胆红素对中枢神经系统的作用及其机制的研究进展

doi:10.3969/j.issn.1674-8115.2022.08.020

上海交通大学学报（医学版） ›› 2022, Vol. 42 ›› Issue (8): 1139-1144.doi: 10.3969/j.issn.1674-8115.2022.08.020

• 综述 • 上一篇

胆红素对中枢神经系统的作用及其机制的研究进展

刘珍齐(), 时海波(), 殷善开

上海交通大学医学院附属第六人民医院耳鼻咽喉头颈外科，上海交通大学耳鼻咽喉头颈外科研究所，上海 200233

收稿日期:2022-05-12 接受日期:2022-08-10 出版日期:2022-08-28 发布日期:2022-10-08
通讯作者: 时海波 E-mail:liuzhenqi@sjtu.edu.cn;hbshi@sjtu.edu.cn
作者简介:刘珍齐（1995—），女，博士生；电子信箱：liuzhenqi@sjtu.edu.cn。
基金资助:
上海市教育委员会高峰高原学科建设计划(20152233);上海市人力资源和社会保障局上海领军人才项目(2017062);上海市高水平地方高校创新团队(SHSMU-ZLCX20211702)

Progress in the study of the effect of bilirubin on the central nervous system and its mechanism

LIU Zhenqi(), SHI Haibo(), YIN Shankai

Department of Otolaryngology Head and Neck Surgery, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine; Otolaryngology Institute, Shanghai Jiao Tong University, Shanghai 200233, China

Received:2022-05-12 Accepted:2022-08-10 Online:2022-08-28 Published:2022-10-08
Contact: SHI Haibo E-mail:liuzhenqi@sjtu.edu.cn;hbshi@sjtu.edu.cn
Supported by:
Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support(20152233);Shanghai Leading Talent Program of Shanghai Municipal Bureau of Human Resources and Social Security(2017062);Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZLCX20211702)

摘要/Abstract

摘要：

在2021年世界卫生组织发布的《世界听力报告》中，新生儿高胆红素血症被认定为感音神经性聋的主要风险因素之一，可导致包括听觉中枢在内的多系统神经损伤。胆红素是血红素的生理代谢产物，目前对胆红素基本生理代谢转运途径已有了充分认识。但新生儿高胆红素血症发病率仍处于较高水平，严重高胆红素血症会影响新生儿神经系统发育，甚至有致残风险。近20年来，上海交通大学医学院附属第六人民医院耳鼻咽喉头颈外科神经电生理研究团队在国际上率先开展了胆红素对神经元兴奋性的研究，揭示了胆红素对一系列离子通道与受体的作用，阐述了胆红素所致中枢损害的兴奋毒性机制，探索了潜在的拮抗药物。该文结合文献回顾与上述团队的研究成果，阐述了胆红素对中枢神经系统的作用及其机制，探讨了胆红素与胶质细胞在内的神经网络交互以及胆红素的潜在益处。其中胆红素毒理作用机制复杂，包括高浓度胆红素对突触结构、离子通道及受体、脂质双分子层胞膜及能量代谢等广泛的调控作用。该综述为更好地认识与防治胆红素神经毒性提供了理论支撑。

关键词: 胆红素, 中枢神经系统, 兴奋毒性, 离子通道, 受体

Abstract:

In the World Hearing Report published by the World Health Organization in 2021, neonatal jaundice hyperbilirubinemia is identified as one of the major risk factors for sensorineural deafness, which can lead to multisystem neurological damage, including the auditory center. Bilirubin is a physiological metabolite of heme, and the basic physiological metabolic transport pathways of bilirubin have been fully understood. But the incidence of neonatal hyperbilirubinemia is still at a high level. Severe hyperbilirubinemia seriously affects neonatal neurological development, and even has a risk of disability. In the past 20 years, this electrophysiology research team of the Department of Otolaryngology Head and Neck Surgery, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine (Sixth Hospital for short) has been the first in the world to conduct studies on the excitability of bilirubin on neurons, reveal the effects of bilirubin on a series of ion channels and receptors, elaborate the excitotoxic mechanism of bilirubin-induced central damage, and explore potential antagonistic drugs. This paper combined previous studies with the findings of the electrophysiology research team of the Sixth Hospital to describe the effects of bilirubin on the central nervous system and its mechanisms, and discuss the interaction between bilirubin and glial cells and the potential benefits of bilirubin. The mechanisms of bilirubin's toxicological effects are complex and include a wide range of regulatory effects of high bilirubin concentrations on synaptic structures, ion channels and receptors, lipid bilayer membranes and energy metabolism. This review aims to provide theoretical support for better understanding and prevention of bilirubin neurotoxicity.

Key words: bilirubin, central nervous system, excitotoxicity, ion channel, receptor

中图分类号:

R764.21

刘珍齐, 时海波, 殷善开. 胆红素对中枢神经系统的作用及其机制的研究进展[J]. 上海交通大学学报（医学版）, 2022, 42(8): 1139-1144.

LIU Zhenqi, SHI Haibo, YIN Shankai. Progress in the study of the effect of bilirubin on the central nervous system and its mechanism[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(8): 1139-1144.

参考文献 35

1	CHADHA S, KAMENOV K, CIEZA A. The world report on hearing, 2021[J]. Bull World Health Organ, 2021, 99(4): 242-242A.
2	VASAVDA C, KOTHARI R, MALLA A P, et al. Bilirubin links heme metabolism to neuroprotection by scavenging superoxide[J]. Cell Chem Biol, 2019, 26(10): 1450-1460.e7.
3	OCHOA E L, WENNBERG R P, AN Y, et al. Interactions of bilirubin with isolated presynaptic nerve terminals: functional effects on the uptake and release of neurotransmitters[J]. Cell Mol Neurobiol, 1993, 13(1): 69-86.
4	YE H B, SHI H B, WANG J, et al. Bilirubin induces auditory neuropathy in neonatal guinea pigs via auditory nerve fiber damage[J]. J Neurosci Res, 2012, 90(11): 2201-2213.
5	GLOWATZKI E, GRANT L, FUCHS P. Hair cell afferent synapses[J]. Curr Opin Neurobiol, 2008, 18(4): 389-395.
6	SHI H B, KAKAZU Y, SHIBATA S, et al. Bilirubin potentiates inhibitory synaptic transmission in lateral superior olive neurons of the rat[J]. Neurosci Res, 2006, 55(2): 161-170.
7	LI C Y, SHI H B, SONG N Y, et al. Bilirubin enhances neuronal excitability by increasing glutamatergic transmission in the rat lateral superior olive[J]. Toxicology, 2011, 284(1/2/3): 19-25.
8	YIN X L, LIANG M, SHI H B, et al. The role of γ-aminobutyric acid/glycinergic synaptic transmission in mediating bilirubin-induced hyperexcitation in developing auditory neurons[J]. Toxicol Lett, 2016, 240(1): 1-9.
9	CHEN X J, ZHOU H Q, YE H B, et al. The effect of bilirubin on the excitability of mitral cells in the olfactory bulb of the rat[J]. Sci Rep, 2016, 6: 32872.
10	SCHUTTA H S, JOHNSON L, NEVILLE H E. Mitochondrial abnormalities in bilirubin encephalopathy[J]. J Neuropathol Exp Neurol, 1970, 29(2): 296-305.
11	WENNBERG R P, JOHANSSON B B, FOLBERGROVÁ J, et al. Bilirubin-induced changes in brain energy metabolism after osmotic opening of the blood-brain barrier[J]. Pediatr Res, 1991, 30(5): 473-478.
12	RODRIGUES C M, SOLÁ S, BRITES D. Bilirubin induces apoptosis via the mitochondrial pathway in developing rat brain neurons[J]. Hepatology, 2002, 35(5): 1186-1195.
13	RAUTI R, QAISIYA M, TIRIBELLI C, et al. Bilirubin disrupts calcium homeostasis in neonatal hippocampal neurons: a new pathway of neurotoxicity[J]. Arch Toxicol, 2020, 94(3): 845-855.
14	DANDEKAR A, MENDEZ R, ZHANG K. Cross talk between ER stress, oxidative stress, and inflammation in health and disease[J]. Methods Mol Biol, 2015, 1292: 205-214.
15	GROJEAN S, KOZIEL V, VERT P, et al. Bilirubin induces apoptosis via activation of NMDA receptors in developing rat brain neurons[J]. Exp Neurol, 2000, 166(2): 334-341.
16	SHAPIRO S M, SOMBATI S, GEIGER A, et al. NMDA channel antagonist MK-801 does not protect against bilirubin neurotoxicity[J]. Neonatology, 2007, 92(4): 248-257.
17	GROJEAN S, VERT P, DAVAL J L. Combined effects of bilirubin and hypoxia on cultured neurons from the developing rat forebrain[J]. Semin Perinatol, 2002, 26(6): 416-424.
18	LAI K, SONG X L, SHI H S, et al. Bilirubin enhances the activity of ASIC channels to exacerbate neurotoxicity in neonatal hyperbilirubinemia in mice[J]. Sci Transl Med, 2020, 12(530): eaax1337.
19	LIANG M, YIN X L, SHI H B, et al. Bilirubin augments Ca²⁺ load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels[J]. Sci Rep, 2017, 7(1): 431.
20	SHI H S, LAI K, YIN X L, et al. Ca²⁺-dependent recruitment of voltage-gated sodium channels underlies bilirubin-induced overexcitation and neurotoxicity[J]. Cell Death Dis, 2019, 10(10): 774.
21	ZHOU C, SUN R, SUN C, et al. Minocycline protects neurons against glial cells-mediated bilirubin neurotoxicity[J]. Brain Res Bull, 2020, 154: 102-105.
22	FERNANDES A, SILVA R F, FALCÃO A S, et al. Cytokine production, glutamate release and cell death in rat cultured astrocytes treated with unconjugated bilirubin and LPS[J]. J Neuroimmunol, 2004, 153(1/2): 64-75.
23	BARATEIRO A, CHEN S, YUEH M F, et al. Reduced myelination and increased glia reactivity resulting from severe neonatal hyperbilirubinemia[J]. Mol Pharmacol, 2016, 89(1): 84-93.
24	FOSTER K W, LIU Z, NAIL C D, et al. Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia[J]. Oncogene, 2005, 24(9): 1491-1500.
25	SILVA S L, VAZ A R, BARATEIRO A, et al. Features of bilirubin-induced reactive microglia: from phagocytosis to inflammation[J]. Neurobiol Dis, 2010, 40(3): 663-675.
26	LIANG M, YIN X L, WANG L Y, et al. NAD+ attenuates bilirubin-induced hyperexcitation in the ventral cochlear nucleus by inhibiting excitatory neurotransmission and neuronal excitability[J]. Front Cell Neurosci, 2017, 11: 21.
27	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.
28	HAN G Y, LI C Y, SHI H B, et al. Riluzole is a promising pharmacological inhibitor of bilirubin-induced excitotoxicity in the ventral cochlear nucleus[J]. CNS Neurosci Ther, 2015, 21(3): 262-270.
29	POSS K D, TONEGAWA S. Reduced stress defense in heme oxygenase 1-deficient cells[J]. Proc Natl Acad Sci U S A, 1997, 94(20): 10925-10930.
30	WANG J, ZHUANG H, DORÉ S. Heme oxygenase 2 is neuroprotective against intracerebral hemorrhage[J]. Neurobiol Dis, 2006, 22(3): 473-476.
31	DORÉ S, SAMPEI K, GOTO S, et al. Heme oxygenase-2 is neuroprotective in cerebral ischemia[J]. Mol Med Camb Mass, 1999, 5(10): 656-663.
32	BARANANO D E, RAO M, FERRIS C D, et al. Biliverdin reductase: a major physiologic cytoprotectant[J]. Proc Natl Acad Sci U S A, 2002, 99(25): 16093-16098.
33	AYCICEK A, EREL O. Total oxidant/antioxidant status in jaundiced newborns before and after phototherapy[J]. J Pediatr (Rio J), 2007, 83(4): 319-322.
34	LIN J P, O'DONNELL C J, SCHWAIGER J P, et al. Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study[J]. Circulation, 2006, 114(14): 1476-1481.
35	MCDONAGH A F. Controversies in bilirubin biochemistry and their clinical relevance[J]. Semin Fetal Neonatal Med, 2010, 15(3): 141-147.

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胆红素对中枢神经系统的作用及其机制的研究进展

Progress in the study of the effect of bilirubin on the central nervous system and its mechanism

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