Entinostat improves motor function and neuronal damage Via downregulating NLRP3 inflammasome activation after spinal cord injury
Open accessAbstract
Background: Spinal cord injury (SCI), a major public health problem, has no effective treatment. A large number of studies have confirmed that histone deacetylases (HDACs) are involved in the physiologic processes that occur following SCI. We tried to uncover the potential neuroprotective role of entinostat (a class I HDAC inhibitor) in SCI. Methods: We conducted a study on a preclinical mouse model of SCI and OGD-induced neuronal damage to present the role of entinostat by the analysis of motor function, histopathologic damage, local NLRP3 inflammasome activation, and neuronal damage. Results: The results showed that entinostat suppressed HDAC activation (including HDAC1 and HDAC3 expression), improved the grip strength and BMS score, spinal edema, cell death, and local NLRP3 inflammasome activation in the spinal cord following SCI. Furthermore, entinostat significantly increased OGD-inhibited neuronal activity and decreased PI-positive cells, HDAC activation, caspase-1 activation, IL-1β and IL-18 levels, and NLRP3 expression. Conclusion: In summary, we first documented that entinostat improved the motor function, histopathologic damage, and local inflammatory response and NLRP3 inflammasome activation in the spinal cord following SCI and also presented the neuroprotective role of OGD-induced neuronal damage via the NLRP3 inflammasome. Thus, our study has the potential to reveal the interaction between the HDAC and NLRP3 inflammasome in the pathologic process as well as SCI and further promote the clinical indications of HDACi entinostat and clinical treatment for the inflammatory response after SCI.
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HDAC inhibitors can improve behavioral outcomes through anti-inflammatory and neuroplastic mechanisms.
“The ability of HDAC inhibitors to improve behavioral outcomes through anti-inflammatory and neuroplastic mechanisms (Dai et al., 2021; Kumar et al., 2022)”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Dai et al., 2021
The Results report improved motor function in entinostat-treated mice after spinal cord injury, and the Discussion links that improvement to reduced inflammation and NLRP3 activation (no page numbers supplied). The Discussion also reports prior findings on synaptic recovery and axonal growth, but this study does not establish neuroplasticity as a mechanism for its observed motor improvement. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn chronic social defeat stress models, entinostat produces antidepressant-like effects.
“In chronic social defeat stress models, entinostat produces antidepressant-like effects (Dai et al., 2021; Covington et al., 2015), reinforcing the link between deacetylation-targeted interventions and stress-related phenotypes.”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Dai et al., 2021
Inhibition of specific isoforms such as HDAC8 can improve immune phenotypes without producing behavioral benefits.
“inhibition of specific isoforms such as HDAC8 can improve immune phenotypes without producing behavioral benefits (Dai et al., 2021)”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Dai et al., 2021
Entinostat suppresses NLRP3 inflammasome activation and downstream cytokine release in spinal cord injury models.
“In spinal cord injury models, entinostat suppresses NLRP3 inflammasome activation and downstream cytokine release (Dai et al., 2021).”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Dai et al., 2021
Class I HDAC inhibition (e.g., entinostat) suppresses the NLRP3 inflammasome pathway and reduces inflammatory cytokine production in spinal cord injury models.
“Evidence from spinal cord injury models shows that class I HDAC inhibition (e.g., entinostat) suppresses the NLRP3 inflammasome pathway and reduces inflammatory cytokine production, highlighting the HDAC–inflammasome axis as a pharmacologically relevant target (Dai et al., 2021).”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Dai et al., 2021
SAHA suppresses NF-κB/mTOR signaling and entinostat inhibits NLRP3.
“Evidence from NF-κB/mTOR suppression by SAHA and NLRP3 inhibition by entinostat illustrates the cross-tissue and cross-disease relevance of this mechanism (Dai et al., 2021; Dai et al., 2025).”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Dai et al., 2021
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References 46 · Cited by 19
- Authors
- Dai, C., Liu, B., Peng, B., Qu, B., Lin, J., Peng, B., & Li, D.-M.
- Affiliations
- Chinese People's Liberation Army (CN)
- General Hospital of Shenyang Military Region (CN)
- Chinese PLA General Hospital (CN)
- Tianjin University (CN)
- Corresponding author
- Peng, Baogan
- Venue
- Frontiers in Pharmacology
- Publisher
- Frontiers Media SA
- Published
- 2021-11-26
- Volume
- 12
- Pages
- 774539-774539
- ISSN
- 1663-9812 (ISSN-L)
- PMC
- PMC8664236
- OpenAlex
- W3217781222
- Cited by
- 19
- References
- 46
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 2 · 2023: 4 · 2022: 2 · 2014: 1
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Pharmacology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- entinostat, spinal cord injury, NLRP3 inflammasome, histone deacetylase inhibitors, HDAC1, HDAC3, neuroprotection, motor recovery, neuronal injury, oxygen-glucose deprivation, caspase-1, IL-1β, IL-18, myelitis
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