Hydrogen-rich saline ameliorates hippocampal neuron apoptosis through up-regulating the expression of cystathionine β-synthase (CBS) after cerebral ischemia- reperfusion in rats

Document Type: Original Article

Authors

1 Department of Rehabilitation Medicine, Weihai Central Hospital, Wendeng 264400, China

2 Department of Emergency, Ji Nan Zhang Qiu District Hospital of Traditional Chinese Medicine, Zhang Qiu 250200, China

3 Department of Neurosurgery, Ji Nan Zhang Qiu District Hospital of Traditional Chinese Medicine, Zhang Qiu 250200, China

4 Department of Neurology, Ji Nan Zhang Qiu District Hospital of TraditionalChinese Medicine, Zhang Qiu 250200, China

5 Department of Critical Care Medicine, Yu Huang Ding Hospital, Qingdao University, Yantai, P. R. China

6 Department of Histology and Embryology, Binzhou Medical University, Yantai, P. R. China

Abstract

Objective(s): This study aimed to evaluate the potential role of hydrogen in rats after cerebral ischemic/reperfusion (I/R) injury.
Materials and Methods: The experimental samples were composed of sham group, model group of rats that received middle cerebral artery occlusion (MCAO) for 2 hr followed by reperfusion for 24 hr, and the hydrogen saline group treated by hydro‌gen-rich saline (1 ml/kg) after MCAO. Hydrogen sulfide (H2S), S100-βprotein (S100-β), and neuron-specific enolase (NSE) levels were measured; the levels of malondialdehyde (MDA), reactive oxygen species (ROS), and superoxide dismutase (SOD) were detected; the histologic structure and apoptotic cells of hippocampus were observed; the expressions of cystathionine β-synthase (CBS), nuclear factor erythroid 2-related factor 2 (Nrf2), and hemeoxygenase-1 (HO-1) were measured. Statistical analyses were performed using one-way analysis of variance (ANOVA) followed by Fisher’s least significant difference (LSD) test.
Results: Our results showed that hydrogen up-regulated H2S levels via promoting the expression of CBS in the hippocampus, and its treatment alleviated oxidative stress via activating the expression of Nrf2 and HO-1, and then cell apoptosis reduced, furthermore, brain function improved by down-regulating the levels of S100-βand NSE.
Conclusion: This study showed that hydrogen-rich saline ameliorates cell injury through up-regulating the expression of CBS in the hippocampus after cerebral ischemia reperfusion (I/R) in rats, this provides new experimental evidence for the treatment of stroke with hydrogen saline.

Keywords


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37. Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 2009; 284:13291-13295.   
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39. Ding Y, Chen M, Wang M, Wang M, Zhang T, Park J, et al. Neuroprotection by acetyl-11-keto-β-Boswellic acid, in ischemic brain injury involves the Nrf2/HO-1 defense pathway. Sci Rep 2014; 4:7002.
40. Alfieri A, Srivastava S, Siow RCM, Cash D, Modo M, Duchen MR, et al. Sulforaphane preconditioning of the Nrf2/HO-1 defense pathway protects the cerebral vasculature against blood-brain barrier disruption and neurologicaldeficits in stroke. Free Radic Biol Med 2013; 65:1012-1022.
41. He M, Pan H, Chang RC, So KF, Brecha NC, Pu M. the Nrf2/HO-1 activation of antioxidant pathway contributes to the protective of Lycium effects barbarum polysaccharides in the rodent retina after ischemia-reperfusion-induced damage. PLoS One 2014; 9: e84800


Reperfusion and neurovascular dysfunction in stroke:from basic mechanisms to potential strategies for neuroprotection. Mol Neurobiol 2010; 41:172-179.
9. Gürsoy-Ozdemir Y, Can A, Dalkara T. Reperfusion-induced oxidative/nitrative injury to neurovascular unit afterfocal cerebral ischemia. Stroke 2004; 35(6):1449-53.
10. Awooda HA , Lutfi MF , Sharara G GM , Saeed AM. Oxidative/nitrosative stress in rats subjected to focal cerebral ischemia/reperfusion. Int J Health Sci (Qassim) 2015; 9:17-24.
11. Simonyi A , Wang Q, Miller RL, Yusof M, Shelat PB, Sun AY, et al. Polyphenols in cerebral ischemia: novel targets for neuroprotection. Mol Neurobiol 2005; 31:135-47.
12. Kimura H. The physiological role of hydrogen sulfide and beyond. Nitric Oxide 2014; 41:4-10.
13. Kimura H, Shibuya N, Kimura Y. Hydrogen sulfide is a signaling molecule and a cytoprotectant. Antioxid Redox Signal 2012; 17:45-57.
14.Qu K, Lee SW,  Bian JS,  Low CM, Wong PT. Hydrogen sulfide: neurochemistry and neurobiology. Neurochem Int 2008; 52:155-165.
15. Kimura H, Shibuya N, Kimura Y. Hydrogen sulfide is a signaling molecule and a cytoprotectant. Antioxid Redox Signal 2012; 17:45-57.
16. Szabó C. Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov 2007; 6: 917-935.
17. Zhang X, Bian JS. Hydrogen sulfide: a neuromodulator and neuroprotectant in the central nervous system. ACS Chem Neurosci 2014; 5:876-883.
18. BJURSTEDT H, SEVERING. The prevention of decompression sickness and nitrogen narcosis by the use of hydrogen as a substitute for nitrogen, Mil Surg 1948; 103:107-116.
19. Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med 2007; 13:688-694.
20. Zhang L, Wang X, Tian X, Zhao W, Liu T, Feng G, et al. Hydrogen has a neuroprotective effect via activation of Nrf-2/HO-1 pathway in ischemia reperfusion rat. Int J Clin Exp Med 2016; 9:10521-10528
21. Wang X, Zhang L, Zhao W, Liu T. The protective effects of hydrogen on HO-1 expression in the brain after focal cerebral ischemia reperfusion in rats. Turk J Med Sci 2016; 46:1534-1539.
22. DU Z, Jia H, Liu J, Zhao X, Wang Y, Sun X. Protective effects of hydrogen-rich saline in uncontrolled hemorrhagic shock. Exp Ther Med 2014; 7:1253-1258.
23. Li L, Bhatia M, Zhu YZ, Zhu YC, Ramnath RD, Wang ZJ, et al. Hydrogen sulfide is a novel mediator of lipopolysaccharide-induced inflammation in the mouse. FASEB J 2005; 19:1196-1198.
24.Łowicka E, Bełtowski J. Hydrogen sulfide (H2S)-the third gas of interest for for pharmacologists. Pharmacol Rep 2007; 59:4-24.
25. Wang R. Hydrogen sulfide: the third gasotransmitter in biology and medicine. Antioxid Redox Signal 2010; 12:1061-1064.
26.Wang R. Two’s company, three’s a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J 2002; 16:1792-1798.
27.Ren C, Du A, Li D, Sui J, Mayhan WG, Zhao H. Dynamic change of hydrogen sulfide during global cerebral ischemia-reperfusion and its effect in rats. Brain Res 2010; 1345:197-205.
28. Kimura Y, Kimura H. Hydrogen sulfide protects neurons from oxidative stress. FASEB J 2004; 18:1165-1167.
29. Bian JS, Yong QC, Pan TT, Feng ZN, Ali MY, Zhou S, et al. Role of hydrogen sulfide in the cardioprotection caused by ischemic preconditioning in the rat heart and cardiac myocytes. J Pharmacol Exp Ther 2006; 316:670-678.
30. Luo Y, Liu X, Zheng Q, Wan X, Ouyang S, Yin Y, et al. an H2O2-activated calcium signaling pathway in mouse hippocampal neurons. Biochem Biophys Res Commun 2012; 425:473-477.
31. Jha S, Calvert JW, Duranski MR, Ramachandran A, Lefer DJ. Hydrogen sulfide attenuates hepatic ischemia-reperfusion injury: role of antioxidant and antiapoptotic signaling. Am J Physiol Heart Circ Physiol 2008; 295:H801-806.
32. Shirley R, Ord EN , Work LM . Oxidative Stress and the Use of Antioxidants in Stroke. Antioxidants (Basel) 2014; 3:472-501.
33. Davis SM, Pennypacker KR. Targeting antioxidant enzyme expression as a therapeutic strategy for ischemic stroke. Neurochem Int 2017; 107:23-32.
34.Gheibi S, Aboutaleb N, Khaksari M, Kalalian-Moghaddam H, Vakili A, Asadi Y, et al. Hydrogen sulfide protects the brain against ischemic reperfusion injury in a transient model of focal cerebral ischemia. J Mol Neurosci 2014; 54:264-270.
35. Yin J, Tu C, Zhao J, Ou D, Chen G, Liu Y, Xiao X.  Exogenous hydrogen sulfide protects against global cerebralischemia/reperfusion injury via its anti-oxidative, anti-inflammatory and anti-apoptotic effects in rats. Brain Res 2013; 1491:188-196.
36. Jiang LH , Luo X, He Wa, Huang XX, Cheng TT. Effects of exogenous hydrogen sulfide on apoptosis proteins and oxidative stress in the hippocampus of rats rats undergoing heroin withdrawal. Arch Pharm Res 2011; 34(12):2155-2162.
37. Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 2009; 284:13291-13295.   
38. Keum YS, Choi BY. Molecular and chemical regulation of the Keap1-Nrf2 signaling pathway. Molecules 2014; 19:10074-10089.
39. Ding Y, Chen M, Wang M, Wang M, Zhang T, Park J, et al. Neuroprotection by acetyl-11-keto-β-Boswellic acid, in ischemic brain injury involves the Nrf2/HO-1  defense pathway. Sci Rep 2014; 4:7002.
40. Alfieri A, Srivastava S, Siow RCM, Cash D, Modo M, Duchen MR, et al. Sulforaphane preconditioning of the Nrf2/HO-1 defense pathway protects the cerebral vasculature against blood-brain barrier disruption and neurologicaldeficits in stroke. Free Radic Biol Med 2013; 65:1012-1022.
41. He M, Pan H, Chang RC, So KF, Brecha NC, Pu M. the Nrf2/HO-1 activation of antioxidant pathway contributes to the protective of Lycium effects barbarum polysaccharides in the rodent retina after ischemia-reperfusion-induced damage. PLoS One 2014; 9: e84800