Effects of chrysophanol on the expressions of p-CREB, BDNF and p-STAT3 in the brain of focal cerebral ischemia/reperfusion mice

doi:10.3969/j.issn.1006-7795.2018.03.010

Abstract

Abstract: Objective To explore the effects of chrysophanol (CHR) on the levels of phosphorylated cyclic adenine monophosphate (AMP) response element binding protein (p-CREB), brain derived neurotrophic factor (BDNF), and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in middle cerebral artery occlusion (MCAO)/reperfusion mice and to investigate the protective efficacy of CHR and the relative mechanism.Methods Totally 18 male C57BL mice were randomly divided into three groups:Sham group (n=6), MCAO group (n=6), and CHR group (CHR was intraperitoneally injected at a dose of 0.1 mg/kg for 14 days after reperfusion, n=6). MCAO was made by using the suture method. The mice were reperfused after right MCAO for 45 minutes. The mice were sacrificed and rapidly decapitated and the brains were separated on 14 d after reperfusion. Immunofluorescent staining was used to detect the levels of p-CREB and BDNF. And double immunofluorescence labeling was used to explore the cellular location of p-CREB and BDNF. Western blotting analysis was used to investigate the level of p-STAT3.Results 1) Many p-CREB positive cells were observed in Sham group. In the penumbra of MCAO group, the expression of p-CREB decreased significantly compared with Sham group (P<0.05). Compared with MCAO group, the expression of p-CREB increased significantly in penumbra zone of cerebral ischemia/reperfusion mice treated with CHR on 14 d after reperfusion (P<0.05). The p-CREB-positive cells were co-localized with general neuronal marker, NeuN, in the penumbra of ischemia/reperfusion mice. 2) A large number of BDNF-positive cells were observed in Sham group. The level of BDNF decreased significantly in the penumbra of MCAO group compared with Sham group (P<0.05). Compared with MCAO group, the expression of BDNF increased significantly in penumbra zone of cerebral ischemia/reperfusion mice treated with CHR 14 d after reperfusion (P<0.05). And BDNF-positive cells were co-localized with NeuN in the penumbra of ischemia/reperfusion mice. 3) The level of p-STAT3 increased significantly in ischemic brain tissue of MCAO group compared with Sham group (P<0.05). Compared with MCAO group, the level of p-STAT3 decreased significantly in ischemic brain tissue of cerebral ischemia/reperfusion mice treated with CHR 14 d after reperfusion (P<0.05).Conclusion CHR may provide long-term neuroprotective effect against cerebral ischemia/reperfusion injury by up-regulating the expressions of p-CREB and BDNF, and inhibiting p-STAT3 protein expression.

Key words: chrysophanol, cerebral ischemia/reperfusion, middle cerebral artery occlusion, phosphorylated cyclic AMP response element binding protein, brain derived neurotrophic factor, phosphorylated signal transducer and activator of transcription 3

CLC Number:

R743.3

Fang Yalan, Huang Yuyou, Zhao Yongmei, Li Jincheng, Duan Yunxia, Gao Li, Luo Yumin. Effects of chrysophanol on the expressions of p-CREB, BDNF and p-STAT3 in the brain of focal cerebral ischemia/reperfusion mice[J]. Journal of Capital Medical University, 2018, 39(3): 360-365.

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URL: https://journal03.magtech.org.cn/Jweb_sdykdxxb/EN/10.3969/j.issn.1006-7795.2018.03.010

https://journal03.magtech.org.cn/Jweb_sdykdxxb/EN/Y2018/V39/I3/360

References

[1] Lin Y, Li Z, Liu C, et al. Towards precision medicine in ischemic stroke and transient ischemic attack[J]. Front Biosci (Landmark Ed), 2018, 23:1338-1359.
[2] Zhao Y, Fang Y, Li J, et al. Neuroprotective effects of chrysophanol against inflammation in middle cerebral artery occlusion mice[J]. Neurosci Lett, 2016, 630:16-22.
[3] Zhao Y, Fang Y, Zhao H, et al. Chrysophanol inhibits endoplasmic reticulum stress in cerebral ischemia and reperfusion mice[J]. Eur J Pharmacol, 2018, 818:1-9.
[4] 房亚兰, 黄语悠, 赵咏梅, 等. 大黄酚对局灶性脑缺血再灌注小鼠缺血半暗带区环氧化酶2和基质金属蛋白酶-9表达的影响[J]. 首都医科大学学报, 2017, 38(1):47-52.
[5] Shichinohe H, Tan C, Abumiya T, et al. Neuroprotective effects of cilostazol are mediated by multiple mechanisms in a mouse model of permanent focal ischemia[J]. Brain Res, 2015, 1602:53-61.
[6] 鲁杨, 张鸿, 马英. CREB与脑缺血神经元损伤[J]. 解剖科学进展, 2010, 16(4):374-376.
[7] Miyamoto N, Tanaka R, Shimosawa T, et al. Protein kinase A-dependent suppression of reactive oxygen species in transient focal ischemia in adrenomedullin-deficient mice[J]. J Cereb Blood Flow Metab, 2009, 29(11):1769-1779.
[8] Dancause N, Nudo R J. Shaping plasticity to enhance recovery after injury[J]. Prog Brain Res, 2011, 192:273-295.
[9] Zou S, Zhang M, Feng L, et al. Protective effects of notoginsenoside R1 on cerebral ischemia-reperfusion injury in rats[J]. Exp Ther Med, 2017, 14(6):6012-6016.
[10] Qin L, Jing D, Parauda S, et al. An adaptive role for BDNF Val66Met polymorphism in motor recovery in chronic stroke[J]. J Neurosci, 2014, 34(7):2493-2502.
[11] Tang Q P, Shen Q, Wu L X, et al. STAT3 signal that mediates the neural plasticity is involved in willed-movement training in focal ischemic rats[J]. J Zhejiang Univ Sci B, 2016, 17(7):493-502.
[12] Hu G Q, Du X, Li Y J, et al. Inhibition of cerebral ischemia/reperfusion injury-induced apoptosis:nicotiflorin and JAK2/STAT3 pathway[J]. Neural Regen Res, 2017, 12(1):96-102.
[13] 陈媛, 吴海金, 黄晓松, 等. 葛根素对脑缺血再灌注大鼠海马组织P-STAT3、P53表达的影响[J]. 湖南中医药大学学报, 2018, 38(1):36-39.
[14] Dong W, Qi Z, Liang J, et al. Reduction of zinc accumulation in mitochondria contributes to decreased cerebral ischemic injury by normobaric hyperoxia treatment in an experimental stroke model[J]. Exp Neurol, 2015, 272:181-189.
[15] Lee J H, Park S Y, Lee W S, et al. Lack of antiapoptotic effects of antiplatelet drug, aspirin and clopidogrel, and antioxidant, MCI-186, against focal ischemic brain damage in rats[J]. Neurol Res, 2005, 27(5):483-492.
[16] Chen A, Xiong L J, Tong Y, et al. The neuroprotective roles of BDNF in hypoxic ischemic brain injury[J]. Biomed Rep, 2013, 1(2):167-176.
[17] Cortes-Mendoza J, Diaz de Leon-Guerrero S, Pedraza-Alva G, et al. Shaping synaptic plasticity:the role of activity-mediated epigenetic regulation on gene transcription[J]. Int J Dev Neurosci, 2013, 31(6):359-369.
[18] Liu B, Li L L, Tan X D, et al. Gadd45b mediates axonal plasticity and subsequent functional recovery after experimental stroke in rats[J]. Mol Neurobiol, 2015, 52(3):1245-1256.
[19] Mohamed R A, Agha A M, Abdel-Rahman A A, et al. Role of adenosine A2A receptor in cerebral ischemia reperfusion injury:signaling to phosphorylated extracellular signal-regulated protein kinase (pERK1/2)[J]. Neuroscience, 2016, 314:145-159.
[20] Jiang Y, Wei N, Lu T, et al. Intranasal brain-derived neurotrophic factor protects brain from ischemic insult via modulating local inflammation in rats[J]. Neuroscience, 2011, 172:398-405.
[21] Satriotomo I, Bowen K K, Vemuganti R. JAK2 and STAT3 activation contributes to neuronal damage following transient focal cerebral ischemia[J]. J Neurochem, 2006, 98(5):1353-1368.
[22] Cheng X, Zhao H, Yan F, et al. Limb remote ischemic post-conditioning mitigates brain recovery in a mouse model of ischemic stroke by regulating reactive astrocytic plasticity[J]. Brain Res, 2018, 1686:94-100.