ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2014
Antidepressant-like properties of novel HDAC6-selective inhibitors with improved brain bioavailability.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 94 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
94 citing papers in PubMed, 1 synthesis or guideline pooled it, 168 citations in OpenAlex.
- Unfolding the pathogenesis of scleroderma through genomics and epigenomics.Journal of autoimmunity · 2017Pooled it
- Epigenetic Control of Stress-Induced Depression: Emerging Roles of HDAC3 and HDAC6.International journal of molecular sciences · 2026Review
- Pharmacological Inhibition of HDAC6 Transiently Reduces Voluntary Ethanol Consumption in Male Mice.Alcohol, clinical & experimental research · 2026Article
- HDAC6 Inhibition Reduces Seeded Tau and α-Synuclein Pathologies in Primary Neuron Cultures and Wild-Type Mice.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Discovery of Pyrazole-Based Positron Emission Tomography Agent that Maps Histone Deacetylase 6 (HDAC6) in the Nonhuman Primate Brain.Journal of medicinal chemistry · 2025Article
- PET imaging evidence of HDAC6 suppression in the amygdala across species in PTSD.Molecular psychiatry · 2025Article
- HDAC6-dependent deacetylation of SAE2 enhances SUMO1 conjugation for mitotic integrity.The EMBO journal · 2025Article
- Single-Nucleus RNA Sequencing of HDAC6 Inhibition in Resolving Doxorubicin-Induced Cognitive Impairment.Molecular neurobiology · 2025Article
- Butyric acid and valeric acid attenuate stress-induced ferroptosis and depressive-like behaviors by suppressing hippocampal neuroinflammation.Journal of translational medicine · 2025Article
- The Gut Microbiota Metabolite Butyrate Modulates Acute Stress-Induced Ferroptosis in the Prefrontal Cortex via the Gut-Brain Axis.International journal of molecular sciences · 2025Article
- Rapid and sustained antidepressant effects of tubastatin A in a mouse model of depression.Scientific reports · 2025Article
- The central role of microglia in major depressive disorder and its potential as a therapeutic target.Frontiers in behavioral neuroscience · 2025Review
- Immunoproteasome Activation Expands the MHC Class I Immunopeptidome, Unmasks Neoantigens, and Enhances T-cell Anti-Myeloma Activity.Molecular cancer therapeutics · 2024Article
- Epigenetic Explorations of Neurological Disorders, the Identification Methods, and Therapeutic Avenues.International journal of molecular sciences · 2024Review
- Article
- Preclinical validation of a novel brain-penetrant PET ligand for visualization of histone deacetylase 6: a potential imaging target for neurodegenerative diseases.European journal of nuclear medicine and molecular imaging · 2024Article
- Histone deacetylase as emerging pharmacological therapeutic target for neuropathic pain: From epigenetic to selective drugs.CNS neuroscience & therapeutics · 2024Review
- Effects of entinostat, quisinostat, and tubastatin-A on alcohol consumption in male high ethanol consuming rats.Frontiers in epigenetics and epigenomics · 2024Article
- Current understanding of the molecular mechanisms of chemotherapy-induced peripheral neuropathy.Frontiers in molecular neuroscience · 2024Review
- Exploring new histone deacetylase 6 inhibitors and their effects on reversing the α-tubulin deacetylation and cell morphology changes caused by methamphetamine.Archives of pharmacal research · 2023Article
34 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
HDAC inhibitors have been reported to produce antidepressant and pro-cognitive effects in animal models, however, poor brain bioavailability or lack of isoform selectivity of current probes has limited our understanding of their mode of action. We report the characterization of novel pyrimidine hydroxyl amide small molecule inhibitors of HDAC6, brain bioavailable upon systemic administration. We show that two compounds in this family, ACY-738 and ACY-775, inhibit HDAC6 with low nanomolar potency and a selectivity of 60- to 1500-fold over class I HDACs. In contrast to tubastatin A, a reference HDAC6 inhibitor with similar potency and peripheral activity, but more limited brain bioavailability, ACY-738 and ACY-775 induce dramatic increases in α-tubulin acetylation in brain and stimulate mouse exploratory behaviors in novel, but not familiar environments. Interestingly, despite a lack of detectable effect on histone acetylation, we show that ACY-738 and ACY-775 share the antidepressant-like properties of other HDAC inhibitors, such as SAHA and MS-275, in the tail suspension test and social defeat paradigm. These effects of ACY-738 and ACY-775 are directly attributable to the inhibition of HDAC6 expressed centrally, as they are fully abrogated in mice with a neural-specific loss of function of HDAC6. Furthermore, administered in combination, a behaviorally inactive dose of ACY-738 markedly potentiates the anti-immobility activity of a subactive dose of the selective serotonin reuptake inhibitor citalopram. Our results validate new isoform-selective probes for in vivo pharmacological studies of HDAC6 in the CNS and reinforce the viability of this HDAC isoform as a potential target for antidepressant development.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.