The effect of melatonin on retinal apoptosis in rats with ischemia-reperfusion injury_Chinese Journal of Ocular Fundus Diseases

Authors：

Li Guangzu , Wang Xiaoli , Li Zhen , Zhang Tingting , Liu Ping , Zhang Shuai ,  Zhao Yansong

Department of Medical Imaging, Weifang Medical University, Weifang 261053, China (Li Guangzu, Wang Xiaoli, Li Zhen, Liu Ping, Zhang Shuai); Department of Ophthalmology, Affiliated Hospital of Weifang Medical University, Weifang 261031, China (Zhang Tingting, Zhao Yansong);

Corresponding author：

Zhao Yansong, Email: zhaoyansong74@163.com

Keywords：

Reperfusion injury/drug therapy; Melatonin/therapeutic use; NF-E2-related factor 2; Heme oxygenase-1; Animal experimentation; Active caspase 3

DOI：

10.3760/cma.j.issn.1005-1015.2018.01.014

Video：

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Objective To observe the effect of melatonin (MT) on retinal apoptosis in rats with ischemia-reperfusion injury (RIRI). Methods A total of 54 male healthy Sprague-Dawley adult rats were randomly divided into the normal control (CON) group (6 rats), RIRI group (24 rats) and MT group (24 rats). The rats of RIRI and MT group were induced using suture-occluded methods to establish RIRI model. The rats of MT group were injected with MT in the left carotid artery 30 minutes after RIRI, and RIRI group was injected with the same amount of saline. On 6, 24 hours and 3, 7 days after RIRI, the morphological changes of retina were evaluated by hematoxylin and eosin (HE) staining; the effects of MT on retinal cell apoptosis and Nrf2, HO-1 proteins were examined by immunohistochemistry staining. The correlation between active Caspase-3 and Nrf2 protein, active Caspase-3 and HO-1 protein in MT group were analyzed by linear regression analysis. Results HE staining results showed that the morphology of retinal cells was regular and retinal cells were well arranged in the CON and MT group. In the RIRI group, both the thickness of inner retinal layer and the number of retinal ganglion cells (RGC) were decreased. On 6, 24 hours and 3, 7 days after RIRI, the thickness of inner retinal layer (F=16.710, 62.303, 68.389, 57.132; P＜0.01) and RGC number (F=24.250, 11.624, 14.155, 32.442; P＜0.05) in MT group were more than those in RIRI group. Immunohistochemistry staining results showed that less active Caspase-3⁺ cells were observed in MT group as compared with those in RIRI group at each time points (F=49.118, 134.173, 76.225, 18.385; P＜0.01). There were more Nrf2⁺ (F=11.041, 31.480, 59.246, 6.740; P＜0.05) and HO-1⁺ cells (F=128.993, 21.606, 51.349, 8.244; P＜0.05) in MT group as compared with those in RIRI group at each time points. Linear regression analysis results showed that the difference of active Caspase-3⁺ cells were all linearly correlated with the Nrf2⁺ cells and HO-1⁺cells in the MT group (r²=0.810, 0.730; P＜0.01). Conclusion MT could reduce retinal cell apoptosis in RIRI rats, and its mechanism may be associated with increased Nrf2 and HO-1 expression, reduced active Caspase-3 expression.

Citation： Li Guangzu, Wang Xiaoli, Li Zhen, Zhang Tingting, Liu Ping, Zhang Shuai, Zhao Yansong. The effect of melatonin on retinal apoptosis in rats with ischemia-reperfusion injury. Chinese Journal of Ocular Fundus Diseases, 2018, 34(1): 55-59. doi: 10.3760/cma.j.issn.1005-1015.2018.01.014 Copy

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7.	Jr SE, Guo Q, Namura S. Filamentous middle cerebral artery occlusion causes ischemic damage to the retina in mice[J]. Stroke, 2008, 39(7): 2099-2104. DOI: 10.1161/STROKEAHA.107.504357.
8.	Longa EZ, Weinstein PR, Carlson S, et al. Reversible middle cerebral artery occlusion without craniectomy in rats[J]. Stroke, 1989, 20(1): 84-91.
9.	蔡立珍, 闫少珍, 王晓莉, 等. MRI-DWI评估褪黑素对脑缺血再灌注损伤保护作用的实验研究[J]. 临床放射学杂志, 2015, 34(12): 1999-2003. DOI: 10.13437/j.cnki.jcr.2015.12.037.Cai LZ, Yan SZ, Wang XL. et al. Investigation of melatonin in acute cerebral ischemia-reperfusion rat using MRI-DW[J]. J Clin Radiol, 2015, 34(12): 1999-2003. DOI: 10.13437/j.cnki.jcr.2015.12.037.
10.	Seong H, Ryu J, Yoo WS, et al. Resveratrol ameliorates retinal ischemia/reperfusion injury in C57BL/6J mice via downregulation of Caspase-3.[J].Curr Eye Res. 2017, 10(6): 1-9. DOI: 10.1080/02713683.2017.1344713.
11.	赵岩松, 赵堪兴, 王晓莉, 等. 低氧预适应对缺血再灌注损伤大鼠视网膜促红细胞生成素及活性Caspase-3蛋白表达的影响[J]. 眼科新进展, 2013, 33(1): 5-8. DOI: 10.13389/j.cnki.rao.2013.01.003.Zhao YS, Zhao KX, Wang XL, et al. Effects of hypoxia preconditioning on expression of EPO and active Caspase-3 protein in retina after ischemia reperfusion injury[J]. Rec Adv Ophthal, 2013, 33(1): 5-8. DOI: 10.13389/j.cnki.rao.2013.01.003.
12.	Cho H, Hartsock MJ, Xu Z, et al. Monomethyl fumarate promotes Nrf2-dependent neuroprotection in retinal ischemia-reperfusion[J]. J Neuroinflammation, 2015, 12(1): 239. DOI: 10.1186/s12974-015-0452-z.
13.	Santofimia-Castaño P, Clea Ruy D, Garcia-Sanchez L, et al. Melatonin induces the expressionof Nrf2-regulated antioxidant enzymes via PKC and Ca2+ influx activation in mouse pancreatic acinar cells[J]Free Radic Biol Med, 2015, 87:226-236. DOI: 10.1016/j.freeradbiomed.2015.06.033.

1. Yue Z, Wei Z, Liu W, et al. Melatonin protects against arsenic trioxide-induced liver injury by the upregulation of Nrf2 expression through the activation of PI3K/AKT pathway[J]. Oncotarget, 2017, 8(3): 3773-3780. DOI: 10.18632/oncotarget.13931.
2. 王海宇, 陈岚芬, 王晓莉, 等. 褪黑素对局灶性脑缺血大鼠扩散加权成像及脑组织中Fas、FasL、活性Caspase-3蛋白表达的影响[J]. 中国医学影像技术, 2017, 33(9): 1309-1314. DOI: 10.13929/j.1003-3289.201701073.Wang HY, Chen LF, Wang XL, et al. Effects of melatonin on diffusion weighted imaging and expression of Fas, FasL, cleaved Caspase-3 proteins in rats of focal cerebral ischemia[J]. Chin J Med Imaging Technol, 2017, 33(9): 1309-1314. DOI: 10.13929/j.1003-3289.201701073.
3. Park SW, Lee HS, Sung MS, et al. The effect of melatonin on retinal ganglion cell survivalin ischemic retina[J]. Chonnam Med J, 2012, 48(2): 116-122. DOI: 10.4068/cmj.2012.48.2.116.
4. 胡流芳, 王迎, 任汝静, 等. Keap1-Nrf2/ARE信号通路的抗氧化应激作用及其调控机制[J]. 国际药学研究杂志, 2016, 43(1): 146-152, 166. DOI: 10.13220/j.cnki.jipr.2016.01.022.Hu LF, Wang Y, Ren RJ, et al. Anti-oxidative stress actions and regulation mechanisms of Keap1-Nrf2/ARE signal pathway[J]. J Int Pharm Res, 2016, 43(1): 146-152, 166. DOI: 10.13220/j.cnki.jipr.2016.01.022.
5. Meng QT, Chen C, Yang W, et al. Ischemic post-conditioning attenuates acute lung injury induced by intestinal ischemia-reperfusion in mice: role of Nrf2[J]. Lab Invest, 2016, 96(10): 1087-1104. DOI: 10.1038/labinvest.2016.87.
6. Zhou L, Zhao D, An H, et al. Melatonin prevents lung injury induced by hepatic ischemia-reperfusion through anti-inflammatory and anti-apoptosis effects[J]. Int Immunopharmacol, 2015, 29(2): 462-467. DOI: 10.1016/j.intimp.2015.10.012.
7. Jr SE, Guo Q, Namura S. Filamentous middle cerebral artery occlusion causes ischemic damage to the retina in mice[J]. Stroke, 2008, 39(7): 2099-2104. DOI: 10.1161/STROKEAHA.107.504357.
8. Longa EZ, Weinstein PR, Carlson S, et al. Reversible middle cerebral artery occlusion without craniectomy in rats[J]. Stroke, 1989, 20(1): 84-91.
9. 蔡立珍, 闫少珍, 王晓莉, 等. MRI-DWI评估褪黑素对脑缺血再灌注损伤保护作用的实验研究[J]. 临床放射学杂志, 2015, 34(12): 1999-2003. DOI: 10.13437/j.cnki.jcr.2015.12.037.Cai LZ, Yan SZ, Wang XL. et al. Investigation of melatonin in acute cerebral ischemia-reperfusion rat using MRI-DW[J]. J Clin Radiol, 2015, 34(12): 1999-2003. DOI: 10.13437/j.cnki.jcr.2015.12.037.
10. Seong H, Ryu J, Yoo WS, et al. Resveratrol ameliorates retinal ischemia/reperfusion injury in C57BL/6J mice via downregulation of Caspase-3.[J].Curr Eye Res. 2017, 10(6): 1-9. DOI: 10.1080/02713683.2017.1344713.
11. 赵岩松, 赵堪兴, 王晓莉, 等. 低氧预适应对缺血再灌注损伤大鼠视网膜促红细胞生成素及活性Caspase-3蛋白表达的影响[J]. 眼科新进展, 2013, 33(1): 5-8. DOI: 10.13389/j.cnki.rao.2013.01.003.Zhao YS, Zhao KX, Wang XL, et al. Effects of hypoxia preconditioning on expression of EPO and active Caspase-3 protein in retina after ischemia reperfusion injury[J]. Rec Adv Ophthal, 2013, 33(1): 5-8. DOI: 10.13389/j.cnki.rao.2013.01.003.
12. Cho H, Hartsock MJ, Xu Z, et al. Monomethyl fumarate promotes Nrf2-dependent neuroprotection in retinal ischemia-reperfusion[J]. J Neuroinflammation, 2015, 12(1): 239. DOI: 10.1186/s12974-015-0452-z.
13. Santofimia-Castaño P, Clea Ruy D, Garcia-Sanchez L, et al. Melatonin induces the expressionof Nrf2-regulated antioxidant enzymes via PKC and Ca2+ influx activation in mouse pancreatic acinar cells[J]Free Radic Biol Med, 2015, 87:226-236. DOI: 10.1016/j.freeradbiomed.2015.06.033.

Chinese Journal of Ocular Fundus Diseases

The effect of melatonin on retinal apoptosis in rats with ischemia-reperfusion injury

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