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Current Neurovascular Research


ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

Research Article

Sodium Hydrosulfide Post-conditioning Protects Hippocampal CA1 Neurons from Neuronal Cell Injury in the Rat Model of Transient Global Cerebral Ischemia Through Activation of Extracellular-regulated Kinases Signaling

Author(s): ChengPing Bai* and ChenLiang Zhao

Volume 16, Issue 2, 2019

Page: [156 - 165] Pages: 10

DOI: 10.2174/1567202616666190618114250

Price: $65


Introduction: The effect of hydrogen sulfide (H2S) on global cerebral ischemia remains partially understood. This study aimed to investigate the neuroprotective effect of sodium hydrosulfide (NaHS, a donor of H2S) post-conditioning and its underlying mechanism in a transient global cerebral ischemia (tGCI) model.

Materials & Methods: The tGCI rat model was established by the four-vessel occlusion method. Wistar rats were randomly assigned into 6 groups: sham, tGCI, tGCI +NaHS, tGCI+vehicle, tGCI+U0126 and tGCI+U0126+NaHS groups. Neurons survival was assessed by Nissl staining and NeuN immunostaining. Levels of extracellular extracellular-regulated kinases (ERK)1/2 and p-ERK1/2 were determined by western blot and immunohistochemistry (IHC). Intraperitoneal injection of NaHS (24 µmol/kg) at 24 h post-tGCI attenuated tGCI-induced decrease of the survival and NeuN-positive neurons in the hippocampal CA1 subregion.

Results: Compared to the sham group, tGCI significantly up-regulated p-ERK1/2 protein at 26 and 48 h post-tGCI. NaHS post-conditioning further enhanced the phosphorylation of ERK1/2 at 26, 48 and 168 h post-tGCI. Nevertheless, U0126 (an inhibitor of MEK1/2) pre-treatment reduced the p-ERK1/2 level in both the tGCI+ U0126 group and the tGCI+ U0126+ NaHS group. IHC staining revealed that p-ERK1/2-positive cell could be observed in several hippocampal subregions of the rats receiving NaHS post-conditioning. Immunofluorescence staining showed that some neurons were double-stained with p-ERK1/2 and NeuN. Furthermore, U0126 pre-treatment significantly attenuated the protective effect of NaHS post-conditioning on the neurons survival and NeuNpositive neurons in CA1 subregion.

Conclusion: These results suggested that NaHS post-conditioning can protect hippocampal CA1 neurons from tGCI-induced injury, at least partially, through activation of ERK1/2 signaling.

Keywords: Hydrogen sulfide, neuroprotection, transient global cerebral ischemia (tGCI), ischemic stroke, extracellular signalregulated kinases 1 and 2 (ERK1/2).

Lee JM, Grabb MC, Zipfel GJ, Choi DW. Brain tissue responses to ischemia. J Clin Invest 2000; 106(6): 723-31. []. [PMID: 10995780].
Benjamin EJ, Virani SS, Callaway CW, et al. Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation 2018; 137(12): e67-e492. []. [PMID: 29386200].
Wu X, Zhu B, Fu L, et al. Prevalence, incidence, and mortality of stroke in the chinese island populations: A systematic review. PLoS One 2013; 8(11)e78629 []. [PMID: 24250804].
Lee M, Schwab C, Yu S, McGeer E, McGeer PL. Astrocytes produce the antiinflammatory and neuroprotective agent hydrogen sulfide. Neurobiol Aging 2009; 30(10): 1523-34. []. [PMID: 19631409].
Zhang X, Bian JS. Hydrogen sulfide: A neuromodulator and neuroprotectant in the central nervous system. ACS Chem Neurosci 2014; 5(10): 876-83. []. [PMID: 25230373].
Li XJ, Li CK, Wei LY, et al. Hydrogen sulfide intervention in focal cerebral ischemia/reperfusion injury in rats. Neural Regen Res 2015; 10(6): 932-7. []. [PMID: 26199610].
Lambert JP, Nicholson CK, Amin H, Amin S, Calvert JW. Hydrogen sulfide provides cardioprotection against myocardial/ischemia reperfusion injury in the diabetic state through the activation of the RISK pathway. Med Gas Res 2014; 4(1): 20. []. [PMID: 25525500].
Snijder PM, de Boer RA, Bos EM, et al. Gaseous hydrogen sulfide protects against myocardial ischemia-reperfusion injury in mice partially independent from hypometabolism. PLoS One 2013; 8(5)e63291 []. [PMID: 23675473].
Tay AS, Hu LF, Lu M, Wong PT, Bian JS. Hydrogen sulfide protects neurons against hypoxic injury via stimulation of ATP-sensitive potassium channel/protein kinase C/extracellular signal-regulated kinase/heat shock protein 90 pathway. Neuroscience 2010; 167(2): 277-86. []. [PMID: 20149843].
Yu Q, Lu Z, Tao L, et al. ROS-dependent neuroprotective effects of NaHS in ischemia brain injury involves the PARP/AIF pathway. Cell Physiol Biochem 2015; 36(4): 1539-51. []. [PMID: 26159361].
Xuan A, Long D, Li J, et al. Hydrogen sulfide attenuates spatial memory impairment and hippocampal neuroinflammation in β-amyloid rat model of Alzheimer’s disease. J Neuroinflammation 2012; 9: 202. []. [PMID: 22898621].
Tyagi N, Moshal KS, Sen U, et al. H2S protects against methionine-induced oxidative stress in brain endothelial cells. Antioxid Redox Signal 2009; 11(1): 25-33. []. [PMID: 18837652].
Gheibi S, Aboutaleb N, Khaksari M, et al. Hydrogen sulfide protects the brain against ischemic reperfusion injury in a transient model of focal cerebral ischemia. J Mol Neurosci 2014; 54(2): 264-70. []. [PMID: 24643521].
Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 2011; 75(1): 50-83. []. [PMID: 21372320].
Hu Y, Duan M, Liang S, Wang Y, Feng Y. Senkyunolide I protects rat brain against focal cerebral ischemia-reperfusion injury by up-regulating p-Erk1/2, Nrf2/HO-1 and inhibiting caspase 3. Brain Res 2015; 1605: 39-48. []. [PMID: 25698615].
Liu C, Du Q, Zhang X, Tang Z, Ji H, Li Y. Clematichinenoside serves as a neuroprotective agent against ischemic stroke: The synergistic action of ERK1/2 and cPKC pathways. Front Cell Neurosci 2016; 9: 517. []. [PMID: 26793066].
Jiang C, Yu K, Wu Y, et al. Enriched environment enhances poststroke neurological function recovery on rat: Involvement of p-ERK1/2. J Stroke Cerebrovasc Dis 2016; 25(7): 1590-8. []. [PMID: 27068861].
Zhou H, Yang WS, Li Y, et al. Oleoylethanolamide attenuates apoptosis by inhibiting the TLR4/NF-κB and ERK1/2 signaling pathways in mice with acute ischemic stroke. Naunyn Schmiedebergs Arch Pharmacol 2017; 390(1): 77-84. []. [PMID: 27738712].
Zheng YQ, Liu JX, Wang JN, Xu L. Effects of crocin on reperfusion-induced oxidative/nitrative injury to cerebral microvessels after global cerebral ischemia. Brain Res 2007; 1138: 86-94. []. [PMID: 17274961].
Sawe N, Steinberg G, Zhao H. Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke. J Neurosci Res 2008; 86(8): 1659-69. []. [PMID: 18189318].
Bai CP, Zhao C, Shen L. Post-treatment with a hydrogen sulfide donor limits neuronal injury and modulates potassium voltage-gated channel subfamily D member 2 (Kv4.2) and Potassium Channel Interacting Protein 3 (KChIP3) during transient global cerebral ischemia. Curr Neurovasc Res 2017; 14(4): 397-405. []. [PMID: 29119925].
Li Z, Wang Y, Xie Y, Yang Z, Zhang T. Protective effects of exogenous hydrogen sulfide on neurons of hippocampus in a rat model of brain ischemia. Neurochem Res 2011; 36(10): 1840-9. []. [PMID: 21603936].
Wei X, Zhang B, Cheng L, et al. Hydrogen sulfide induces neuroprotection against experimental stroke in rats by down-regulation of AQP4 via activating PKC. Brain Res 2015; 1622: 292-9. []. [PMID: 26168888].
Kimura Y, Goto Y, Kimura H. Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria. Antioxid Redox Signal 2010; 12(1): 1-13. []. [PMID: 19852698].
Sugawara T, Fujimura M, Morita-Fujimura Y, Kawase M, Chan PH. Mitochondrial release of cytochrome c corresponds to the selective vulnerability of hippocampal CA1 neurons in rats after transient global cerebral ischemia. J Neurosci 1999; 19(22): RC39. []. [PMID: 10559429].
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. []. [PMID: 20478278].
Irving EA, Barone FC, Reith AD, Hadingham SJ, Parsons AA. Differential activation of MAPK/ERK and p38/SAPK in neurones and glia following focal cerebral ischaemia in the rat. Brain Res Mol Brain Res 2000; 77(1): 65-75. []. [PMID: 10814833].
Lee CH, Yoo KY, Park OK, et al. Phosphorylated extracellular signal-regulated kinase 1/2 immunoreactivity and its protein levels in the gerbil hippocampus during normal aging. Mol Cells 2010; 29(4): 373-8. []. [PMID: 20213312].
Hu X, Wu X, Xu J, Zhou J, Han X, Guo J. Src kinase up-regulates the ERK cascade through inactivation of protein phosphatase 2A following cerebral ischemia. BMC Neurosci 2009; 10: 74. []. [PMID: 19602257].
Zhan L, Yan H, Zhou H, Sun W, Hou Q, Xu E. Hypoxic preconditioning attenuates neuronal cell death by preventing MEK/ERK signaling pathway activation after transient global cerebral ischemia in adult rats. Mol Neurobiol 2013; 48(1): 109-19. []. [PMID: 23519519].
Hausenloy DJ, Tsang A, Mocanu MM, Yellon DM. Ischemic preconditioning protects by activating prosurvival kinases at reperfusion. Am J Physiol Heart Circ Physiol 2005; 288(2): H971-6. []. [PMID: 15358610].
Nozaki K, Nishimura M, Hashimoto N. Mitogen-activated protein kinases and cerebral ischemia. Mol Neurobiol 2001; 23(1): 1-19. []. [PMID: 11642541].
Wang S, Wei H, Cai M, et al. Genistein attenuates brain damage induced by transient cerebral ischemia through up-regulation of ERK activity in ovariectomized mice. Int J Biol Sci 2014; 10(4): 457-65. []. [PMID: 24719563].
Ishigami M, Hiraki K, Umemura K, Ogasawara Y, Ishii K, Kimura H. A source of hydrogen sulfide and a mechanism of its release in the brain. Antioxid Redox Signal 2009; 11(2): 205-14. []. [PMID: 18754702].
Jang H, Oh MY, Kim YJ, et al. Hydrogen sulfide treatment induces angiogenesis after cerebral ischemia. J Neurosci Res 2014; 92(11): 1520-8. []. [PMID: 24939171].
Schrader LA, Birnbaum SG, Nadin BM, et al. ERK/MAPK regulates the Kv4.2 potassium channel by direct phosphorylation of the pore-forming subunit. Am J Physiol Cell Physiol 2006; 290(3): C852-61. []. [PMID: 16251476].

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