RGFP966通过HDAC3/Nrf2途径在大鼠手术性脑损伤后发挥神经保护作用。
RGFP966 exerts neuroprotective effect via HDAC3/Nrf2 pathway after surgical brain injury in rats.
发表日期:2023 Jul
作者:
Hai-Ping Gu, Xiao-Feng Wu, Ya-Ting Gong, Mu-Yao Wu, Meng-Ying Shi, Ya-Ming Sun, Bao-Qi Dang, Gang Chen
来源:
ANTIOXIDANTS & REDOX SIGNALING
摘要:
组蛋白去乙酰化酶3(HDAC3)将染色质核小体恢复至转录抑制状态,从而抑制基因表达。研究发现,HDAC3的表达在中枢神经系统多种病理状态中上调,并与其神经毒性相关。然而,HDAC3在手术性脑损伤(SBI)中的作用尚未深入探讨。本研究旨在观察HDAC3在SBI中的作用以及其抑制后对SBI结果的影响。使用大鼠SBI模型,并通过腹腔注射RGFP966(HDAC3特异性抑制剂),检测SBI大鼠周围皮质中HDAC3表达和神经元凋亡指标的变化,并观察大鼠的脑水肿和神经功能恢复。结果显示,SBI大鼠外周皮层中HDAC3的表达增加,RGFP966抑制了HDAC3的上调,并拯救了受损区域周围的神经细胞。此外,RGFP966增加了抗氧化应激蛋白,如血红素氧合酶-1(HO-1)和超氧化物歧化酶2(SOD2)的表达。同时,细胞凋亡标记物蛋白酶3的裂解形式(cle-caspase-3)的表达下降,而细胞凋亡保护性标记物B细胞淋巴瘤2(Bcl-2)的表达水平上升。此外,本研究证明,在RGFP966大鼠SBI模型中,抗氧化修饰因子核因子红细胞2相关因子2(Nrf2)的表达水平上升。RGFP966可能通过抑制HDAC3激活HDAC3/Nrf2信号通路,在大鼠SBI模型中调节由SBI诱导的氧化应激和神经细胞凋亡,减少脑水肿,对神经损伤具有保护作用。这可能是SBI病理学的潜在靶点。© 2023 Elsevier Ltd. 发表。
Histone deacetylase 3 (HDAC3) restores chromatin nucleosomes to a transcriptional repression state, thereby inhibiting gene expression. Studies have found that HDAC3 expression is upregulated in a variety of pathological states of the central nervous system and related to its neurotoxicity. However, the role of HDAC3 in surgical brain injury (SBI) has not been thoroughly explored.To observe the role of HDAC3 in SBI and the outcome of SBI after its suppression.Rat SBI model was used, and intraperitoneal injection of RGFP966 (HDAC3 specific inhibitor) was used to detect the changes of HDAC3 expression and neuronal apoptosis indexes in the surrounding cortex of SBI rats, and the cerebral edema and neurological outcome of rats were observed.The expression of HDAC3 in the peripheral cortex of SBI rats was increased, and RGFP966 inhibited the upregulation of HDAC3 and saved the nerve cells around the damaged area. In addition, RGFP966 increased the expression of anti-oxidative stress proteins such as heme oxygenase-1 (HO-1) and superoxide dismutase 2 (SOD2). At the same time, the expression of apoptotic marker protein cleaved-caspase-3 (cle-caspase-3) was decreased, while the expression level of apoptotic protective marker protein B-cell lymphoma 2 (Bcl-2) was increased. In addition, this research demonstrated that in the RGFP966 rat SBI model, the expression level of antioxidant modifier nuclear factor-erythroid 2-related factor 2 (Nrf2) was increased.RGFP966 might activate HDAC3/Nrf2 signaling pathway by inhibiting HDAC3, regulated oxidative stress and nerve cell apoptosis induced by SBI in rat SBI model, reduced brain edema, and had a protective effect on nerve injury. It might be a potential target of SBI pathology.© 2023 Published by Elsevier Ltd.