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Cited by 68Spinal Cord Injury ResearchHistone Deacetylase Inhibitors ResearchNerve injury and regeneration

Class I histone deacetylase (HDAC) inhibitor CI-994 promotes functional recovery following spinal cord injury

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Zhang, Suxiang, Fujita, Yuki, Matsuzaki, Rieko, Yamashita, Toshihide·2018·Cell Death & Disease
DOI 10.1038/s41419-018-0543-8PMC PMC5919919
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Abstract

Spinal cord injury (SCI) induces severe and long-lasting neurological disability. Accumulating evidence has suggested that histone deacetylase (HDAC) inhibitors exert neuroprotective effects against various insults and deficits in the central nervous system. In the present study, we assessed the effect of the class I HDAC inhibitor CI-994 in a mouse model of SCI. Following SCI, mice were treated with either dimethyl sulfoxide (control vehicle) or 1, 10, or 30 mg/kg CI-994. Level of acetylated histone H3 expression was increased in the motor cortex and spinal cord of 10 mg/kg CCI-994-treated mice after SCI. CI-994 increased histone H3 acetylation in the myeloperoxidase-positive neutrophils and CD68-positive microglia/macrophages in the spinal cord. Although it did not appear to contribute to corticospinal tract axonal reorganization, intraperitoneal injection of CI-994 promoted behavioral recovery following SCI. Furthermore, administration of CI-994 suppressed neutrophil accumulation, inflammatory cytokine expressions, and neuronal loss as early as 3 days following injury. Thus, our findings indicate that HDAC inhibitors may improve functional recovery following SCI, especially during the early stages of the disease.

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  • 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 [21]

    The Introduction says previous evidence suggests CI-994 attenuates fear memories, rather than promoting memory formation. The Discussion reports improved motor recovery after spinal cord injury, not improved cognitive function. (LLM, conf=0.76)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • 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 [21]

    The Introduction says CI-994 has been reported to attenuate fear memories, while the Results and Discussion report motor recovery after spinal cord injury—not improved cognitive function. A search for cognition and cognitive enhancement found no passage in our copy establishing that CI-994 is a cognitive enhancer. (LLM, conf=0.76)

    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 [21]

    The Introduction says CI-994 attenuates fear memories, while the Results examine neuronal loss and motor recovery after spinal cord injury. A search for memory enhancement and cognitive deficits in neurodegenerative mouse models found no passage addressing that claim. Attenuating fear memories does not, by itself, establish or contradict cognitive enhancement. (LLM, conf=0.76)

    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 [21]

    The Results section reports improved motor recovery after spinal cord injury, not alleviation of cognitive deficits in models of neurodegenerative disorders. The Introduction mentions CI-994 and fear memories, while the Discussion refers to HDAC inhibition and age-associated memory impairment generally; neither states the attributed claim. Searches for cognitive deficits and memory enhancement found no supporting passage in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Cites

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Cited by

Sorted by citations

Authors
Zhang, S., Fujita, Y., Matsuzaki, R., & Yamashita, T.
Affiliations
  • The University of Osaka (JP)
  • Immunology Frontier Research Center, The University of Osaka (JP)
Corresponding author
  • Fujita, Yuki
  • Yamashita, Toshihide
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2018-04-27
Volume
9
Issue
5
Pages
460-460
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-018-0543-8
PMC
PMC5919919
OpenAlex
W2802371149
Cited by
68
References
5
Citations by year
2026: 9 · 2025: 9 · 2024: 8 · 2023: 9 · 2022: 7 · 2021: 8 · 2020: 10 · 2019: 6 · 2018: 2
FWCI
4.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Ministry of Education, India
  • Japan Society for the Promotion of Science (17H05767, 17H06178)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
Keywords
spinal cord injury, histone deacetylase inhibitors, CI-994, histone H3 acetylation, functional recovery, neuroinflammation, neutrophil accumulation, microglia/macrophages, neuronal loss, inflammatory cytokines, neuroprotection
MeSH terms
Acetylation, Animals, Benzamides, Disease Models, Animal, Histones, Macrophages, Motor Cortex, Neutrophils, Phenylenediamines, Spinal Cord, Spinal Cord Injuries, Microglia, Mice, Histone Deacetylase Inhibitors

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