Study on the effect of N-acetylserotonin on the expression of tumor necrosis factor-α in retina of rats with retinal ischemia-reperfusion injury_Chinese Journal of Ocular Fundus Diseases

Authors：

Yin Huiwen ¹ , Zhang Ning ¹ , Yin Yi ¹ , Zhang Xuening ² , Liu Jianxiao ³ , Liu Xiaoyang ² , Wang Xiaoli ² ,  Zhao Yansong ³

1. Teaching and Research Office of Ophthalmology, Weifang Medical University, Weifang 261053, China;
2. School of Medical Imaging, Weifang Medical University, Weifang 261053, China;
3. Department of Ophthalmology, The Affiliated Hospital of Weifang Medical University, Weifang 261031, China;

Corresponding author：

Zhao Yansong, Email: zhaoyansong74@163.com

Keywords：

Reperfusion injury; Tumor necrosis factor-alpha; Animal experimentation; N-acetylserotonin

DOI：

10.3760/cma.j.cn511434-20210222-00091

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Objective To dynamically observe the effect of N-acetylserotonin (NAS) on the expression of tumor necrosis factor-α (TNF-α) protein in retina of retinal ischemia reperfusion injury (RIRI) rats, and to explore the mechanism.Methods By using random number table method, 90 healthy male Sprague-Dawley rats were divided into sham operation group (n=10), RIRI group (n=40), and NAS group (n=40). The right eye was as the experimental eye. In the RIRI group and NAS group, the anterior chamber high intraocular pressure method was used to establish the RIRI model. In the NAS group, 10 mg/kg NAS was injected intraperitoneally before modeling and 30 minutes after modeling. At 6, 12, 24, 72 h after modeling, hematoxylin-eosin staining was used to observe the pathological changes of the retina, and the retinal ganglion cells (RGC) were counted. Each group was detected by immunohistochemical staining and Western blot about the relative expression of TNF-α, nuclear factor E2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) protein in the rat retina. One-way analysis of variance was used for differences between groups. The general linear regression method was used to analyze the correlation between the relative expression changes of TNF-α protein and the changes of Nrf2 and HO-1 protein expression after NAS intervention.Results Optical microscope observation revealed that the retinal edema of rats in the RIRI group was observed at 6, 12, and 24 h after modeling; the thickness of the retina in the NAS group was significantly thinner than that in the RIRI group, and the difference was statistically significant (F=9.645, 477.150, 2.432; P＜0.01). At 6, 12, 24, and 72 h after modeling, the retinal RGC counts in the NAS group were significantly higher than those in the RIRI group, and the difference was statistically significant (F=12.225, 12.848, 117.655, 306.394; P＜0.05). The results of immunohistochemical staining and Western blot showed that 6 h after modeling, the relative expression of TNF-α protein in the retina of the RIRI group increased significantly compared with that in the sham operation group, reaching a higher level at 12 h, and decreased at 24 and 72 h. But all were significantly higher than the sham operation group, the difference was statistically significant (immunohistochemical staining: F=105.893, 1 356.076, 434.026, 337.351; P＜0.01; Western blot: F=92.906, 534.948, 327.600, 385.324; P＜0.01). At different time points after modeling, the relative expression of TNF-α protein in the retina of the NAS group was significantly lower than that of the RIRI group (immunohistochemical staining: F=15.408, 570.482, 21.070, 13.767; P＜0.05; Western blot: F=12.618, 115.735, 13.176, 111.108; P＜0.05), but still higher than the sham operation group (immunohistochemical staining: F=40.709, 151.032, 156.321, 216.035; P＜0.01; Western blot: F=33.943, 79.729, 74.057, 64.488; P＜0.01), the difference was statistically significant; 12 h after modeling, Nrf2 in the retina of the NAS group (immunohistochemical staining: F=51.122, P＜0.05; Western blot: F=33.972, P＜0.05), HO-1 (immunohistochemical staining: F=30.750, P＜0.05; Western blot: F=18.283, P＜0.05) protein relative expression was significantly higher than that of RIRI group, and the differences were statistically significant. The results of linear regression analysis showed that the difference in the number of TNF-α⁺ cells in the RIRI group and the NAS group was negatively correlated with the difference in the number of Nrf2⁺ and HO-1⁺ cells (r²=0.923, 0.936; P＜0.01).Conclusions NAS can inhibit the expression of TNF-α protein in the retina of RIRI rats and reduce RIRI. The mechanism may be related to the Nrf2/HO-1 pathway.

Citation： Yin Huiwen, Zhang Ning, Yin Yi, Zhang Xuening, Liu Jianxiao, Liu Xiaoyang, Wang Xiaoli, Zhao Yansong. Study on the effect of N-acetylserotonin on the expression of tumor necrosis factor-α in retina of rats with retinal ischemia-reperfusion injury. Chinese Journal of Ocular Fundus Diseases, 2021, 37(6): 462-469. doi: 10.3760/cma.j.cn511434-20210222-00091 Copy

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3.	Liu J, Zhang N, Zhang M, et al. N-acetylserotonin alleviated the expression of interleukin-1β in retinal ischemia-reperfusion rats via the TLR4/NF-κB/NLRP3 pathway[J/OL]. Exp Eye Res, 2021, 208: 108595[2020-05-14]. https://pubmed.ncbi.nlm.nih.gov/34000276/. DOI: 10.1016/j.exer.2021.108595.
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6.	张婷婷, 赵岩松, 王海宇, 等. N-乙酰-5羟色胺(NAS)对视网膜缺血再灌注损伤(RIRI)大鼠视网膜活性Caspase-3、Bcl-2、Bax表达的影响[J]. 眼科新进展, 2017, 37(8): 701-704, 708. DOI: 10.13389/j.cnki.rao.2017.0178.Zhang TT, Zhao YS, Wang HY, et al. Effects of N-acetylserotonin on expression of active caspase-3, Bcl-2 and Bax protein in rat retina after ischemia-reperfusion injury[J]. Rec Adv Ophthalmol, 2017, 37(8): 701-704, 708. DOI: 10.13389/j.cnki.rao.2017.0178.
7.	刘建晓, 殷慧文, 陈伟, 等. 不同剂量N-乙酰-5羟色胺(NAS)对视网膜缺血-再灌注损伤大鼠视网膜细胞凋亡的影响[J]. 眼科新进展, 2019, 39(8): 728-731, 736. DOI: 10.13389/j.cnki.rao.2019.0166.Liu JX, Yin HW, Chen W, et al. The effect of melatonin on retinal apoptosis in rats with ischemia-reperfusion injury[J]. Rec Adv Ophthalmol, 2019, 39(8): 728-731, 736. DOI: 10.13389/j.cnki.rao.2019.0166.
8.	Lezoualc'h F, Sparapani M, Behl C. N-acetyl-aerotonin (normelatonin) and melatonin protect neurons against oxidative challenges and suppress the activity of the transcription factor NF-kappaB[J]. J Pineal Res, 1998, 24(3): 168-178. DOI: 10.1111/j.1600-079x.1998.tb00530.x.
9.	李光祖, 王晓莉, 李振, 等. 褪黑素对视网膜缺血再灌注损伤大鼠视网膜细胞凋亡的影响及机制探讨[J]. 中华眼底病杂志, 2018, 34(1): 55-59. DOI: 10.3760/cma.j.issn.1005-1015.2018.01.014.Li GZ, Wang XL, Li Z, et al. The effect of melatonin on retinal apoptosis in rats with ischemia-reperfusion injury[J]. Chin J Ocul Fundus Dis, 2018, 34(1): 55-59. DOI: 10.3760/cma.j.issn.1005-1015.2018.01.014.
10.	Aparicio-Soto M, Alarcón-de-la-Lastra C, Cárdeno A, et al. Melatonin modulates microsomal PGE synthase 1 and NF-E2-related factor-2-regulated antioxidatant enzyme expression in LPS-induced murine peritoneal macrophages[J]. Br J Pharmacol, 2014, 171(1): 134-144. DOI: 10.1111/bph.12428.
11.	Liu XQ, Wu BJ, Pan WH, et al. Resveratrol mitigates rat retinal ischemic injury: the roles of matrix metalloproteinase-9, inducible nitric oxide, and hemeoxygenase1[J]. J Ocul Pharmacol Ther, 2013, 29(1): 33-40. DOI: 10.1089/jop.2012.0141.
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14.	Sheng L, Lu B, Chen H, et al. Marine-steroid derivative 5α-androst-3β, 5α, 6β-triol protects retinal ganglion cells from ischemia-reperfusion injury by activating Nrf2 pathway[J/OL]. Mar Drugs, 2019, 17(5): 267[2019-05-05]. https://pubmed.ncbi.nlm.nih.gov/31060323/. DOI: 10.3390/md17050267.
15.	Deliyanti D, Alrashdi SF, Tan SM, et al. Nrf2 activation is a potential therapeutic approach to attenuate diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2018, 59(2): 815-825. DOI: 10.1167/iovs.17-22920.
16.	Yan J, Li J, Zhang L, et al. Nrf2 protects against acute lung injury and inflammation by modulating TLR4 and Akt signaling[J]. Free Radic Biol Med, 2018, 121: 78-85. DOI: 10.1016/j.freeradbiomed.2018.04.557.
17.	Yoo JM, Lee BD, Sok DE, et al. Neuroprotective action of N-acetyl serotonin in oxidative stress-induced apoptosis through the activation of both TrkB/CREB/BDNF pathway and Akt/Nrf2/Antioxidant enzyme in neuronal cells[J]. Redox Biol, 2017, 11: 592-599. DOI: 10.1016/j.redox.2016.12.034.

1. Li L, Wang Y, Qin X, et al. Echinacoside protects retinal ganglion cells from ischemia/reperfusion-induced injury in the rat retina[J]. Mol Vis, 2018, 24: 746-758.
2. Deng C, Chen S, Li X, et al. Role of the PGE2 receptor in ischemia-reperfusion injury of the rat retina[J]. Mol Vis, 2020, 26: 36-47.
3. Liu J, Zhang N, Zhang M, et al. N-acetylserotonin alleviated the expression of interleukin-1β in retinal ischemia-reperfusion rats via the TLR4/NF-κB/NLRP3 pathway[J/OL]. Exp Eye Res, 2021, 208: 108595[2020-05-14]. https://pubmed.ncbi.nlm.nih.gov/34000276/. DOI: 10.1016/j.exer.2021.108595.
4. Gray CB, Surtomi T, Xiang S, et al. CaMKIIδ subtype differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-κB and TNF-α[J]. J Mol Cell Cardiol, 2017, 103: 48-55. DOI: 10.1016/j.yjmcc.2017.01.002.
5. Chen XL, Kunsch C. Induction of cytoprotective genes through Nrf2/antioxidant response element pathway: a new therapeutic approach for the treatment of inflammatory diseases[J]. Curr Pharm Des, 2004, 10(8): 879-891. DOI: 10.2174/1381612043452901.
6. 张婷婷, 赵岩松, 王海宇, 等. N-乙酰-5羟色胺(NAS)对视网膜缺血再灌注损伤(RIRI)大鼠视网膜活性Caspase-3、Bcl-2、Bax表达的影响[J]. 眼科新进展, 2017, 37(8): 701-704, 708. DOI: 10.13389/j.cnki.rao.2017.0178.Zhang TT, Zhao YS, Wang HY, et al. Effects of N-acetylserotonin on expression of active caspase-3, Bcl-2 and Bax protein in rat retina after ischemia-reperfusion injury[J]. Rec Adv Ophthalmol, 2017, 37(8): 701-704, 708. DOI: 10.13389/j.cnki.rao.2017.0178.
7. 刘建晓, 殷慧文, 陈伟, 等. 不同剂量N-乙酰-5羟色胺(NAS)对视网膜缺血-再灌注损伤大鼠视网膜细胞凋亡的影响[J]. 眼科新进展, 2019, 39(8): 728-731, 736. DOI: 10.13389/j.cnki.rao.2019.0166.Liu JX, Yin HW, Chen W, et al. The effect of melatonin on retinal apoptosis in rats with ischemia-reperfusion injury[J]. Rec Adv Ophthalmol, 2019, 39(8): 728-731, 736. DOI: 10.13389/j.cnki.rao.2019.0166.
8. Lezoualc'h F, Sparapani M, Behl C. N-acetyl-aerotonin (normelatonin) and melatonin protect neurons against oxidative challenges and suppress the activity of the transcription factor NF-kappaB[J]. J Pineal Res, 1998, 24(3): 168-178. DOI: 10.1111/j.1600-079x.1998.tb00530.x.
9. 李光祖, 王晓莉, 李振, 等. 褪黑素对视网膜缺血再灌注损伤大鼠视网膜细胞凋亡的影响及机制探讨[J]. 中华眼底病杂志, 2018, 34(1): 55-59. DOI: 10.3760/cma.j.issn.1005-1015.2018.01.014.Li GZ, Wang XL, Li Z, et al. The effect of melatonin on retinal apoptosis in rats with ischemia-reperfusion injury[J]. Chin J Ocul Fundus Dis, 2018, 34(1): 55-59. DOI: 10.3760/cma.j.issn.1005-1015.2018.01.014.
10. Aparicio-Soto M, Alarcón-de-la-Lastra C, Cárdeno A, et al. Melatonin modulates microsomal PGE synthase 1 and NF-E2-related factor-2-regulated antioxidatant enzyme expression in LPS-induced murine peritoneal macrophages[J]. Br J Pharmacol, 2014, 171(1): 134-144. DOI: 10.1111/bph.12428.
11. Liu XQ, Wu BJ, Pan WH, et al. Resveratrol mitigates rat retinal ischemic injury: the roles of matrix metalloproteinase-9, inducible nitric oxide, and hemeoxygenase1[J]. J Ocul Pharmacol Ther, 2013, 29(1): 33-40. DOI: 10.1089/jop.2012.0141.
12. Zelová H, Hošek J. TNF-α signalling and inflammation: interactions between old acquaintances[J]. Inflamm Res, 2013, 62(7): 641-651. DOI: 10.1007/s00011-013-0633-0.
13. Berger S, Savitz SI, Nijhawan S, et al. Deleterious role of TNF-alpha in retinal ischemia-reperfusion injury[J]. Invest Ophthalmol Vis Sci, 2008, 49(8): 3605-3610. DOI: 10.1167/iovs.07-0817.
14. Sheng L, Lu B, Chen H, et al. Marine-steroid derivative 5α-androst-3β, 5α, 6β-triol protects retinal ganglion cells from ischemia-reperfusion injury by activating Nrf2 pathway[J/OL]. Mar Drugs, 2019, 17(5): 267[2019-05-05]. https://pubmed.ncbi.nlm.nih.gov/31060323/. DOI: 10.3390/md17050267.
15. Deliyanti D, Alrashdi SF, Tan SM, et al. Nrf2 activation is a potential therapeutic approach to attenuate diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2018, 59(2): 815-825. DOI: 10.1167/iovs.17-22920.
16. Yan J, Li J, Zhang L, et al. Nrf2 protects against acute lung injury and inflammation by modulating TLR4 and Akt signaling[J]. Free Radic Biol Med, 2018, 121: 78-85. DOI: 10.1016/j.freeradbiomed.2018.04.557.
17. Yoo JM, Lee BD, Sok DE, et al. Neuroprotective action of N-acetyl serotonin in oxidative stress-induced apoptosis through the activation of both TrkB/CREB/BDNF pathway and Akt/Nrf2/Antioxidant enzyme in neuronal cells[J]. Redox Biol, 2017, 11: 592-599. DOI: 10.1016/j.redox.2016.12.034.

Chinese Journal of Ocular Fundus Diseases

Study on the effect of N-acetylserotonin on the expression of tumor necrosis factor-α in retina of rats with retinal ischemia-reperfusion injury

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