依达拉奉右莰醇通过铁死亡-脂质过氧化通路对脑出血大鼠神经保护的作用机制

doi:10.11958/20221777

天津医药 ›› 2023, Vol. 51 ›› Issue (11): 1199-1204.doi: 10.11958/20221777

依达拉奉右莰醇通过铁死亡-脂质过氧化通路对脑出血大鼠神经保护的作用机制

毛权西(), 李作孝^△()

西南医科大学附属医院神经内科（邮编646000）

收稿日期:2022-11-07 修回日期:2023-03-13 出版日期:2023-11-15 发布日期:2023-11-07
通讯作者: ^△E-mail：lzx3235@sina.com
作者简介:毛权西（1990），男，硕士在读，主要从事神经免疫方向研究。E-mail：369868558@qq.com
基金资助:
泸州市人民政府-西南医科大学科技战略合作基金项目(2018LZXNYD-ZK17)

Neuroprotective mechanism of edaravone dexborneol in rats with cerebral hemorrhage through ferroptosis-lipid peroxidation pathway

MAO Quanxi(), LI Zuoxiao^△()

Department of Neurology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China

Received:2022-11-07 Revised:2023-03-13 Published:2023-11-15 Online:2023-11-07
Contact: ^△E-mail：lzx3235@sina.com

毛权西, 李作孝. 依达拉奉右莰醇通过铁死亡-脂质过氧化通路对脑出血大鼠神经保护的作用机制[J]. 天津医药, 2023, 51(11): 1199-1204.

MAO Quanxi, LI Zuoxiao. Neuroprotective mechanism of edaravone dexborneol in rats with cerebral hemorrhage through ferroptosis-lipid peroxidation pathway[J]. Tianjin Medical Journal, 2023, 51(11): 1199-1204.

摘要/Abstract

摘要：

目的探讨依达拉奉右莰醇对脑出血大鼠的神经保护作用及血肿周围脑组织脂质过氧化的影响。方法将128只SD大鼠随机分为假手术组、脑出血组、依达拉奉组和依达拉奉右莰醇组，每组32只。除假手术组外，其余组大鼠构建急性脑出血模型，依达拉奉组、依达拉奉右莰醇组于造模后分别腹腔注射依达拉奉6 mg/kg、依达拉奉右莰醇7.5 mg/kg，每12 h注射1次，假手术组和脑出血组腹腔注射等量生理盐水。术后1 d、3 d、7 d和14 d按Garcia评分标准进行神经功能评分，HE染色观察血肿周围脑组织病理变化，化学荧光法检测血肿周围脑组织活性氧（ROS）含量，微量酶标法检测血肿周围脑组织还原型谷胱甘肽（GSH）含量，蛋白免疫印迹法检测血肿周围脑组织谷胱甘肽过氧化物酶4（GPX4）、长链脂酰辅酶A合成酶4（ACSL4）和磷脂胆碱酰基转移酶3（LPCAT3）表达。结果与假手术组比较，脑出血组大鼠神经功能评分降低，血肿周围脑组织出现大量炎性细胞浸润及神经细胞变性，ROS含量、ACSL4和LPCAT3蛋白表达水平升高，GSH含量、GPX4蛋白表达水平降低（P<0.05）；与脑出血组比较，依达拉奉组和依达拉奉右莰醇组大鼠神经功能评分升高，血肿周围脑组织病理损伤明显减轻，ROS含量、ACSL4和LPCAT3蛋白表达水平降低，GSH含量、GPX4蛋白表达水平增加（P<0.05）；依达拉奉右莰醇组干预效果优于依达拉奉组（P<0.05）；除假手术组外，其余各组均在术后3 d时变化最明显，术后7 d、14 d逐渐恢复（P<0.05）。结论依达拉奉右莰醇可能通过调节脑出血大鼠神经细胞铁死亡相关蛋白的表达，减少脑组织脂质过氧化，抑制神经细胞铁死亡，从而发挥脑保护作用。

关键词: 依达拉奉右莰醇, 依达拉奉, 脑出血, 铁死亡, 脂质过氧化

Abstract:

Objective To investigate the neuroprotective effect of edaravone dexborneol on cerebral hemorrhage in rats and the effect of lipid peroxidation on perihematomal brain tissue. Methods A total of 128 SD rats were randomly divided into the sham-operated group, the cerebral hemorrhage group, the edaravone group and the edaravone dexborneol group, with 32 rats in each group. The acute cerebral hemorrhage model was constructed in all groups except for the sham-operated group. The edaravone group and edaravone dexamphene group were injected intraperitoneally with 6 mg/kg of edaravone and edaravone dexamphene 7.5 mg/kg, one injection every 12 hours. The sham-operated group and the cerebral hemorrhage group were injected intraperitoneally with equal amounts of saline. The neurological function was scored according to Garcia score at 1 d, 3 d, 7 d, and 14 d after surgery. Brain tissue around hematoma was stained with HE staining. Chemo fluorescence assay was used to observe pathological changes and reactive oxygen species (ROS) content of brain tissue around hematoma. Micro enzyme labeling assay was used to detect glutathione (GSH) content of brain tissue around hematoma. The expression levels of glutathione peroxidase 4 (GPX4), long-chain lipid acyl-coenzyme A synthase 4 (ACSL4) and phospholipid choline acyltransferase 3 (LPCAT3) in brain tissue around hematoma were detected by protein immunoblotting. Results Compared with the sham-operated group, neurological function scores were decreased in the cerebral hemorrhage group. Massive inflammatory cell infiltration and neuronal degeneration in brain tissue around hematoma were found, and ROS content, ACSL4 and LPCAT3 protein expression level increased. GSH content and GPX4 protein expression level decreased in the cerebral hemorrhage group (P<0.05). Compared with the cerebral hemorrhage group, neurological function scores were increased, histopathological damage around the hematoma was significantly reduced, ROS content, ACSL4 and LPCAT3 protein expression level were decreased, and the GSH content and GPX4 protein expression level were increased in the edaravone group and the edaravone dexborneol group (P<0.05). The intervention effect was better in the edaravone dexcamphenol group than that of the edaravone group (P<0.05). Except for the sham operated group, changes of the other groups were the most obvious at 3 d postoperatively, and gradually recovered at 7 d and 14 d postoperatively (P<0.05). Conclusion Edaravone dexborneol may play a protective role in cerebral hemorrhage by regulating the expression of ferroptosis-related proteins in nerve cells, reducing lipid peroxidation in brain tissue, and inhibiting iron death of nerve cells.

Key words: edaravone dexborneol, edaravone, cerebral hemorrhage, ferroptosis, lipid peroxidation

中图分类号:

R743.34

图/表 6

参考文献 25

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组别	n	神经功能评分				F
组别	n	1 d	3 d	7 d	14 d	F
假手术组	8	17.75±0.46	17.75±0.46	17.88±0.35	18.00±0.00	0.828
脑出血组	8	11.88±1.13^a	9.50±0.93^aA	13.38±0.92^aAB	14.75±0.89^aABC	43.110^＊
依达拉奉组	8	13.25±1.28^b	11.63±1.06^bA	14.75±1.04^bAB	16.00±0.76^bABC	25.950^＊
依达拉奉右莰醇组	8	14.25±0.89^bc	13.38±0.74^bcA	15.88±0.64^bcAB	17.50±0.53^bcABC	52.234^＊
F		55.514^＊	142.848^＊	47.331^＊	42.507^＊

组别	n	神经功能评分				F
组别	n	1 d	3 d	7 d	14 d	F
假手术组	8	17.75±0.46	17.75±0.46	17.88±0.35	18.00±0.00	0.828
脑出血组	8	11.88±1.13^a	9.50±0.93^aA	13.38±0.92^aAB	14.75±0.89^aABC	43.110^＊
依达拉奉组	8	13.25±1.28^b	11.63±1.06^bA	14.75±1.04^bAB	16.00±0.76^bABC	25.950^＊
依达拉奉右莰醇组	8	14.25±0.89^bc	13.38±0.74^bcA	15.88±0.64^bcAB	17.50±0.53^bcABC	52.234^＊
F		55.514^＊	142.848^＊	47.331^＊	42.507^＊

组别	ROS含量				F
组别	1 d	3 d	7 d	14 d	F
假手术组	401.13±34.85	419.31±12.77	469.35±50.88	423.93±40.35	3.006
脑出血组	2 627.93±191.86^a	4 843.82±248.58^aA	4 259.69±252.67^aAB	2 301.21±162.10^aABC	161.608^＊
依达拉奉组	2 575.42±232.30	4 208.64±151.22^bA	2 780.60±307.92^bB	1 353.92±130.66^bBC	145.064^＊
依达拉奉右莰醇组	2 378.65±193.52^b	2 850.56±271.71^bcA	1 560.46±181.28^bcAB	648.05±29.06^bcABC	129.150^＊
F	176.405^＊	438.943^＊	273.577^＊	311.623^＊

组别	ROS含量				F
组别	1 d	3 d	7 d	14 d	F
假手术组	401.13±34.85	419.31±12.77	469.35±50.88	423.93±40.35	3.006
脑出血组	2 627.93±191.86^a	4 843.82±248.58^aA	4 259.69±252.67^aAB	2 301.21±162.10^aABC	161.608^＊
依达拉奉组	2 575.42±232.30	4 208.64±151.22^bA	2 780.60±307.92^bB	1 353.92±130.66^bBC	145.064^＊
依达拉奉右莰醇组	2 378.65±193.52^b	2 850.56±271.71^bcA	1 560.46±181.28^bcAB	648.05±29.06^bcABC	129.150^＊
F	176.405^＊	438.943^＊	273.577^＊	311.623^＊

组别	GSH含量				F
组别	1 d	3 d	7 d	14 d	F
假手术组	15.44±1.19	15.19±1.27	15.16±1.18	16.04±0.40	0.725
脑出血组	5.54±0.60^a	0.90±0.76^aA	2.14±0.86^aAB	7.28±1.18^aABC	56.782^＊
依达拉奉组	6.54±1.10	1.27±0.98^A	6.11±0.95^bB	9.8±0.79^bABC	67.218^＊
依达拉奉右莰醇组	6.92±0.71^b	2.95±1.04^bcA	7.55±0.94^bcB	14.89±1.34^bcABC	116.679^＊
F	121.032^＊	219.383^＊	152.153^＊	86.897^＊

依达拉奉右莰醇通过铁死亡-脂质过氧化通路对脑出血大鼠神经保护的作用机制

Neuroprotective mechanism of edaravone dexborneol in rats with cerebral hemorrhage through ferroptosis-lipid peroxidation pathway

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组别	ACSL4				F
组别	1 d	3 d	7 d	14 d	F
假手术组	0.06±0.01	0.06±0.01	0.06±0.01	0.06±0.01	0.000
脑出血组	0.43±0.03^a	0.72±0.03^aA	0.59±0.02^aAB	0.28±0.04^aABC	209.196^＊
依达拉奉组	0.38±0.04^b	0.65±0.04^bA	0.48±0.03^bAB	0.18±0.03^bABC	164.729^＊
依达拉奉右莰醇组	0.30±0.03^bc	0.49±0.05^bcA	0.19±0.04^bcAB	0.09±0.01^bcABC	125.193^＊
F	162.535^＊	383.899^＊	451.068^＊	76.947^＊
组别	LPCAT3				F
组别	1 d	3 d	7 d	14 d	F
假手术组	0.08±0.01	0.08±0.01	0.08±0.01	0.08±0.01	0.000
脑出血组	0.59±0.03^a	0.84±0.03^aA	0.71±0.04^aAB	0.39±0.02^aABC	194.560^＊
依达拉奉组	0.55±0.06	0.74±0.07^bA	0.57±0.03^bB	0.27±0.03^bABC	76.592^＊
依达拉奉右莰醇组	0.41±0.03^bc	0.54±0.04^bcA	0.24±0.04^bcAB	0.12±0.04^bcABC	120.285^＊
F	191.531^＊	338.113^＊	366.208^＊	128.922^＊
组别	GPX4				F
组别	1 d	3 d	7 d	14 d	F
假手术组	0.70±0.03	0.70±0.03	0.70±0.03	0.70±0.03	0.000
脑出血组	0.41±0.04^a	0.15±0.04^aA	0.25±0.03^aAB	0.49±0.03^aABC	84.135^＊
依达拉奉组	0.49±0.04^b	0.27±0.03^bA	0.32±0.03^bAB	0.58±0.02^bABC	111.808^＊
依达拉奉右莰醇组	0.56±0.04^bc	0.35±0.03^bcA	0.49±0.06^bcAB	0.66±0.03^bcABC	50.498^＊
F	491.616^＊	865.259^＊	749.863^＊	134.870^＊

组别	ACSL4				F
组别	1 d	3 d	7 d	14 d	F
假手术组	0.06±0.01	0.06±0.01	0.06±0.01	0.06±0.01	0.000
脑出血组	0.43±0.03^a	0.72±0.03^aA	0.59±0.02^aAB	0.28±0.04^aABC	209.196^＊
依达拉奉组	0.38±0.04^b	0.65±0.04^bA	0.48±0.03^bAB	0.18±0.03^bABC	164.729^＊
依达拉奉右莰醇组	0.30±0.03^bc	0.49±0.05^bcA	0.19±0.04^bcAB	0.09±0.01^bcABC	125.193^＊
F	162.535^＊	383.899^＊	451.068^＊	76.947^＊
组别	LPCAT3				F
组别	1 d	3 d	7 d	14 d	F
假手术组	0.08±0.01	0.08±0.01	0.08±0.01	0.08±0.01	0.000
脑出血组	0.59±0.03^a	0.84±0.03^aA	0.71±0.04^aAB	0.39±0.02^aABC	194.560^＊
依达拉奉组	0.55±0.06	0.74±0.07^bA	0.57±0.03^bB	0.27±0.03^bABC	76.592^＊
依达拉奉右莰醇组	0.41±0.03^bc	0.54±0.04^bcA	0.24±0.04^bcAB	0.12±0.04^bcABC	120.285^＊
F	191.531^＊	338.113^＊	366.208^＊	128.922^＊
组别	GPX4				F
组别	1 d	3 d	7 d	14 d	F
假手术组	0.70±0.03	0.70±0.03	0.70±0.03	0.70±0.03	0.000
脑出血组	0.41±0.04^a	0.15±0.04^aA	0.25±0.03^aAB	0.49±0.03^aABC	84.135^＊
依达拉奉组	0.49±0.04^b	0.27±0.03^bA	0.32±0.03^bAB	0.58±0.02^bABC	111.808^＊
依达拉奉右莰醇组	0.56±0.04^bc	0.35±0.03^bcA	0.49±0.06^bcAB	0.66±0.03^bcABC	50.498^＊
F	491.616^＊	865.259^＊	749.863^＊	134.870^＊