牛磺酸对胆红素脑病脑水通道蛋白4的表达调控及其治疗作用

doi:10.3969/j.issn.1674-490X.2026.01.001

医学研究与教育 ›› 2026, Vol. 43 ›› Issue (1): 1-10.DOI: 10.3969/j.issn.1674-490X.2026.01.001

• 基础医学 •

牛磺酸对胆红素脑病脑水通道蛋白4的表达调控及其治疗作用

樊萍¹,高宇阳²,肖泽宇³,董泽琳³,郭可云³,毛玢懿³,陈屿潇²,张妤涵²,甘胜伟^3,4

1.重庆大学附属仁济医院(重庆市第五人民医院)妇产科, 重庆401336;
2.重庆医科大学莱斯特大学联合学院, 重庆 400016;
3.重庆医科大学国家级基础医学实验教学示范中心, 重庆 400016;
4.重庆医科大学基础医学院人体解剖学教研室, 重庆 400016

收稿日期:2025-11-25 发布日期:2026-03-10
通讯作者: 甘胜伟(1980—),男,湖北武汉人,副教授,博士,硕士生导师,主要从事神经生物学研究。E-mail: 100364@cqmu.edu.cn
作者简介:樊萍(1979—),女,湖北随州人,主任医师,硕士,主要从事围生期疾病及卵巢癌研究。 E-mail: 32532887@qq.com
基金资助:
重庆市大学生创新创业训练计划项目(S202510631085);重庆医科大学第二临床学院第六届“启航宽仁”大学生创新创业训练自主项目(2)

Regulatory effect of taurine on the expression of aquaporin 4(AQP4)in the brain and its therapeutic role in bilirubin encephalopathy

FAN Ping¹, GAO Yuyang², XIAO Zeyu³, DONG Zelin³, GUO Keyun³, MAO Binyi³, CHEN Yuxiao², ZHANG Yuhan², GAN Shengwei^3,4

1. Department of Obstetrics and Gynecology, Chongqing University Affiliated Renji Hospital (the Fifth People's Hospital of Chongqing), Chongqing 401336, China; 2. University of Leicester Joint Institute, Chongqing Medical University, Chongqing 400016, China; 3. National Demonstration Center for Experimental Basic Medical Education Teaching, Chongqing Medical University, Chongqing 400016, China; 4. Department of Human Anatomy, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China

Received:2025-11-25 Published:2026-03-10

摘要/Abstract

摘要： 目的评估外源性牛磺酸对胆红素脑病(bilirubin encephalopathy, BE)乳鼠模型脑顶叶皮质水通道蛋白4(aquaporin 4,AQP4)表达的调控作用,明确其对BE的治疗效果及潜在分子机制。方法选取体质量10~15 g的新生SD乳鼠,随机分为假手术组(Sham组)、胆红素脑病组(BE组)及牛磺酸治疗组(BE+Tau组)。其中,BE组腹腔注射牛磺酸溶剂,4 h后经小脑延髓池注射胆红素(20 mg/kg)诱导BE模型;BE+Tau组先腹腔注射牛磺酸(15 mg/kg),4 h后经小脑延髓池注射胆红素;Sham组先腹腔注射牛磺酸溶剂,4 h后经小脑延髓池注射胆红素溶剂。造模后观察各组乳鼠神经行为学表现。各组于造模24 h后取脑,采用苏木精-伊红染色及尼氏染色评估神经细胞损伤程度;通过干湿重法测定脑含水量;利用罗丹明B异硫氰酸酯渗漏法明确BE脑水肿类型;采用Western blot检测脑顶叶皮质AQP4表达水平。结果与Sham组相比,BE组乳鼠出现角弓反张、爬行不稳等明显神经行为学异常,脑含水量显著高,神经细胞水肿损伤明显,脑水肿类型为细胞毒性水肿,且脑顶叶皮质AQP4表达显著上调;与BE组相比,BE+Tau组乳鼠神经行为学异常明显减轻,脑含水量低,神经细胞水肿损伤改善,未结合胆红素诱导的AQP4表达上调被显著抑制。结论外源性牛磺酸可通过抑制未结合胆红素所致BE乳鼠脑顶叶皮质AQP4表达上调,延缓细胞毒性水肿发生,减轻神经细胞损伤,从而抑制BE进展。

关键词: 牛磺酸, 胆红素脑病, 水通道蛋白4, 细胞毒性水肿

Abstract: Objective To evaluate the regulatory effect of exogenous taurine(Tau)on the expression of aquaporin 4(AQP4)in the parietal cerebral cortex of a rat pup model of bilirubin encephalopathy(BE)and clarify its therapeutic effect on BE and the underlying molecular mechanism. Methods Neonatal SD rats weighing 10-15 g were randomly divided into three groups: sham operation group(Sham group), bilirubin encephalopathy group(BE group), and taurine treatment group(BE+Tau group). The BE group was intraperitoneally injected with taurine solvent, followed by cisterna magna injection of bilirubin(20 mg/kg body weight)4 hours later to induce the BE model. The BE+Tau group was first intraperitoneally injected with taurine(15 mg/kg body weight), and bilirubin was injected via cisterna magna 4 hours later. The Sham group was first administered with taurine solvent via intraperitoneal injection, followed by an injection of bilirubin solvent via cisterna magna at 4 hours post the initial treatment. After modeling, the neurobehavioral manifestations of rats in each group were observed. At 24 hours after modeling, brain tissues were harvested from all rat pups. HE staining and Nissl staining were used to assess the degree of neuronal damage. The water content of brain tissue was measured by the dry-wet weight method. Rhodamine B isothiocyanate leakage assay was used to determine the type of cerebral edema in BE. Western blot was employed to detect the expression level of AQP4 in the parietal cortex. Results Compared with the Sham group, rats in the BE group showed obvious neurobehavioral abnormalities such as opisthotonus and unsteady crawling, significantly increased brain water content, obvious neuronal edema and damage, and the type of cerebral edema was cytotoxic edema. Additionally, the expression of AQP4 in the parietal cortex was significantly upregulated. Compared with the BE group, the neurobehavioral abnormalities of rats in the BE+Tau group were significantly alleviated, the brain water content was decreased, the neuronal edema and damage were improved, and the upregulation of AQP4 expression induced by unconjugated bilirubin(UCB)was significantly inhibited. Conclusion Exogenous taurine can delay the occurrence of cytotoxic edema, alleviate neuronal damage, and thereby inhibit the progression of BE by suppressing the UCB-induced upregulation of AQP4 expression in the parietal cortex of BE neonatal rats.

Key words: taurine, bilirubin encephalopathy, aquaporin 4, cytotoxic edema

中图分类号:

R737.31

樊萍,高宇阳,肖泽宇,董泽琳,郭可云,毛玢懿,陈屿潇,张妤涵,甘胜伟. 牛磺酸对胆红素脑病脑水通道蛋白4的表达调控及其治疗作用[J]. 医学研究与教育, 2026, 43(1): 1-10.

FAN Ping, GAO Yuyang, XIAO Zeyu, DONG Zelin, GUO Keyun, MAO Binyi, CHEN Yuxiao, ZHANG Yuhan, GAN Shengwei. Regulatory effect of taurine on the expression of aquaporin 4(AQP4)in the brain and its therapeutic role in bilirubin encephalopathy[J]. Journal of Hebei Medical College for Continuing Education, 2026, 43(1): 1-10.

参考文献

[1] QIAN S, KUMAR P, TESTAI F D. Bilirubin encephalopathy[J]. Curr Neurol Neurosci Rep, 2022, 22(7): 343-353. DOI: 10.1007/s11910-022-01204-8.
[2] OLUSANYA B O, KAPLAN M, HANSEN T W R. Neonatal hyperbilirubinaemia: a global perspective[J]. Lancet Child Adolesc Health, 2018, 2(8): 610-620. DOI: 10.1016/S2352-4642(18)30139-1.
[3] WENNBERG R P, AHLFORS C E, RASMUSSEN L F. The pathochemistry of kernicterus[J]. Early Hum Dev, 1979, 3(4): 353-372. DOI: 10.1016/0378-3782(79)90047-1.
[4] CAYABYAB R,RAMANATHAN R. High unbound bilirubin for age: a neurotoxin with major effects on the developing brain[J].Pediatr Res, 2019, 85(2): 183-190. DOI: 10.1038/s41390-018-0224-4.
[5] ALKÉN J, HÅKANSSONS, EKÉUSC, et al. Rates of extreme neonatal hyperbilirubinemia and kernicterus in children and adherence to national guidelines for screening, diagnosis, and treatment in Sweden[J]. JAMA Netw Open, 2019, 2(3): e190858. DOI: 10.1001/jamanetworkopen.2019.0858.
[6] TIRIBELLI C,OSTROW J D. New concepts in bilirubin and jaundice: report of the Third International Bilirubin Workshop, April 6-8, 1995, Trieste, Italy[J]. Hepatology, 1996, 24(5): 1296-1311. DOI: 10.1002/hep.510240551.
[7] KAPLAN M,HAMMERMAN C. Understanding severe hyperbilirubinemia and preventing kernicterus: adjuncts in the interpretation of neonatal serum bilirubin[J]. Clin Chim Acta, 2005, 356(1/2): 9-21.DOI: 10.1016/j.cccn.2005.01.008.
[8] RIORDAN S M,SHAPIRO S M. Review of bilirubin neurotoxicity I: molecular biology and neuropathology of disease[J]. Pediatr Res, 2020, 87(2): 327-331. DOI: 10.1038/s41390-019-0608-0.
[9] 胡媛,史源.新生儿胆红素脑损伤的研究进展[J].发育医学电子杂志, 2020, 8(4): 365-369.DOI: 10.3969/j.issn.2095-5340.2020.04.016.
[10] TURKEL S B, MILLER C A, GUTTENBERG M E, et al. A clinical pathologic reappraisal of kernicterus[J]. Pediatrics, 1982, 69(3): 267-272.
[11] ZHANG Y, ZHANG J, CHEN Y C, et al. Microstructure and perfusion alterations of globus pallidus in neonates with hyperbilirubinemia[J]. Curr Med Imaging, 2024, 20: e15734056266762. DOI: 10.2174/0115734056266762231206074419.
[12] JORGACEVSKI J, ZOREC R, POTOKAR M. Insights into cell surface expression, supramolecular organization, and functions of aquaporin 4 isoforms in astrocytes[J]. Cells, 2020, 9(12): 2622. DOI: 10.3390/cells9122622.
[13] SUCHA P, HERMANOVA Z, CHMELOVA M, et al. The absence of AQP4/TRPV4 complex substantially reduces acute cytotoxic edema following ischemic injury[J]. Front Cell Neurosci, 2022, 16: 1054919. DOI: 10.3389/fncel.2022.1054919.
[14] 文凤,樊萍,隆令,等.胆红素脑病SD乳鼠模型中脑水通道蛋白-4表达发生变化[J].中国生物化学与分子生物学报, 2019,35(12): 1384-1391.DOI: 10.13865/j.cnki.cjbmb.2019.10.1246.
[15] VAN PRAAGH R. Diagnosis of kernicterus in the neonatal period[J]. Pediatrics, 1961, 28(6): 870-876. DOI: 10.1542/peds.28.6.870.
[16] 黄国英,孙锟,罗少平.儿科学[M].10版. 北京:人民卫生出版社,2024:117.
[17] GAO X L, YANG X, ZHANG B Z. Neuroprotection of taurine against bilirubin-induced elevation of apoptosis and intracellular free calcium ionin vivo[J]. Toxicol Mech Meth, 2011, 21(5): 383-387. DOI: 10.3109/15376516.2010.546815.
[18] SCHAFFER S W, JONG C J, ITO T, et al. Effect of taurine on ischemia-reperfusion injury[J]. Amino Acids, 2014, 46(1): 21-30. DOI: 10.1007/s00726-012-1378-8.
[19] YE H B, WANG J, ZHANG W T, et al. Taurine attenuates bilirubin-induced neurotoxicity in the auditory system in neonatal guinea pigs[J]. Int J Pediatr Otorhinolaryngol, 2013, 77(5): 647-654.DOI: 10.1016/j.ijporl.2012.11.037.
[20] SONG N Y, LI C Y, YIN X L, et al. Taurine protects against bilirubin-induced hyperexcitation in rat anteroventral cochlear nucleus neurons[J]. Exp Neurol, 2014, 254: 216-223.DOI: 10.1016/j.expneurol.2013.12.014.
[21] 张茗越,周龙洋,蒲淞,等.褪黑素对胆红素脑病大鼠脑顶叶皮质AQP4的调控及其保护机制研究[J].中国病理生理杂志, 2023, 39(7): 1199-1208.DOI: 10.3969/j.issn.1000-4718.2023.07.006.
[22] WADDELL J, HE M, TANG N F, et al. A Gunn rat model of preterm hyperbilirubinemia[J]. Pediatr Res, 2020, 87(3): 480-484. DOI: 10.1038/s41390-019-0599-x.
[23] HANKØ E, TOMMARELLO S, WATCHKO J F, et al. Administration of drugs known to inhibit P-glycoprotein increases brain bilirubin and alters the regional distribution of bilirubin in rat brain[J]. Pediatr Res, 2003, 54(4): 441-445.DOI: 10.1203/01.PDR.0000085169.87948.B6.
[24] SARATHY L, CHOU J H, ROMANO-CLARKE G, et al. Bilirubin measurement and phototherapy use after the AAP 2022 newborn hyperbilirubinemia guideline[J]. Pediatrics, 2024, 153(4): e2023063323. DOI: 10.1542/peds.2023-063323.
[25] LIANG T Q, KONG Y X, TANG L J, et al. Network pharmacology-based analysis on the potential biological mechanisms of Yinzhihuang oral liquid in treating neonatal hyperbilirubinemia[J]. Evid Based Complement Alternat Med, 2022, 2022: 1672670. DOI: 10.1155/2022/1672670.
[26] 李金玲,李林,李翠玲,等.亚低温对胆红素脑病仔鼠脑保护作用的实验研究[J].中国康复理论与实践, 2007, 13(10): 928-930.DOI: 10.3969/j.issn.1006-9771.2007.10.013.
[27] 蒙莉,古玉芳,姜宁宁, 等.高压氧治疗新生儿高胆红素血症的临床效果及安全性分析[J]. 智慧健康, 2018,4(24): 58-59.DOI: 10.19335/j.cnki.2096-1219.2018.24.028.
[28] 温明哲,马延斌.给氧治疗对颅脑损伤的作用与机制研究进展[J].中国临床神经外科杂志, 2014,19(7): 441-443.DOI: 10.13798/j.issn.1009-153X.2014.07.023.
[29] 王岩,黎有东.神经节苷脂(GM1)治疗新生儿胆红素脑病疗效观察[J].中国优生与遗传杂志, 2008, 16(4): 76-77.DOI: 10.13404/j.cnki.cjbhh.2008.04.052.
[30] ZHU A Q, LIN Y, HU X B, et al. Treadmill exercise decreases cerebral edema in rats with local cerebral infarction by modulating AQP4 polar expression through the caveolin-1/TRPV4 signaling pathway[J]. Brain Res Bull, 2022, 188: 155-168.DOI: 10.1016/j.brainresbull.2022.08.003.
[31] WU J Y, WU H, JIN Y, et al. Mechanism of neuroprotective function of taurine[M].Taurine 7. New York,NY:Springer New York, 2009: 169-179.
[32] PRANTY A I, SHUMKA S, ADJAYE J. Bilirubin-induced neurological damage: current and emerging iPSC-derived brain organoid models[J]. Cells, 2022, 11(17): 2647. DOI: 10.3390/cells11172647.
[33] FOOS T M,WU J Y. The role of taurine in the central nervous system and the modulation of intracellular calcium homeostasis[J]. Neurochem Res, 2002, 27(1/2): 21-26. DOI: 10.1023/a: 1014890219513.
[34] HUANG S F, JIANG H L, HU H L, et al. Targeting AQP4 localization as a novel therapeutic target in CNS edema[J]. Acta Biochim Biophys Sin, 2021, 53(2): 269-272. DOI: 10.1093/abbs/gmaa158.

牛磺酸对胆红素脑病脑水通道蛋白4的表达调控及其治疗作用

Regulatory effect of taurine on the expression of aquaporin 4(AQP4)in the brain and its therapeutic role in bilirubin encephalopathy

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