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Cited by 25Treatment of Major DepressionTryptophan and brain disordersHistone Deacetylase Inhibitors Research

SAHA improves depressive symptoms, cognitive impairment and oxidative stress: rise of a new antidepressant class

Ershadi, Amir Sasan Bayani, Amini-Khoei, Hossein, Hosseini, Mir-Jamal, Dehpour, Ahmad Reza·2021·Neurochemical Research
DOI 10.1007/s11064-021-03263-8
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Abstract

Depression is a disabling psychiatric disorder affecting millions of people all around the world. Under current therapeutic choices, a portion of patients are not responsive, have relapses, or experience cognitive side effects. Hence, the present study aimed to find other antidepressant compounds lacking the mentioned deficiency. Since epigenetic regulations have attracted more attention in etiology of depression, histone deacetylase (HDAC) inhibitors have gained more importance due to their possible antidepressant activity. We selected a promising member of HDAC inhibitors named suberanilohydroxamic acid (SAHA) to evaluate its antidepressant properties. Early life stress disarrays many neurodevelopmental factors and consequently, leads to the destruction of hippocampus and prefrontal cortex synapses as areas highly related to emotion and memory so that any destruction on them can cause lasting impairments. For that reason, we used maternal separation (MS) paradigm to investigate depression in male mice. To compare the efficacy of SAHA with current treatment options, we also treated a group of MS mice with fluoxetine (FLX) as first-line pharmacological drugs of depression. The results demonstrated that depressive-like behavior, cognitive function and inflammatory response of MS mice were attenuated with SAHA. Our data showed that, besides anti-depressant and cognition-boosting effects similar to FLX, SAHA counteracted inflammatory response caused by depression and reversed the coenzyme Q 10 (CoQ 10) level in hippocampus. SAHA's effect on alleviating depressive behavior was accompanied with memory enhancement and hippocampus biochemical tests. These findings may propose SAHA as another therapeutic option for depressive symptoms, especially with comorbid cognitive impairment.

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  • HDACs and HMTs regulate stress susceptibility, neural plasticity, cognitive function, and comorbid somatic conditions.

    “Preclinical studies consistently show that HDACs and HMTs regulate stress susceptibility, neural plasticity, cognitive function, and comorbid somatic conditions (Li et al., 2024; Nasehi et al., 2022; Ershadi et al., 2021).”

    From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Ershadi et al., 2021

  • The broad-spectrum HDAC inhibitor SAHA exhibits antidepressant effects across multiple animal models, with benefits that extend beyond mood improvement.

    “The broad-spectrum HDAC inhibitor SAHA exhibits antidepressant effects across multiple animal models, with benefits that extend beyond mood improvement (Nasehi et al., 2022; Ershadi et al., 2021; Chen et al., 2019; Meylan et al., 2016).”

    From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Ershadi et al., 2021

  • HDAC5-mediated H4K12 deacetylation in the hippocampus contributes to stress vulnerability.

    “HDAC5-mediated H4K12 deacetylation in the hippocampus contributes to stress vulnerability, indicating its value as a potential therapeutic target in susceptible populations (Dai et al., 2023; Li et al., 2024; Ershadi et al., 2021).”

    From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Ershadi et al., 2021

  • Widely used animal models, which predominantly rely on acute or chronic stress paradigms, incompletely capture the clinical heterogeneity, chronicity, and multidimensional symptom profiles characteristic of human depression.

    “Widely used animal models, which predominantly rely on acute or chronic stress paradigms, have been instrumental in identifying histone modification abnormalities and probing the effects of epigenetic modulators. However, these models incompletely capture the clinical heterogeneity, chronicity, and multidimensional symptom profiles characteristic of human depression (Li et al., 2024; Ershadi et al”

    From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Ershadi et al., 2021

  • HDAC inhibitors such as sodium butyrate and SAHA may provide therapeutic options for depressed patients with cognitive impairment.

    “HDACis, such as sodium butyrate and SAHA, promote cognitive function, and may provide therapeutic options for depressed patients with cognitive impairment.405–407”

    From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [406]

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Authors
Ershadi, A. S. B., Amini-Khoei, H., Hosseini, M.-J., & Dehpour, A. R.
Affiliations
  • Zanjan University of Medical Sciences (IR)
  • Tehran University of Medical Sciences (IR)
Corresponding author
  • Hosseini, Mir-Jamal
  • Dehpour, Ahmad Reza
ORCID
Venue
Neurochemical Research
Publisher
Springer Science and Business Media LLC
Published
2021-02-12
Volume
46
Issue
5
Pages
1252-1263
ISSN
  • 0364-3190 (ISSN-L)
  • 1573-6903
DOI
10.1007/s11064-021-03263-8
OpenAlex
W3128137353
Cited by
25
References
90
Citations by year
2026: 4 · 2025: 4 · 2024: 3 · 2023: 5 · 2022: 5 · 2021: 4
FWCI
2.49
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Neurochemical Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Zanjan University of Medical Sciences (A-12-769-18)
  • Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences (42068-158-01-98)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
Keywords
vorinostat, histone deacetylase inhibitors, antidepressant effects, maternal separation, early life stress, depression-like behavior, cognitive impairment, oxidative stress, coenzyme Q10, hippocampus, neuroinflammation, fluoxetine comparison, memory enhancement
MeSH terms
Vorinostat, Animals, Antidepressive Agents, Behavior, Animal, Depression, Female, Fluoxetine, Hippocampus, Locomotion, Male, Maternal Deprivation, Pregnancy, Ubiquinone, Oxidative Stress, Mice, Histone Deacetylase Inhibitors, Cognitive Dysfunction

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