Study of magnesium isoglycyrrhizinate in ameliorating cisplatin induced myocardial injury in rats

doi:10.11958/20231833

Abstract

Abstract:

Objective To investigate the protective effect and mechanism of magnesium isoglycyrrhizinate (MgIG) on cisplatin (CDDP)-induced myocardial injury in rats. Methods Twenty-four Wistar rats were randomly divided into the normal control group, the cisplatin model group (CDDP group), the cisplatin + magnesium isoglycyrrhizinate low-dose group (MgIG-L group) and the cisplatin + magnesium isoglycyrrhizinate high-dose group (MgIG-H group), with 6 rats in each group. Changes of body mass of rats were monitored daily. At the end of drug administration, cardiac function indexes including left ventricular ejection fraction (LVEF), left ventricular short-axis narrowing rate (LVFS), left ventricular end-systolic internal diameter (LVESD) and left ventricular end-diastolic internal diameter (LVEDD) were detected by echocardiography. The morphology of myocardial tissue was observed by HE staining. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum levels of creatine kinase isoenzyme MB (CK-MB) and troponin I (cTnI). Levels of superoxide dismutase (SOD), malondialdehyde (MDA), glutathione synthase (GSH), reactive oxygen species (ROS) and ferrous ion (Fe²⁺) in homogenates of myocardial tissue were measured biochemically. The protein expressions of nuclear factor E2-associated factor 2 (Nrf2), long-chain fatty acyl coenzyme A synthase 4 (ACSL4), glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1) protein were detected by Western blot assay. Results The body mass of rats in the control group showed an increasing trend during feeding, and the body mass of rats in the CDDP group showed a decreasing trend. Compared with the CDDP group, the body mass of rats in the MgIG-L group and the MgIG-H group increased after 5 d, 9 d and 13 d of treatment (P<0.05). Compared with the control group, the CDDP group showed decreased LVEF and LVFS, increased LVESD and LVEDD, disturbed myocardial fiber alignment, myocardial fiber degeneration and fracture, increased serum CK-MB and cTnI levels, increased levels of MDA, Fe²⁺ and ROS in myocardial tissue, decreased levels of SOD and GSH, and decreased levels of Nrf2, GPX4, and decreased FTH1 protein expression levels and increased ACSL4 protein expression levels in myocardial tissue (P<0.05). Compared with the CDDP group, the above indicators and myocardial histopathological changes were significantly improved in the MgIG-L group and the MgIG-H group. Conclusion Magnesium isoglycyrrhizinate can ameliorate cisplatin-induced myocardial injury by regulating myocardial oxidative stress and inhibiting cardiomyocyte iron death in rats.

Key words: glycyrrhizic acid, cisplatin, myocardium, oxidative stress, ferroptosis

CLC Number:

R285.5

Figures/Tables 7

References 23

[1]	CUI Y, LI C, ZENG C, et al. Tongmai Yangxin pills anti-oxidative stress alleviates cisplatin-induced cardiotoxicity:Network pharmacology analysis and experimental evidence[J]. Biomed Pharmacother, 2018, 108:1081-1089. doi:10.1016/j.biopha.2018.09.095.
[2]	马治, 王欣爽, 刘玥, 等. 甘草次酸的差向异构体对顺铂诱导H9c2心肌细胞损伤的保护机制[J]. 天津医药, 2022, 50(12):1264-1269.
	MA Z, WANG X S, LIU Y, et al. The protective mechanism of differential isomers of glycyrrhetinic acid on cisplatin-induced H9c2 cardiomyocyte injury[J]. Tianjin Med J, 2022, 50(12):1264-1269. doi:10.11958/20220987.
[3]	XU J, ZHANG B, CHU Z, et al. Wogonin alleviates cisplatin-induced cardiotoxicity in mice via inhibiting gasdermin D-mediated pyroptosis[J]. J Cardiovasc Pharmacol, 2021, 78(4):597-603. doi:10.1097/FJC.0000000000001085.
[4]	XIA J, HU J N, ZHANG R B, et al. Icariin exhibits protective effects on cisplatin-induced cardiotoxicity via ROS-mediated oxidative stress injury in vivo and in vitro[J]. Phytomedicine, 2022, 104:154331. doi:10.1016/j.phymed.2022.154331.
[5]	ZHAO L, TAO X, QI Y, et al. Protective effect of dioscin against doxorubicin-induced cardiotoxicity via adjusting microRNA-140-5p-mediated myocardial oxidative stress[J]. Redox Biol, 2018, 16:189-198. doi:10.1016/j.redox.2018.02.026.
[6]	王栋, 黄凯, 郭淑贞. 致心脏毒性中药的减毒及防治心脏毒性中药的研究进展[J]. 中国中药杂志, 2022, 47(1):18-23.
	WANG D, HUANG K, GUO S Z. Detoxification of cardiotoxic traditional Chinese medicine and traditional Chinese medicine for prevention of cardiotoxicity:a review[J]. China Journal of Chinese Materia Medica, 2022, 47(1):18-23. doi:10.19540/j.cnki.cjcmm.20210917.703.
[7]	邓桃妹, 彭灿, 彭代银, 等. 甘草化学成分和药理作用研究进展及质量标志物的探讨[J]. 中国中药杂志, 2021, 46(11):2660-2676.
	DENG T M, PENG C, PENG D Y, et al. Research progress on chemical constituents and pharmacological effects of Glycyrrhizae Radix et Rhizoma and discussion of Q-markers[J]. China Journal of Chinese Materia Medica, 2021, 46(11):2660-2676. doi:10.19540/j.cnki.cjcmm.20210304.201.
[8]	YANG Y Z, LIU Z H, WANG S C, et al. Magnesium isoglycyrrhizinate alleviates fructose-induced liver oxidative stress and inflammatory injury through suppressing NOXs[J]. Eur J Pharmacol, 2020, 883:173314. doi:10.1016/j.ejphar.2020.173314.
[9]	韩竹俊, 许美娟, 刘玲, 等. 异甘草酸镁的药理作用及临床应用研究进展[J]. 药学与临床研究, 2023, 31(3):238-242.
	HAN Z J, XU M J, LIU L, et al. Pharmacological effects and clinical application progress of magnesium isoglycyrrhizinate[J]. Pharmaceutical and Clinical Research, 2023, 31(3):238-242. doi:10.13664/j.cnki.pcr.2023.03.011.
[10]	李艳阳, 王云姣, 吕仕超. 中药注射液防治抗肿瘤药物心脏毒性的效应和机制[J]. 中国临床药理学与治疗学, 2023, 28(5):572-577.
	LI Y Y, WANG Y J, LYU S C. Effects and mechanism of traditional Chinese medicine injection in prevention and treatment of cardiotoxicity induced by antineoplastic drugs[J]. Chin J Clin Pharm Therap, 2023, 28(5):572-577. doi:10.12092/j.issn.1009-2501.2023.05.012.
[11]	邱月清, 王振涛, 郭宗耀. 炙甘草汤防治心血管疾病的实验与机制概述[J]. 中华中医药学刊, 2023(8):1-12.
	QIU Y Q, WNAG Z T, GUO Z Y. Experiment and Mechanism of Zhigancao Decoction in the Prevention and Treatment of Cardiovascular Diseases[J]. Chinese Archives of Traditional Chinese Medicine, 2023(8):1-12.
[12]	杨梦霞, 芦殿荣, 朱世杰, 等. 炙甘草汤治疗抗肿瘤药物致心脏毒性作用机制的网络药理学研究[J]. 中国中医急症, 2022, 31(5):753-757.
	YANG M X, LU D R, ZHU S J, et al. Study on the mechanism of zhigancao decoction in the treatment of antineoplastic drug-induced cardiotoxicity[J]. Journal of Emergency in Traditional Chinese Medicine, 2022, 31(5):753-757. doi:10.3969/j.issn.1004-745X.2022.05.001.
[13]	蔡晓月, 邓林华, 李甜, 等. 基于cAMP/PKA信号通路探讨通脉养心丸对缓慢性心律失常大鼠心率的影响[J]. 现代中西医结合杂志, 2022, 31(17):2337-2341,2373.
	CAI X Y, DENG L H, LI T, et al. Effect of Tongmai Yangxin pill on heart rate of rats with bradyarrhythmia based on cAMP/PKA signaling pathway[J]. Modern Journal of Integrated Traditional Chinese and Western Medicine, 2022, 31(17):2337-2341,2373. doi:10.3969/j.issn.1008-8849.2022.17.001.
[14]	CHENG M, ZHANG J, YANG L, et al. Recent advances in chemical analysis of licorice (Gan-Cao)[J]. Fitoterapia, 2021, 149:104803. doi:10.1016/j.fitote.2020.104803.
[15]	WANG L, ZHANG Y, WAN H, et al. Glycyrrhetinic acid protects H9c2 cells from oxygen glucose deprivation-induced injury through the PI3K/AKt signaling pathway[J]. J Nat Med, 2017, 71(1):27-35. doi:10.1007/s11418-016-1023-z.
[16]	YU Y, YAN Y, NIU F, et al. Ferroptosis:a cell death connecting oxidative stress,inflammation and cardiovascular diseases[J]. Cell Death Discov, 2021, 7(1):193. doi:10.1038/s41420-021-00579-w.
[17]	ROSIC G, SREJOVIC I, ZIVKOVIC V, et al. The effects of N-acetylcysteine on cisplatin-induced cardiotoxicity on isolated rat hearts after short-term global ischemia[J]. Toxicol Rep, 2015, 2:996-1006. doi:10.1016/j.toxrep.2015.07.009.
[18]	LI J, ZHOU Y, WANG H, et al. Oxidative stress-induced ferroptosis in cardiovascular diseases and epigenetic mechanisms[J]. Front Cell Dev Biol, 2021, 9:685775. doi:10.3389/fcell.2021.685775.
[19]	MANCARDI D, MEZZANOTTE M, ARRIGO E, et al. Iron overload,oxidative stress,and ferroptosis in the failing heart and liver[J]. Antioxidants(Basel), 2021, 10(12):1864. doi:10.3390/antiox10121864.
[20]	DODSON M, CASTRO-PORTUGUEZ R, ZHANG D D. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis[J]. Redox Biol, 2019, 23:101107. doi:10.1016/j.redox.2019.101107.
[21]	LI J, CAO F, YIN H L, et al. Ferroptosis:past, present and future[J]. Cell Death Dis, 2020, 11(2):88. doi:10.1038/s41419-020-2298-2.
[22]	王青青, 张莉芬, 马金苗, 等. 附萸汤通过调控Nrf2/GPX4介导的铁死亡对心力衰竭大鼠心肌纤维化的影响[J]. 中国中药杂志, 2023(8):1-10.
	WANG Q Q, ZHANG L F, MA J M, et al. Fuyu Decoction ameliorates myocardial fibrosis in rat model of heart failure by regulating Nrf2/GPX4-mediated ferroptosis[J]. China Journal of Chinese Materia Medica, 2023(8):1-10. doi:10.19540/j.cnki.cjcmm.20230815.703.
[23]	蒋志明, 张辽, 刘磊, 等. 电针心经激活核因子E2相关因子2/血红素氧合酶信号通路抑制铁死亡改善急性心肌缺血[J]. 针刺研究, 2023, 48(5):461-468.
	JIANG Z M, ZHANG L, LIU L, et al. Elextroacupuncture improves ischemic myocardial injury by activating Nrf2/HO-1 signaling pathway to inhibit ferroptosis in rat[J]. Acupuncture Research, 2023, 48(5):461-468. doi:10.13702/j.1000-0607.20211358.

组别	1 d	5 d	9 d	13 d	F
Control组	251.83±7.41	282.50±9.13^A	302.67±11.78^AB	323.17±10.26^ABC	58.006^＊＊
CDDP组	251.00±10.41	239.33±20.05^aA	216.33±28.31^aAB	194.33±31.08^aABC	6.661^＊＊
MgGL-L组	250.16±7.57	243.33±11.52^b	243.67±15.53^b	246.33±13.35^b	0.393
MgGL-H组	250.00±17.58	259.50±27.70^b	269.50±32.00^b	282.67±21.00^bc	1.847
F	0.032	6.655^＊	14.762^＊＊	42.542^＊＊

组别	1 d	5 d	9 d	13 d	F
Control组	251.83±7.41	282.50±9.13^A	302.67±11.78^AB	323.17±10.26^ABC	58.006^＊＊
CDDP组	251.00±10.41	239.33±20.05^aA	216.33±28.31^aAB	194.33±31.08^aABC	6.661^＊＊
MgGL-L组	250.16±7.57	243.33±11.52^b	243.67±15.53^b	246.33±13.35^b	0.393
MgGL-H组	250.00±17.58	259.50±27.70^b	269.50±32.00^b	282.67±21.00^bc	1.847
F	0.032	6.655^＊	14.762^＊＊	42.542^＊＊

组别	LVEF/%	LVFS/%	LVEDD/mm	LVESD/mm
Control组	81.63±1.06	51.49±1.13	6.64±0.33	3.22±0.18
CDDP组	63.59±3.30^a	35.68±2.49^a	7.22±0.14^a	4.64±0.17^a
MgIG-L组	71.18±4.65^b	41.76±4.20^b	6.91±0.17^b	4.02±0.31^b
MgIG-H组	77.42±5.38^bc	47.54±5.49^bc	6.81±0.22^b	3.57±0.37^b
F	23.660^＊＊	20.666^＊＊	6.960^＊＊	30.931^＊＊

组别	LVEF/%	LVFS/%	LVEDD/mm	LVESD/mm
Control组	81.63±1.06	51.49±1.13	6.64±0.33	3.22±0.18
CDDP组	63.59±3.30^a	35.68±2.49^a	7.22±0.14^a	4.64±0.17^a
MgIG-L组	71.18±4.65^b	41.76±4.20^b	6.91±0.17^b	4.02±0.31^b
MgIG-H组	77.42±5.38^bc	47.54±5.49^bc	6.81±0.22^b	3.57±0.37^b
F	23.660^＊＊	20.666^＊＊	6.960^＊＊	30.931^＊＊

组别	CK-MB/（μg/L）	cTnI/（ng/L）
Control组	6.58±2.19	209.48±38.26
CDDP组	14.27±2.08^a	482.88±57.12^a
MgIG-L组	11.47±0.63^b	363.18±33.56^b
MgIG-H组	9.74±0.87^b	306.94±25.14^bc
F	24.247^＊＊	48.211^＊＊