水杨酸盐诱发大鼠听皮层中TNF-α和GluA1表达的改变
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摘要
目的通过检测水杨酸盐诱导耳鸣大鼠听皮层中TNF-α和AMPA受体亚基(GluA1)蛋白的表达,研究耳鸣大鼠听皮层是否出现炎症因子和膜受体表达的改变,探讨TNF-α在耳鸣中的作用机制。方法 24只SD大鼠,随机等分成4组:对照组、慢性注射7天组、慢性注射14天组、停药后恢复14天组。前脉冲抑制实验评估动物是否发生耳鸣样行为。Western Blot检测听皮层中TNF-α和GluA1蛋白表达。结果⑴长期注射水杨酸盐后,大鼠的前脉冲抑制率增加,差异有统计学意义(P<0.05)。⑵在慢性注射7天组,TNF-α和GluA1蛋白表达水平较对照组升高,差异有统计学意义(P=0.036,P=0.019,P<0.05);在慢性注射14天组,TNF-α和GluA1蛋白表达水平较对照组、停药后恢复14天组升高,差异有统计学意义(P=0.003,P=0.002,P<0.01)。⑶TNF-α和GluA1蛋白表达具有显著正相关(P=0.000,P<0.001)。结论耳鸣模型大鼠听皮层中TNF-α和GluA1蛋白表达均上调且两者变化有显著正相关性,推测TNF-α可能通过调节GluA1的表达导致大鼠耳鸣。
Objective To investigate the central mechanisms of tinnitus in a rat model by examining expression levels of TNF-α and AMPA receptor subunit(GluA1) in the auditory cortex following salicylate exposure. Methods Twenty-four SD rats were randomly divided into a control group, a treatment group with daily salicylate injection for 7 days(S7), a treatment group with daily salicylate injection for 14 days(S14), and a group examined 14 days after salicylate administration(S14+R14). Salicylate-induced tinnitus-like behavior was assessed using the pre-pulse inhibition test.Western Blot was used to examine the expression of TNF-α and GluA1 in the auditory cortex. Results(1) After salicylate injection, the rate of pre-pulse inhibition increased(P<0.05).(2) Compared to the control group, the protein expression levels of TNF-α and GluA1 increased in the S7 treatment groups(P<0.05). Compared with the control and S14+R14 groups, the protein expression levels of TNF-α and GluA1 in S14 treatment group were significantly higher(P<0.01).(3) The protein expression levels of TNF-α and GluA1 were positively correlated(P<0.001). Conclusion The change of protein expressions levels of TNF-α and GluA1 in the auditory cortex and their correlation may be suggestive of a TNF-α modulated GluA1 elevation responsible for salicylate-induced tinnitus.
Objective To investigate the central mechanisms of tinnitus in a rat model by examining expression levels of TNF-α and AMPA receptor subunit(GluA1) in the auditory cortex following salicylate exposure. Methods Twenty-four SD rats were randomly divided into a control group, a treatment group with daily salicylate injection for 7 days(S7), a treatment group with daily salicylate injection for 14 days(S14), and a group examined 14 days after salicylate administration(S14+R14). Salicylate-induced tinnitus-like behavior was assessed using the pre-pulse inhibition test.Western Blot was used to examine the expression of TNF-α and GluA1 in the auditory cortex. Results(1) After salicylate injection, the rate of pre-pulse inhibition increased(P<0.05).(2) Compared to the control group, the protein expression levels of TNF-α and GluA1 increased in the S7 treatment groups(P<0.05). Compared with the control and S14+R14 groups, the protein expression levels of TNF-α and GluA1 in S14 treatment group were significantly higher(P<0.01).(3) The protein expression levels of TNF-α and GluA1 were positively correlated(P<0.001). Conclusion The change of protein expressions levels of TNF-α and GluA1 in the auditory cortex and their correlation may be suggestive of a TNF-α modulated GluA1 elevation responsible for salicylate-induced tinnitus.
引文
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2 Rauschka H,Aboul-Enein F,Bauer J,et al.Acute cerebral white matter damage in lethal salicylate intoxication[J].Neurotoxicology,2007,28(1):33-37.
3 Alwina S,Alva E,Pia L,et al.Enhancing inhibition-induced plasticity in tinnitus--spectral energy contrasts in tailor-made notched music matter[J].Plo S one,2015,10(5):e0126494
4 Yang G,Lobarinas E,Zhang L,et al.Salicylate induced tinnitus:behavioral measures and neural activity in auditory cortex of awake rats[J].Hearing Research,2007,226(1):244-253.
5 Sun W,Lu J,Stolzberg D,et al.Salicylate increases the gain of the central auditory system[J].Neuroscience,2009,159(1):325-334.
6 Guang-Di C,Daniel S,Edward L,et al.Salicylate-induced cochlear impairments,cortical hyperactivity and re-tuning,and tinnitus[J].Hearing Research,2013,295(3):100-113.
7兰家辉,李明,张剑宁.耳鸣中枢机制的基础研究进展[J].中华耳科学杂志,2018,16(1):102-106.Lan JH,Li M,Zhang JN.Progress in Basic Research on Neuronal Mechanisms of Tinnitus[J].Chinese Journal of Otology,2018,16(1):102-106.
8 Glaser R,Kiecolt Glaser JK.Stress-induced immune dysfunction:implications for health[J].Nature Reviews Immunology,2005,5(3):243-251.
9 Cora W,Petra A,Birgit M,et al.Impact of a relaxation training on psychometric and immunologic parameters in tinnitus sufferers[J].Journal of Psychosomatic Research,2002,52(1):29-33.
10 Chen XH,Zheng LL.Expression of pro-inflammatory cytokines in the auditory cortex of rats with salicylate-induced tinnitus[J].Molecular medicine reports,2017,16(4):5643-5648.
11胡守森,梅玲,陈建勇,等.水杨酸盐毒性与大鼠耳蜗核炎症因子表达[J].中华耳科学杂志,2015,1):136-140.Hu SS,Mei L,Chen JY,et al.Effects of salicylate on imflammatory cytokines expression in cochlear nucleus in rats[J].Chinese Journal of Otology,2015,1):136-140.
12 Hwang JH,Huang DC,Lu YC,et al.Effects of Tumor Necrosis Factor Blocker on Salicylate-Induced Tinnitus in Mice[J].International Tinnitus Journal,2017,21(1):24-29.
13 Bobinska K,Galecka E,Szemraj J,et al.Is there a link between TNF gene expression and cognitive deficits in depression?[J].Acta biochimica Polonica,2017,64(1):65-73.
14 Hu SS,Mei L,Chen JY,et al.Expression of Immediate-Early Genes in the Inferior Colliculus and Auditory Cortex in Salicylate-Induced Tinnitus in Rat[J].European Journal of Histochemistry Ejh,2014,58(1):2294.
15 Niu H,Ding S,Li H,et al.Effect of Long-Term Sodium Salicylate Administration on Learning,Memory,and Neurogenesis in the Rat Hippocampus[J].Bio Med research international,2018,2018:7807426.
16 Bjornsson CS,Oh SJ,Al-Kofahi YA,et al.Effects of insertion conditions on tissue strain and vascular damage during neuroprosthetic device insertion[J].Journal of Neural Engineering,2006,3(3):196-207.
17 Park KM,Bowers WJ.Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction[J].Cellular Signalling,2010,22(7):977-983.
18 David S,Malenka RC.Synaptic scaling mediated by glial TNF-alpha[J].Nature,2006,440(7087):1054-9.
19 Kalappa BI,Anderson CT,Goldberg JM,et al.AMPA receptor inhibition by synaptically released zinc[J].Proceedings of the National Academy of Sciences of the United States of America,2015,112(51):15749-15754.
20 Beattie MS.Inflammation and apoptosis:linked therapeutic targets in spinal cord injury[J].Trends in Molecular Medicine,2004,10(12):580-583.
21 Stellwagen D,Beattie EC,Seo JY,et al.Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha[J].The Journal of neuroscience:the official journal of the Society for Neuroscience,2005,25(12):3219-3228.
22 He P,Liu Q,Wu J,et al.Genetic deletion of TNF receptor suppresses excitatory synaptic transmission via reducing AMPA receptor synaptic localization in cortical neurons[J].FASEB journal:official publication of the Federation of American Societies for Experimental Biology,2012,26(1):334-345.