Neuroprotective effect of histone deacetylase 3 specific inhibitor RGFP966 on traumatic brain injury by inhibiting pyroptosis
10.3760/cma.j.cn115354-20230628-00358
- VernacularTitle:组蛋白去乙酰化酶3特异性抑制剂RGFP966通过抑制神经细胞焦亡对创伤性脑损伤产生神经保护作用
- Author:
Lanjuan XU
1
;
Baohui JIA
;
Tingting AN
;
Qiong WU
;
Xiangyang LI
;
Yifan MA
;
Huihui DING
;
Tao SONG
;
Liqing LI
;
Chengjian LI
Author Information
1. 郑州大学附属郑州中心医院重症医学科，郑州 450001
- Keywords:
Traumatic brain injury;
RGFP966;
Pyroptosis;
Inflammatory reaction
- From:
Chinese Journal of Neuromedicine
2023;22(9):875-883
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate the neuroprotective effect of histone deacetylase 3 (HDAC3) specific inhibitor RGFP966 on traumatic brain injury (TBI) and its mechanism in rats.Methods:Forty-eight SD rats were randomly divided into sham-operated group, TBI group, TBI+vehicle group and TBI+RGFP966 group ( n=12). Rats in the later 3 groups accepted hydraulic impact brain injury to establish TBI models; and then, RGFP966 (dissolved in 1% DMSO at a dose of 10 mg/kg) was injected intraperitoneally 30 min after modeling, twice a day for 3 d, in TBI+RGFP966 group; same amount of DMSO was injected into TBI+vehicle group at the same time. Three d after modeling, neurological function was tested by modified neurological severity score (mNSS), water content of brain tissues was detected by dry-wet weight method, proportion of injured neurons at the frontal cortical tissues on the affected side was detected by Nissl staining, expressions of HDAC3 and pyroptosis related proteins were detected by immunohistochemical staining and Western blotting, and serum content of inflammatory factors was detected by ELISA. Results:Three d after modeling, compared with the TBI+vehicle group, the TBI+RGFP966 group had significantly decreased mNSS scores (9.83±0.75 vs. 6.67±0.82), water content of the injured cerebral cortex (82.73%±0.36% vs. 80.92%±0.66%), proportion of damaged neurons (75.60%±7.44% vs. 55.87%±4.10%), and HDAC3 protein expression (0.67±0.09 vs. 0.51±0.07), and significantly increased acetylated H3 (Ace-H3) and acetylated H4 (Ace-H4) protein expressions (0.81±0.02 vs. 1.22±0.02; 0.74±0.01 vs. 1.07±0.02), and statistically decreased protein expressions of nuclear factor-κB (NF-κB, 1.20±0.05 vs. 0.94±0.04), NOD-like receptor thermal protein domain associated protein 3 (NLRP3, 0.72±0.02 vs. 0.40±0.03), Caspase-1 containing cysteine (Caspase-1), dermatin D N-terminal fragment (GSDMD-N, 0.71±0.03 vs. 0.52±0.01), significantly decreased NF-κB and NLRP3 immunohistochemical staining scores, and significantly decreased serum contents of tumor necrosis factor-α, interleukin(IL)-1β and IL-18 ( P<0.05). Conclusion:Early intervention with RGFP966 after TBI can reduce the pyroptosis and inflammatory reaction of nerve cells and play neuroprotective role, whose mechanism may be related to inhibited activation of NF-κB/NLRP3/GSDMD pathway.
