水杨酸盐致大鼠耳鸣相关神经通路递质变化的初步研究

A Preliminary Study on the Changes of Neurotransmitters in Neural Pathways Related to Tinnitus Induced by Salicylate in Rats

易彬;马青坪;汪雪玲;刘辉辉;顾佳怡;杜婷婷;王文枭;石润杰;黄治物

1:上海交通大学医学院附属第九人民医院耳鼻咽喉-头颈外科

2:上海交通大学医学院耳科学研究所

3:上海市耳鼻疾病转化医学重点实验室

摘要
目的 初步研究听觉中枢脑区谷氨酸(Glu)及γ-氨基丁酸(GABA)分泌的动态变化,探讨水杨酸钠对听觉通路不同位置的影响。方法 126只SD大鼠,6只作为空白对照组,不作任何处理,余120只根据腹腔注射水杨酸盐的方式,分为急性注射1、2、4、8、24 h组(400 mg/kg水杨酸钠注射1次)、慢性注射3、7、14 d组(200 mg/kg水杨酸钠腹腔注射,每天两次,间隔大于8 h)和慢性恢复21、28 d组(每天注射水杨酸模式与慢性注射组相同,14 d注射完毕后停止,继续常规饲养至第21、28 d作为恢复期)共10小组及与其相对应的标准对照组(水杨酸钠替换为生理盐水),每组6只。各组大鼠麻醉后取材,行高效液相色谱法(HPLC)检测听觉中枢的听皮层、下丘、耳蜗核、海马的Glu及GABA在不同时间点的动态含量。结果 与对照组相比较,急性注射水杨酸盐24 h内,听皮层的Glu含量在1 h到达高峰,海马在注射后第4 h到达高峰,之后缓慢下降。听皮层、下丘、耳蜗核、海马四个脑区的GABA含量在慢性注射期均出现了上升趋势,第7 d到达了顶峰值,在第14 d时出现了下降并趋近于正常,在恢复期则基本回归正常水平。结论 水杨酸盐对听觉中枢有一定的短期兴奋刺激作用,在中枢可塑性的机制作用下,长期注射水杨酸盐后,神经递质释放达成了一个新的兴奋/抑制平衡状态,这个过程是可逆的。Glu和GABA各自起到了不同的作用,最终可能导致了耳鸣的形成。
关键词
耳鸣;水杨酸盐;听觉中枢;神经递质;中枢可塑性
基金项目(Foundation):
上海市“科技创新行动计划”自然科学基金(20ZR1431200);; 上海交通大学“交大这星”计划医工交叉研究基金(YG2021ZD14)
作者
易彬;马青坪;汪雪玲;刘辉辉;顾佳怡;杜婷婷;王文枭;石润杰;黄治物
参考文献

[1] WU C,BAO W,YI B,et al.Increased metabolic activity and hysteretic enhanced GABAA receptor binding in a rat model of salicylate-induced tinnitus[J].Behav Brain Res,2019,364:348-355.

[2] YI B,WU C,SHI R,et al.Long-term administration of salicylate-induced changes in BDNF expression and CREB phosphorylation in the auditory cortex of rats[J].Otol Neurotol,2018,39(3):e173-e180.

[3] CAMPBELL S,MACQUEEN G.The role of the hippocampus in the pathophysiology of major depression[J].J Psychiatry Neurosci,2004,29(6):417-426.

[4] BAGULEY D,MCFERRAN D,HALL D.Tinnitus[J].Lancet,2013,382(9904):1600-1607.

[5] LANGGUTH B,KREUZER P M,KLEINJUNG T,et al.Tinnitus:causes and clinical management[J].Lancet Neurol,2013,12(9):920-930.

[6] SHORE S E,ROBERTS L E,LANGGUTH B.Maladaptive plasticity in tinnitus—triggers,mechanisms and treatment[J].Nat Rev Neurol,2016,12(3):150-160.

[7] BROZOSKI T,ODINTSOV B,BAUER C.Gamma-aminobutyric acid and glutamic acid levels in the auditory pathway of rats with chronic tinnitus:a direct determination using high resolution point-resolved proton magnetic resonance spectroscopy (H-MRS)[J].Front Syst Neurosci,2012,6:9.

[8] ELGOYHEN A B,LANGGUTH B,DE RIDDER D,et al.Tinnitus:perspectives from human neuroimaging[J].Nat Rev Neurosci,2015,16(10):632-642.

[9] JIN Y,LUO B,SU Y Y,et al.Sodium salicylate suppresses GABAergic inhibitory activity in neurons of rodent dorsal raphe nucleus[J].PLoS One,2015,10(5):e0126956.

[10] LU J,LOBARINAS E,DENG A,et al.GABAergic neural activity involved in salicylate-induced auditory cortex gain enhancement[J].Neuroscience,2011,189:187-198.

[11] YI B,HU S,ZUO C,et al.Effects of long-term salicylate administration on synaptic ultrastructure and metabolic activity in the rat CNS[J].Sci Rep,2016,6:24428.

[12] NAMIKAWA M,SANO A,TATENO T.Salicylate-induced suppression of electrically driven activity in brain slices from the auditory cortex of aging mice[J].Front Aging Neurosci,2017,9:395.

[13] NORENA A J,MOFFAT G,BLANC J L,et al.Neural changes in the auditory cortex of awake guinea pigs after two tinnitus inducers:salicylate and acoustic trauma[J].Neuroscience,2010,166(4):1194-1209.

[14] HU S S,MEI L,CHEN J Y,et al.Expression of immediate-early genes in the dorsal cochlear nucleus in salicylate-induced tinnitus[J].Eur Arch Otorhinolaryngol,2016,273(2):325-332.

[15] MULDERS W H,BARRY K M,ROBERTSON D.Effects of furosemide on cochlear neural activity,central hyperactivity and behavioural tinnitus after cochlear trauma in guinea pig[J].PLoS One,2014,9(5):e97948.

[16] LOBARINAS E,HAYES S H,ALLMAN B L.The gap-startle paradigm for tinnitus screening in animal models:limitations and optimization[J].Hear Res,2013,295:150-160.

[17] WU C,WU X,YI B,et al.Changes in GABA and glutamate receptors on auditory cortical excitatory neurons in a rat model of salicylate-induced tinnitus[J].Am J Transl Res,2018,10(12):3941-3955.

[18] 易彬,鲍伟奇,石润杰,等.水杨酸盐对大鼠听觉中枢代谢功能影响的研究[J].听力学及言语疾病杂志,2018,26(1):73-77.

[19] CROW J M.Biomedicine:move over,morphine[J].Nature,2016,535(7611):S4-6.