褪黑素抑制NLRP3炎症小体延缓C57BL/6J小鼠老年性聋的研究

Melatonin inhibits NLRP3 inflammasome activation and delays presbycusis in C57BL/6J mice

刘广胜;梁运升;林欣然;司勇锋;刘金兰

1:桂林医学院临桂临床医学院

2:广西中医药大学附属国际壮医医院

摘要
目的 探讨褪黑素对C57BL/6J小鼠老年性聋的保护作用及对核苷酸寡结合聚结构域样受体蛋白3(NOD-like receptor family pyrin domain containing 3,NLRP3)炎症小体的影响。方法 将27只雄性C57BL/6J小鼠分为褪黑素组、老年性聋组和正常对照组,每组9只。褪黑素组小鼠从3月龄开始口服褪黑素(10 mg·kg~(-1)·d~(-1))直到12月龄,老年性聋组小鼠从3月龄开始口服等量乙醇载体溶液直到12月龄,正常对照组不予特殊处理。采用听性脑干反应(auditory brainstem response, ABR)评估小鼠听力,采用实时定量PCR和蛋白免疫印迹技术检测小鼠耳蜗和听皮层组织炎症因子和NLRP3炎症小体表达的变化。结果 与正常对照组小鼠相比,老年性聋组小鼠ABR阈值显著升高,炎症因子IL-1β和IL-18表达增加,NLRP3炎症小体激活。与老年性聋组小鼠相比,褪黑素组小鼠ABR阈值显著降低,IL-1β和IL-18表达下调,NLRP3炎症小体活性降低。结论 褪黑素可延缓C57BL/6J小鼠老年性聋的进展,其机制可能与抑制听觉通路NLRP3炎症小体激活有关。
关键词
老年性聋;褪黑素;NLRP3炎症小体;神经炎症;听觉通路
基金项目(Foundation):
广西自然科学基金(2024GXNSFBA010028);; 广西中医药大学博士科研启动基金(2022BS042);; 广西高校中青年教师科研基础能力提升项目(2024KY0305)
作者
刘广胜;梁运升;林欣然;司勇锋;刘金兰
参考文献

[1] 杨军,陈建勇,侯书乐,等.老年性聋的研究和防治任重道远[J].听力学及言语疾病杂志,2024,32(1):1-6.

[2] ZHANG X,ZHANG Y,LI R,et al.Salidroside ameliorates Parkinson’s disease by inhibiting NLRP3-dependent pyroptosis[J].Aging (Albany NY),2020,12(10):9405-9426.

[3] 王胜,张兆玉.NLRP3、Caspase-1、IL-6、TNF-α与突发性聋疗效的关系[J].听力学及言语疾病杂志,2022,30(4):406-409.

[4] SHI X,QIU S,ZHUANG W,et al.NLRP3-inflammasomes are triggered by age-related hearing loss in the inner ear of mice[J].Am J Transl Res,2017,9(12):5611-5618.

[5] KIM Y,LEE S Y,KIM M Y,et al.Auditory phenotype and histopathologic findings of a mutant nlrp3 expression mouse model[J].Front Neurol,2022,13:890256.

[6] CARRASCAL L,NUNEZ-ABADES P,AYALA A,et al.Role of melatonin in the inflammatory process and its therapeutic potential[J].Curr Pharm Des,2018,24(14):1563-1588.

[7] MANCHESTER L C,COTO-MONTES A,BOGA J A,et al.Melatonin:an ancient molecule that makes oxygen metabolically tolerable[J].J Pineal Res,2015,59(4):403-419.

[8] CIPOLLA-NETO J,AMARAL F G D.Melatonin as a hormone:new physiological and clinicalinsights[J].Endocr Rev,2018,39(6):990-1028.

[9] SERRA L S M,ARA■JO J G,VIEIRA A L S,et al.Role of melatonin in prevention of age-related hearing loss[J].PLoS One,2020,15(2):e0228943.

[10] NOPPARAT C,BOONTOR A,KUTPRUEK S,et al.The role of melatonin in amyloid beta-induced inflammation mediated by inflammasome signaling in neuronal cell lines[J].Sci Rep,2023,13(1):17841.

[11] ZHANG M,LIN J,WANG S,et al.Melatonin protects against diabetic cardiomyopathy through Mst1/Sirt3 signaling[J].J Pineal Res,2017,63(2).DOI:10.1111/jpi.12418.

[12] SU Z,XIONG H,LIU Y,et al.Transcriptomic analysis highlights cochlear inflammation associated with age-related hearing loss in C57BL/6 mice using next generation sequencing[J].Peer J,2020,8:e9737.

[13] LYU A R,KIM T H,PARK S J,et al.Mitochondrial damage and necroptosis in aging cochlea[J].Int J Mol Sci,2020,21(7).DOI:10.3390/ijms21072505.

[14] LI D D,FAN H X,YANG R,et al.Dendrobiumnobilelindl alkaloid suppresses NLRP3-mediated pyroptosis to alleviate LPS-induced neurotoxicity[J].Front Pharmacol,2022,13:846541.

[15] 翟思佳,尹时华.与NLRP3炎性小体通路相关感音神经性聋的研究现状[J].听力学及言语疾病杂志,2022,30(1):101-104.

[16] OZI■B??O D,LEJA M L,JEZNACH A,et al.Hearing loss as the main clinical presentation in NLRP3-associated autoinflammatory disease[J].Front Immunol,2022,13:904632.

[17] YANG X,WU Y,ZHANG M,et al.Piceatannol protects against age-related hearing loss by inhibiting cellular pyroptosis and inflammation through regulated caspase11-GSDMD pathway[J].Biomed Pharmacother,2023,163:114704.

[18] AGORASTOS A,LINTHORST A C.Potential pleiotropic beneficial effects of adjuvant melatonergic treatment in posttraumatic stress disorder[J].J Pineal Res,2016,61(1):3-26.

[19] JIANG W,LIU J,ZHAO X,et al.Melatonin-induced upregulation of telomerase activity interferes with macrophage mitochondrial metabolism and suppresses NLRP3 inflammasome activation in the treatment of Pneumonia[J].Heli-yon,2024,10(8):e29681.

[20] GAO Y,LI Y,WANG J,et al.Melatonin alleviates lipopolysaccharide-induced endometritis by inhibiting the activation of NLRP3 inflammasome through autophagy[J].Animals (Basel),2023,13(15).DOI:10.3390/ani13152449.

[21] LIU J,CHEN H,LIN X,et al.Melatonin suppresses cyclic GMP-AMP synthase-stimulator of interferon genes signaling and delays the development of hearing loss in the C57BL/6J presbycusis mouse model[J].Neuroscience,2023,517:84-95.

[22] RILEY J S,TAIT S W.Mitochondrial DNA in inflammation and immunity[J].EMBO Rep,2020,21(4):e49799.

[23] LUO F,SANDHU A F,RUNGRATANAWANICH W,et al.Melatonin and autophagy in aging-related neurodegenerative diseases[J].Int J Mol Sci,2020,21(19).DOI:10.3390/ijms21197174.