ArticlePloS one2013
SAHA enhances synaptic function and plasticity in vitro but has limited brain availability in vivo and does not impact cognition.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 117 citations in OpenAlex.
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- Targeting the HDAC4-NHE6-endosomal pH axis restores amyloid-β clearance and cognitive function in Alzheimer's disease mice.Journal of nanobiotechnology · 2026Article
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- Histone deacetylase inhibitors sensitize glioblastoma models to temozolomide and reprogram immunosuppressive myeloid cells.Scientific reports · 2025Article
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- Histone Deacetylation in Alzheimer's Diseases (AD); Hope or Hype.Cell biochemistry and biophysics · 2025Review
- Tip60 HAT activators as therapeutic modulators for Alzheimer's disease.Nature communications · 2025Article
- Generation and validation of a novel multitarget small molecule in glioblastoma.Cell death & disease · 2025Article
- Repurposing Linezolid in Conjunction with Histone Deacetylase Inhibitor Access in the Realm of Glioblastoma Therapies.Journal of medicinal chemistry · 2025Article
- Central nervous system distributional kinetics of selected histone deacetylase inhibitors.The Journal of pharmacology and experimental therapeutics · 2025Article
- Review
- Deciphering the Mysterious Relationship between the Cross-Pathogenetic Mechanisms of Neurodegenerative and Oncological Diseases.International journal of molecular sciences · 2023Review
- Low-Dose Chidamide Treatment Displays Sex-Specific Differences in the 3xTg-AD Mouse.Biomolecules · 2023Article
- Identification of HDAC4 as a potential therapeutic target and prognostic biomarker for ZFTA-fused ependymomas.Cancer gene therapy · 2023Article
- Histone Modifications in Alzheimer's Disease.Genes · 2023Review
- Final Report on Clinical Outcomes and Tumor Recurrence Patterns of a Pilot Study Assessing Efficacy of Belinostat (PXD-101) with Chemoradiation for Newly Diagnosed Glioblastoma.Tomography (Ann Arbor, Mich.) · 2022Article
- Development of a Novel, Small-Molecule Brain-Penetrant Histone Deacetylase Inhibitor That Enhances Spatial Memory Formation in Mice.Journal of medicinal chemistry · 2022Article
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Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Suberoylanilide hydroxamic acid (SAHA) is an inhibitor of histone deacetylases (HDACs) used for the treatment of cutaneous T cell lymphoma (CTCL) and under consideration for other indications. In vivo studies suggest reducing HDAC function can enhance synaptic function and memory, raising the possibility that SAHA treatment could have neurological benefits. We first examined the impacts of SAHA on synaptic function in vitro using rat organotypic hippocampal brain slices. Following several days of SAHA treatment, basal excitatory but not inhibitory synaptic function was enhanced. Presynaptic release probability and intrinsic neuronal excitability were unaffected suggesting SAHA treatment selectively enhanced postsynaptic excitatory function. In addition, long-term potentiation (LTP) of excitatory synapses was augmented, while long-term depression (LTD) was impaired in SAHA treated slices. Despite the in vitro synaptic enhancements, in vivo SAHA treatment did not rescue memory deficits in the Tg2576 mouse model of Alzheimer's disease (AD). Along with the lack of behavioral impact, pharmacokinetic analysis indicated poor brain availability of SAHA. Broader assessment of in vivo SAHA treatment using high-content phenotypic characterization of C57Bl6 mice failed to demonstrate significant behavioral effects of up to 150 mg/kg SAHA following either acute or chronic injections. Potentially explaining the low brain exposure and lack of behavioral impacts, SAHA was found to be a substrate of the blood brain barrier (BBB) efflux transporters Pgp and Bcrp1. Thus while our in vitro data show that HDAC inhibition can enhance excitatory synaptic strength and potentiation, our in vivo data suggests limited brain availability may contribute to the lack of behavioral impact of SAHA following peripheral delivery. These results do not predict CNS effects of SAHA during clinical use and also emphasize the importance of analyzing brain drug levels when interpreting preclinical behavioral pharmacology.
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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.