements)

References 91 publications

(140 reference statements)

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“…More importantly, the balance between transplantderived excitatory and inhibitory neuronal subtypes was delicately achieved, with 16.9 ± 2.3% VGLUT-2-positive (glutamatergic) neurons and 70.1 ± 1.8% GAD-65-positive (GABAergic) neurons [10], which is consistent with the in vitro results of VPA enhancement of the GABAergic neuronal differentiation of NSCs [16]. The underlying mechanism was closely associated with its potent role in HDAC inhibition by enhanced histone acetylation and upregulation of the neurogenic basic helix-loop-helix transcription factor NeuroD [15,61]. Moreover, a novel study demonstrated that VPA treatment further enhanced neuronal survival and maturation into synapse-forming GABAergic interneurons during SOX2-induced adult neurogenesis in the injured spinal cord through HDAC inhibition [14], which is consistent with the finding that VPA stimulates normal neurogenesis, especially GABA neurogenesis, and maturation [16,18].…”

Section: Neuronal Differentiation and Maturationsupporting

confidence: 81%

“…Valproic acid-mediated neuroprotection & neurogenesis after spinal cord injury Review epigenetic modulations, which discounts the vital role that VPA plays as a potent HDAC inhibitor [8,61]. Hence, studies using genomic sequencing, microarrays, and chromatin immunoprecipitation are recommended to investigate the epigenetic regulation of VPA in the rebalancing of SCI-disrupted acetylation homeostasis.…”

Section: Future Science Groupmentioning

confidence: 99%

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Valproic Acid-Mediated Neuroprotection and Neurogenesis After Spinal Cord Injury: From Mechanism to Clinical Potential

Chu

Zhou

et al. 2014

Regen. Med.

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Spinal cord injury (SCI) is difficult to treat because of secondary injury. Valproic acid (VPA) is clinically approved for mood stabilization, but also counteracts secondary damage to functionally rescue SCI in animal models by improving neuroprotection and neurogenesis via inhibition of HDAC and GSK-3. However, a comprehensive review summarizing the therapeutic benefits and mechanisms of VPA for SCI and the issues affecting clinical trials is lacking, limiting future research on VPA and impeding its translation into clinical therapy for SCI. This article presents the current status of VPA treatment for SCI, emphasizing interactions between enhanced neuroprotection and neurogenesis. Crucial issues are discussed to optimize its clinical potential as a safe and effective treatment for SCI.

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Section: Neuronal Differentiation and Maturationsupporting

confidence: 81%

Section: Future Science Groupmentioning

confidence: 99%

Valproic Acid-Mediated Neuroprotection and Neurogenesis After Spinal Cord Injury: From Mechanism to Clinical Potential

Chu

Zhou

et al. 2014

Regen. Med.

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“…Numerous natural and synthetic products, including a broad range of dietary agents (e.g., short‐chain fatty acids sodium butyrate and sodium proprionate, genistein, quercetin, trichostatin A, sulforaphane, resveratrol, caffeine) exhibit HDAC inhibitory activity in vitro and/or in vivo (Myzak et al, ; Seidel et al, ). HDAC inhibition has also been considered a therapeutic approach for a number of neuropathologies, including neurodegenerative disorders (e.g., Alzheimer's disease, Huntington's disease, Parkinson's disease) (Konsoula and Barile, ), cerebral ischemia (Schweizer et al, ), acute central nervous system injury (Shein and Shohami, ; Moffett et al, ), neuropsychiatric disorders (Ariyannur et al, ), muscular dystrophies (Consalvi et al, ), and multiple sclerosis (Faraco et al, ). We acknowledge that GTA provides acetate globally; thus, we cannot target specific cells or proteins.…”

Section: Discussionmentioning

confidence: 99%

Acetate Supplementation as a Means of Inducing Glioblastoma Stem-Like Cell Growth Arrest

et al. 2015

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Glioblastoma (GBM), the most common primary adult malignant brain tumor, is associated with a poor prognosis due, in part, to tumor recurrence mediated by chemotherapy and radiation resistant glioma stem-like cells (GSCs). The metabolic and epigenetic state of GSCs differs from their non-GSC counterparts, with GSCs exhibiting greater glycolytic metabolism and global hypoacetylation. However, little attention has been focused on the potential use of acetate supplementation as a therapeutic approach. N-acetyl-L-aspartate (NAA), the primary storage form of brain acetate, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis, are significantly reduced in GBM tumors. We recently demonstrated that NAA supplementation is not an appropriate therapeutic approach since it increases GSC proliferation and pursued an alternative acetate source. The FDA approved food additive Triacetin (glyceryl triacetate, GTA) has been safely used for acetate supplementation therapy in Canavan disease, a leukodystrophy due to ASPA mutation. This study characterized the effects of GTA on the proliferation and differentiation of six primary GBM-derived GSCs relative to established U87 and U251 GBM cell lines, normal human cerebral cortical astrocytes, and murine neural stem cells. GTA reduced proliferation of GSCs greater than established GBM lines. Moreover, GTA reduced growth of the more aggressive mesenchymal GSCs greater than proneural GSCs. Although sodium acetate induced a dose-dependent reduction of GSC growth, it also reduced cell viability. GTA-mediated growth inhibition was not associated with differentiation, but increased protein acetylation. These data suggest that GTA-mediated acetate supplementation is a novel therapeutic strategy to inhibit GSC growth.

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“…Valproic acid, a compound frequently used as a mood stabilizer and as an anticonvulsant, is a HDAC inhibitor [42]. Further, several other HDAC inhibitors alter the fate of neural cells, and are now intensive research targets as potential therapeutic agents for several neurodegenerative diseases, cognitive disorders, multiple sclerosis and CNS trauma/injuries [39, 43 – 45]. Thus, it is quite interesting to elucidate the exact roles of HDAC subtypes on the functions/differentiation of NSCs.…”

Section: Discussionmentioning

confidence: 99%

Expression Profiles of the Nuclear Receptors and Their Transcriptional Coregulators During Differentiation of Neural Stem Cells

Androutsellis-Theotokis

Chrousos

McKay

et al. 2012

Horm Metab Res

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Neural stem cells (NSCs) are pluripotent precursors with the ability to proliferate and differentiate into 3 neural cell lineages, neurons, astrocytes and oligodendrocytes. Elucidation of the mechanisms underlying these biologic processes is essential for understanding both physiologic and pathologic neural development and regeneration after injury. Nuclear hormone receptors (NRs) and their transcriptional coregulators also play crucial roles in neural development, functions and fate. To identify key NRs and their transcriptional regulators in NSC differentiation, we examined mRNA expression of 49 NRs and many of their coregulators during differentiation (0–5 days) of mouse embryonic NSCs induced by withdrawal of fibroblast growth factor-2 (FGF2). 37 out of 49 NRs were expressed in NSCs before induction of differentiation, while receptors known to play major roles in neural development, such as THRα, RXRs, RORs, TRs, and COUPTFs, were highly expressed. CAR, which plays important roles in xenobiotic metabolism, was also highly expressed. FGF2 withdrawal induced mRNA expression of RORγ, RXRγ, and MR by over 20-fold. Most of the transcriptional coregulators examined were expressed basally and throughout differentiation without major changes, while FGF2 withdrawal strongly induced mRNA expression of several histone deacetylases (HDACs), including HDAC11. Dexamethasone and aldosterone, respectively a synthetic glucocorticoid and natural mineralocorticoid, increased NSC numbers and induced differentiation into neurons and astrocytes. These results indicate that the NRs and their coregulators are present and/or change their expression during NSC differentiation, suggesting that they may influence development of the central nervous system in the absence or presence of their ligands.

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Histone Deacetylase Inhibitors as Therapeutic Agents for Acute Central Nervous System Injuries

Cited by 72 publications

References 91 publications

Valproic Acid-Mediated Neuroprotection and Neurogenesis After Spinal Cord Injury: From Mechanism to Clinical Potential

Valproic Acid-Mediated Neuroprotection and Neurogenesis After Spinal Cord Injury: From Mechanism to Clinical Potential

Acetate Supplementation as a Means of Inducing Glioblastoma Stem-Like Cell Growth Arrest

Expression Profiles of the Nuclear Receptors and Their Transcriptional Coregulators During Differentiation of Neural Stem Cells

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