Inhibition of HDAC3 induces neuroprotection by activating the Npas4 signaling pathway following surgical brain injury in rats

Articles in Press

Document Type : Original Article

Authors

1 Department of Neurology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China

2 Department of Rehabilitation, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China

3 Department of Anesthesiology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China

4 Department of Emergency, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China

5 Department of Orthopaedics, The Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China

10.22038/ijbms.2025.80235.17372

Abstract

Objective(s): Histone deacetylase 3 (HDAC3) can acetylate histones, negatively regulating Neuronal Per-Arnt-Sim domain protein 4 (Npas4) and participating in various pathological processes of central nervous system lesions. However, the role of HDAC3 in early surgical brain injury (SBI) remains elusive. This study aimed to determine the role of HDAC3 in early rat SBI and its underlying mechanism.
Materials and Methods: The SBI model was constructed using the right frontal lobotomy of adult male Sprague-Dawley rats. The effects of RGFP966, a specific HDAC3 inhibitor, were assessed by western blotting, immunofluorescence, neurological scoring, and fluoro-Jade C staining.
Results: HDAC3 protein expression was up-regulated after SBI and peaked at 24 hr relative to the Sham group. RGFP966 application can significantly improve brain edema and neurological dysfunction 24 hr after SBI, enhance autophagy, and reduce inflammation. In addition, we observed that Npas4 expression increased in SBI rats and was further up-regulated after HDAC3 inhibition.
Conclusion: HDAC3 plays a role in rats’ complex pathogenesis of SBI. HDAC3 inhibition imparts a protective role in early brain injury in SBI in rats by regulating autophagy and inflammation via up-regulation of Npas4.

Keywords

Main Subjects

References

1. Eser Ocak P, Ocak U, Sherchan P, Gamdzyk M, Tang J, Zhang JH. Overexpression of Mfsd2a attenuates blood brain barrier dysfunction via Cav-1/Keap-1/Nrf-2/HO-1 pathway in a rat model of surgical brain injury. Exp Neurol 2020; 326: 113203-113236.
2. Wu. M-Y, Gao F, Tang J-F, Shen J-C, Gao R, Dang B-Q, et al. Possible mechanisms of the PERK pathway on neuronal apoptosis in a rat model of surgical brain injury. Am J Transl Res 2021; 13: 732-742.
3. Shi M, Gong Y, Wu M, Gu H, Yu J, Gao F, et al. Downregulation of TREM2/NF-кB signaling may damage the blood-brain barrier and aggravate neuronal apoptosis in experimental rats with surgically injured brain. Brain Res Bull 2022; 183: 116-126.
4. Di Q, Zhao X, Tang H, Li X, Xiao Y, Wu H, et al. USP22 suppresses the NLRP3 inflammasome by degrading NLRP3 via ATG5-dependent autophagy. Autophagy 2023; 19: 873-885.
5. Liu H, Zhen C, Xie J, Luo Z, Zeng L, Zhao G, et al. TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA. Nat Cell Biol 2024; 26: 878-891.
6. Hegdekar N, Sarkar C, Bustos S, Ritzel RM, Hanscom M, Ravishankar P, et al. Inhibition of autophagy in microglia and macrophages exacerbates innate immune responses and worsens brain injury outcomes. Autophagy 2023; 19: 2026-2044.
7. Chen X, Wang H, Zhou M, Li X, Fang Z, Gao H, et al. Valproic acid attenuates traumatic brain injury-induced inflammation in vivo: Involvement of autophagy and the Nrf2/ARE signaling pathway. Front Mol Neurosci 2018; 11: 117-131.
8. Jeong S, Chokkalla AK, Davis CK, Vemuganti R. Post-stroke depression: Epigenetic and epitranscriptomic modifications and their interplay with gut microbiota. Mol Psychiatry 2023; 28: 4044-4055.
9. Armstrong MJ, Jin Y, Vattathil SM, Huang Y, Schroeder JP, Bennet DA, et al. Role of TET1-mediated epigenetic modulation in Alzheimer’s disease. Neurobiol Dis 2023; 185: 106257-106288.
10. Wang J, Feng S, Zhang Q, Qin H, Xu C, Fu X, et al. Roles of histone acetyltransferases and deacetylases in the retinal development and diseases. Mol Neurobiol 2023; 60: 2330-2354.
11. Yu N, Chen P, Wang Q, Liang M, Qiu J, Zhou P, et al. Histone deacetylase inhibitors differentially regulate c-Myc expression in retinoblastoma cells. Oncol Lett 2020; 19: 460-468.
12. Zhang SY, Zhang LY, Wen R, Yang N, Zhang TN. Histone deacetylases and their inhibitors in inflammatory diseases. Biomed Pharmacother 2024; 179: 117295-117313.
13. Wang C, Shen D, Hu Y, Chen J, Liu J, Huang Y, et al. Selective targeting of class I HDAC reduces microglial inflammation in the entorhinal cortex of young APP/PS1 mice. Int J Mol Sci 2023; 24: 4805-4820.
14. Broide RS, Redwine JM, Aftahi N, Young W, Bloom FE, Winrow CJ. Distribution of histone deacetylases 1-11 in the rat brain. J Mol Neurosci 2007; 31: 47-58.
15. Davis N, Taylor B, Abelleira-Hervas L, Karimian-Marnani N, Aleksynas R, Syed N, et al. Histone deacetylase-3 regulates the expression of the amyloid precursor protein and its inhibition promotes neuroregenerative pathways in Alzheimer’s disease models. FASEB J 2024; 38: e23659.
16. Lu J, Huang X, Deng A, Yao H, Wu G, Wang N, et al. miR-452-3p targets HDAC3 to inhibit p65 deacetylation and activate the NF-kappaB signaling pathway in early brain injury after subarachnoid hemorrhage. Neurocrit Care 2022; 37: 558-571.
17. Zhang Y, Li J, Zhao Y, Huang Y, Shi Z, Wang H, et al. Arresting the bad seed: HDAC3 regulates proliferation of different microglia after ischemic stroke. Sci Adv 2024; 10: eade6900-6921.
18. Zhai X, Wang Z, Gao J. Quercetin alleviates microglial-induced inflammation after traumatic brain injury via the PGC-1alpha/Nrf2 pathway dependent on HDAC3 inhibition. Brain Res Bull 2024; 217: 111080-111091.
19. Chen LF, Lin YT, Gallegos DA, Hazlett MF, Gómez-Schiavon M, Yang MG, et al. Enhancer histone acetylation modulates transcriptional bursting dynamics of neuronal activity-inducible genes. Cell Rep 2019; 26: 1174-1188.
20. Louis Sam Titus ASC, Sharma D, Kim MS, D’Mello SR. The Bdnf and Npas4 genes are targets of HDAC3-mediated transcriptional repression. BMC Neurosci 2019; 20: 65-78.
21. Forstner P, Knoll B. Interference of neuronal activity-mediated gene expression through serum response factor deletion enhances mortality and hyperactivity after traumatic brain injury. FASEB J 2020; 34: 3855-3873.
22. Takahashi H, Yamamoto T, Tsuboi A. Molecular mechanisms underlying activity-dependent ischemic tolerance in the brain. Neurosci Res 2023; 186: 3-9.
23. Fan W, Long Y, Lai Y, Wang X, Chen G, Zhu B. NPAS4 facilitates the autophagic clearance of endogenous tau in rat cortical neurons. J Mol Neurosci 2016; 58: 401-410.
24. Choy FC, Klarić TS, Leong WK, Koblar SA, Lewis MD. Reduction of the neuroprotective transcription factor Npas4 results in increased neuronal necrosis, inflammation and brain lesion size following ischaemia. J Cereb Blood Flow Metab 2016; 36: 1449-1463.
25. Zakhary G, Sherchan P, Li Q, Tang J, Zhang JH. Modification of kynurenine pathway via inhibition of kynurenine hydroxylase attenuates surgical brain injury complications in a male rat model. J Neurosci Res 2020; 98: 155-167.
26. Lu H, Ashiqueali R, Lin CI, Walchale A, Clendaniel V, Matheson R, et al. Histone deacetylase 3 inhibition decreases cerebral edema and protects the blood-brain barrier after stroke. Mol Neurobiol 2023; 60: 235-246.
27. Malvaez M, McQuown SC, Rogge GA, Astarabadi M, Jacques V, Carreiro S, et al. HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner. Proc Natl Acad Sci U S A 2013; 110: 2647-2652.
28. Zhang MJ, Zhao QC, Xia MX, Chen J, Chen YT, Cao X, et al. The HDAC3 inhibitor RGFP966 ameliorated ischemic brain damage by downregulating the AIM2 inflammasome. FASEB J 2020; 34: 648-662.
29. Zhao Y, Mu H, Huang Y, Li S, Wang Y, Stetler RA, et al. Microglia-specific deletion of histone deacetylase 3 promotes inflammation resolution, white matter integrity, and functional recovery in a mouse model of traumatic brain injury. J Neuroinflammation 2022; 19: 201-220.
30. Xu L, An T, Jia B, Wu Q, Shen J, Jin J, et al. Histone deacetylase 3-specific inhibitor RGFP966 attenuates oxidative stress and inflammation after traumatic brain injury by activating the Nrf2 pathway. Burns Trauma 2024; 12: tkad062-079.
31. Chen Y, He W, Qiu J, Luo Y, Jiang C, Zhao F, et al. Pterostilbene improves neurological dysfunction and neuroinflammation after ischaemic stroke via HDAC3/Nrf1-mediated microglial activation. Cell Mol Biol Lett 2024; 29: 114-133.
32. Guan X, Zhu S, Song J, Liu K, Liu M, Xie L, et al. Microglial CMPK2 promotes neuroinflammation and brain injury after ischemic stroke. Cell Rep Med 2024; 5: 101522-101545.
33. Hummel R, Dorochow E, Zander S, Ritter K, Hahnefeld L, Gurke R, et al. Valproic acid treatment after traumatic brain injury in mice alleviates neuronal death and inflammation in association with increased plasma lysophosphatidylcholines. Cells 2024; 13: 734-756.
34. Ma C, Gou C, Sun S, Wang J, Wei X, Xing F, et al. Unraveling the molecular complexity: Wtap/Ythdf1 and Lcn2 in novel traumatic brain injury secondary injury mechanisms. Cell Biol Toxicol 2024; 40: 65-93.
35. Limanaqi F, Zecchini S, Ogno P, Artusa V, Fenizia C, Saulle I, et al. Alpha-synuclein shapes monocyte and macrophage cell biology and functions by bridging alterations of autophagy and inflammatory pathways. Front Cell Dev Biol 2024; 12: 1421360-1421382.
 
Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 12 April 2025

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