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Cited by 19Histone Deacetylase Inhibitors ResearchSchizophrenia research and treatmentNeurotransmitter Receptor Influence on Behavior

Dose Effects of Histone Deacetylase Inhibitor Tacedinaline (CI-994) on Antipsychotic Haloperidol-Induced Motor and Memory Side Effects in Aged Mice

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McClarty, Bryan, Rodriguez, Guadalupe, Dong, Hongxin·2021·Frontiers in Neuroscience
DOI 10.3389/fnins.2021.674745PMC PMC8526546
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Abstract

Background: Elderly patients treated with antipsychotic drugs often experience increased severity and frequency of side effects, yet the mechanisms are not well understood. Studies from our group indicate age-related histone modifications at drug targeted receptor gene promoters may contribute to the increased side effects, and histone deacetylase (HDAC) inhibitors entinostat (MS-275) and valproic acid (VPA) could reverse typical antipsychotic haloperidol (HAL) induced motor-side effects. However, whether such effects could be dose dependent and whether HDAC inhibitors could improve memory function in aged mice is unknown. Methods: We co-treated selective class 1 HDAC inhibitor tacedinaline (CI-994) at different doses (10, 20, and 30 mg/kg) with HAL (0.05 mg/kg) in young (3 months) and aged (21 months) mice for 14 consecutive days, then motor and memory behavioral tests were conducted, followed by biochemical measurements. Results: CI-994 at doses of 10 and 20 mg/kg could decrease HAL-induced cataleptic episodes but only 20 mg/kg was sufficient to improve motor coordination in aged mice. Additionally, CI-994 at 10 and 20 mg/kg mitigate HAL-induced memory impairment in aged mice. Biochemical analyses showed increased acetylation of histone marks H3K27ac and H3K18ac at the dopamine 2 receptor (D2R) gene (Drd2) promoter and increased expression of the Drd2 mRNA and D2R protein in the striatum of aged mice after administration of CI-994 at 20 mg/kg. Conclusions: Our results suggest CI-994 can reduce HAL-induced motor and memory side effects in aged mice. These effects may act through an increase of acetylation at the Drd2 promoter, thereby restoring D2R expression and improving antipsychotic drug action.

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  • CI-994 is a cognitive enhancer / improves cognitive function.

    “CI-994 can cross the blood–brain barrier and is a cognitive enhancer.”

    From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [23]

    The Results (Dose Dependent Effects of CI-994 on Haloperidol Induced Memory Impairment; page unavailable) show that CI-994 improved recognition memory in aged mice whose memory was impaired by haloperidol. The same section reports no significant memory difference between CI-994 alone and vehicle, so the unqualified description of CI-994 as a cognitive enhancer overstates this study’s finding. Our copy also does not establish the citing sentence’s blood–brain-barrier claim (searched: blood–brain barrier, cross). (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • CI-994 is a molecular memory aid and promotes memory formation and cognitive function in vivo.

    “CI-994 is a molecular memory aid and promotes memory formation and cognitive function in vivo [9, 17, 21–24].”

    From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [23]

    The Results report that CI-994 improved recognition memory in haloperidol-treated aged mice, supporting an in vivo memory benefit. But the study did not test memory formation or broad cognitive function, and Figure 2 reports no significant memory difference between CI-994 alone and vehicle in aged mice. The claim generalizes beyond the effect this study demonstrated. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • CI-994 acts as a memory enhancer in mouse models of neurodegenerative disorders.

    “CI-994 acts as a memory enhancer and alleviates cognitive deficits in mouse models of neurodegenerative disorders [9, 17, 21–24].”

    From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [23]

    The Discussion reports that previous studies found CI-994 improved memory in aging and Alzheimer’s disease (AD) mice, supporting the claim for an AD mouse model. This paper’s own Results concern haloperidol-induced memory impairment in aged mice, not models of multiple neurodegenerative disorders; the broader wording is not established by our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • CI-994 alleviates cognitive deficits in mouse models of neurodegenerative disorders.

    “CI-994 acts as a memory enhancer and alleviates cognitive deficits in mouse models of neurodegenerative disorders [9, 17, 21–24].”

    From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [23]

    The Discussion reports that prior studies found improved memory in aging and Alzheimer’s disease (AD) mice after CI-994 treatment. This paper’s own Results show reversal of haloperidol-induced memory impairment in aged mice, not deficits in multiple neurodegenerative-disorder models. The broader plural claim is therefore not fully supported by this source. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
McClarty, B., Rodriguez, G., & Dong, H.
Affiliations
Northwestern University (US)
Corresponding author
Dong, Hongxin
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2021-10-06
Volume
15
Pages
674745-674745
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2021.674745
PMC
PMC8526546
OpenAlex
W3203275991
Cited by
19
References
7
Citations by year
2026: 4 · 2025: 3 · 2024: 3 · 2023: 8 · 2022: 1
FWCI
0.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute of Mental Health
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
CI-994, histone deacetylase inhibitors, haloperidol, antipsychotic adverse effects, tardive dyskinesia, catalepsy, memory impairment, aging, dopamine D2 receptor, histone acetylation, H3K27ac, H3K18ac, striatum, aged mice

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