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Cellular and Molecular Neurobiology

, Volume 39, Issue 5, pp 671–686 | Cite as

Involvement of Endothelin-1, H2S and Nrf2 in Beneficial Effects of Remote Ischemic Preconditioning in Global Cerebral Ischemia-Induced Vascular Dementia in Mice

  • Jin-Ting He
  • Haiqi Li
  • Le YangEmail author
  • Kai-Liang ChengEmail author
Original Research
  • 42 Downloads

Abstract

The present study explored the role of endothelin-1, H2S, and Nrf2 in remote preconditioning (RIPC)-induced beneficial effects in ischemia–reperfusion (I/R)-induced vascular dementia. Mice were subjected to 20 min of global ischemia by occluding both carotid arteries to develop vascular dementia, which was assessed using Morris water maze test on 7th day. RIPC was given by subjecting hind limb to four cycles of ischemia (5 min) and reperfusion (5 min) and it significantly restored I/R-induced locomotor impairment, neurological severity score, cerebral infarction, apoptosis markers along with deficits in learning and memory. Biochemically, there was increase in the plasma levels of endothelin-1 along with increase in the brain levels of H2S and its biosynthetic enzymes viz., cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CLS). There was also an increase in the expression of Nrf2 and glutathione reductase in the brain in response to RIPC. Pretreatment with bosentan (dual blocker of ETA and ETB receptors), amino-oxyacetic acid (CBS synthase inhibitor), and DL-propargylglycine (CLS inhibitor) significantly attenuated RIPC-mediated beneficial effects and biochemical alterations. The effects of bosentan on behavioral and biochemical parameters were more significant than individual treatments with CBS or CLS inhibitors. Moreover, CBS and CLS inhibitors did not alter the endothelin-1 levels possibly suggesting that endothelin-1 may act as upstream mediator of H2S. It is concluded that RIPC may stimulate the release endothelin-1, which may activate CBS and CLS to increase the levels of H2S and latter may increase the expression of Nrf2 to decrease oxidative stress and prevent vascular dementia.

Keywords

Cerebral ischemia Dementia Remote preconditioning Remote postconditioning 

Notes

Author Contributions

JTH did the experiments; HL helped JTH in experimental work and participated in writing; LY helped in writing the manuscript; KLC conceived the idea and edited the manuscript.

Funding

The project was supported by Jilin Provincial Department of Finance funds in China (No. Sczsy201512), Jilin Provincial Department of Health funds (No. 20152085), The National Natural Science Fund Projects (No. 81671159), Jilin Province Department of International Cooperation Projects (No. 20170414014GH), Jilin University Outstanding Young Teacher Training Program (No. 450060472325).

Compliance with Ethical Standards

Conflict of interest

There is no conflict exists among the authors.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

References

  1. Bugge E, Ytrehus K (1996) Endothelin-1 can reduce infarct size through protein kinase C and KATP channels in the isolated rat heart. Cardiovasc Res 32:920–929CrossRefGoogle Scholar
  2. Cabrera-Fuentes HA, Alba-Alba C, Aragones J, Bernhagen J, Boisvert WA, Bøtker HE, Cesarman-Maus G, Fleming I, Garcia-Dorado D, Lecour S, Liehn E, Marber MS, Marina N, Mayr M, Perez-Mendez O, Miura T, Ruiz-Meana M, Salinas-Estefanon EM, Ong SB, Schnittler HJ, Sanchez-Vega JT, Sumoza-Toledo A, Vogel CW, Yarullina D, Yellon DM, Preissner KT, Hausenloy DJ (2016a) Meeting report from the 2nd international symposium on new frontiers in cardiovascular research. Protecting the cardiovascular system from ischemia: between bench and bedside. Basic Res Cardiol 111(1):7CrossRefGoogle Scholar
  3. Cabrera-Fuentes HA, Aragones J, Bernhagen J, Boening A, Boisvert WA, Bøtker HE, Bulluck H, Cook S, Di Lisa F, Engel FB, Engelmann B, Ferrazzi F, Ferdinandy P, Fong A, Fleming I, Gnaiger E, Hernández-Reséndiz S, Kalkhoran SB, Kim MH, Lecour S, Liehn EA, Marber MS, Mayr M, Miura T, Ong SB, Peter K, Sedding D, Singh MK, Suleiman MS, Schnittler HJ, Schulz R, Shim W, Tello D, Vogel CW, Walker M, Li QO, Yellon DM, Hausenloy DJ, Preissner KT (2016b) From basic mechanisms to clinical applications in heart protection, new players in cardiovascular diseases and cardiac theranostics: meeting report from the third international symposium on “New frontiers in cardiovascular research”. Basic Res Cardiol 111(6):69CrossRefGoogle Scholar
  4. Cao H, Li J, Wang J, Duan SM, Zeng YM (2003) Effects of lidocaine and thiopental on the neuronal injury in rat hippocampus slice cultures. Zhongguo Ying Yong Sheng Li Xue Za Zhi 19(3):245–248Google Scholar
  5. Chan MV, Wallace JL (2013) Hydrogen sulfide-based therapeutics and gastrointestinal diseases: translating physiology to treatments. Am J Physiol Gastrointest Liver Physiol 305(7):G467–G473CrossRefGoogle Scholar
  6. Chen C, Jiang W, Liu Z, Li F, Yang J, Zhao Y, Ran Y, Meng Y, Ji X, Geng X, Du H, Hu X (2018) Splenic responses play an important role in remote ischemic preconditioning-mediated neuroprotection against stroke. J Neuroinflammation 15(1):167CrossRefGoogle Scholar
  7. Diwan V, Jaggi AS, Singh M, Singh N, Singh D (2008) Possible involvement of erythropoietin in remote renal preconditioning-induced cardioprotection in rats. J Cardiovasc Pharmacol 51(2):126–130CrossRefGoogle Scholar
  8. Donovan LM, Moore MW, Gillombardo CB, Chai S, Strohl KP (2011) Effects of hydrogen sulfide synthesis inhibitors on posthypoxic ventilatory behavior in the C57BL/6J mouse. Respiration 82(6):522–529CrossRefGoogle Scholar
  9. Duan YF, Liu C, Zhao YF, Duan WM, Zhao LR (2009) Thiopental exaggerates ischemic brain damage and neurological deficits after experimental stroke in spontaneously hypertensive rats. Brain Res 1294:176–182CrossRefGoogle Scholar
  10. Emontzpohl C, Stoppe C, Theißen A, Beckers C, Neumann UP, Lurje G, Ju C, Bernhagen J, Tolba RH, Czigany Z (2018) The role of macrophage migration inhibitory factor in remote ischemic conditioning induced hepatoprotection in a rodent model of liver transplantation. Shock.  https://doi.org/10.1097/SHK.0000000000001307 Google Scholar
  11. Giuliani D, Ottani A, Zaffe D, Galantucci M, Strinati F, Lodi R, Guarini S (2013) Hydrogen sulfide slows down progression of experimental Alzheimer’s disease by targeting multiple pathophysiological mechanisms. Neurobiol Learn Mem 104:82–91CrossRefGoogle Scholar
  12. Gomes PFM, Tannuri ACA, Nogueira TM, Iuamoto LR, Paes VR, Coelho MCM, Gonçalves JO, Serafini S, Tannuri U (2018) Remote ischemic preconditioning is efficient in reducing hepatic ischemia-reperfusion injury in a growing rat model and does not promote histologic lesions in distant organs. Transplant Proc 50:3840–3844CrossRefGoogle Scholar
  13. Gourine AV, Molosh AI, Poputnikov D, Bulhak A, Sjöquist PO, Pernow J (2005) Endothelin-1 exerts a preconditioning-like cardioprotective effect against ischaemia/reperfusion injury via the ET(A) receptor and the mitochondrial K(ATP) channel in the rat in vivo. Br J Pharmacol 144(3):331–337CrossRefGoogle Scholar
  14. Han SJ, Kim JI, Park JW, Park KM (2015) Hydrogen sulfide accelerates the recovery of kidney tubules after renal ischemia/reperfusion injury. Nephrol Dial Transplant 30(9):1497–1506CrossRefGoogle Scholar
  15. Harukuni I, Bhardwaj A (2006) Mechanisms of brain injury after global cerebral ischemia. Neurol Clin 24(1):1–21CrossRefGoogle Scholar
  16. Hausenloy DJ, Barrabes JA, Bøtker HE, Davidson SM, Di Lisa F, Downey J, Engstrom T, Ferdinandy P, Carbrera-Fuentes HA, Heusch G, Ibanez B, Iliodromitis EK, Inserte J, Jennings R, Kalia N, Kharbanda R, Lecour S, Marber M, Miura T, Ovize M, Perez-Pinzon MA, Piper HM, Przyklenk K, Schmidt MR, Redington A, Ruiz-Meana M, Vilahur G, Vinten-Johansen J, Yellon DM, Garcia-Dorado D (2016) Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery. Basic Res Cardiol 111(6):70CrossRefGoogle Scholar
  17. Hwang SY, Sarna LK, Siow YL, and K. O (2013) High-fat diet stimulates hepatic cystathionine beta-synthase and cystathionine gamma-lyase expression. Can J Physiol Pharmacol 91:913–919CrossRefGoogle Scholar
  18. Khaksari M, Mehrjerdi FZ, Rezvani ME, Safari F, Mirgalili A, Niknazar S (2017) The role of erythropoietin in remote renal preconditioning on hippocampus ischemia/reperfusion injury. J Physiol Sci 67(1):163–171CrossRefGoogle Scholar
  19. Kim H, Jung Y, Shin BS, Kim H, Song H, Bae SH, Rhee SG, Jeong W (2010) Redox regulation of lipopolysaccharide-mediated sulfiredoxin induction, which depends on both AP-1 and Nrf2. J Biol Chem 285(45):34419–34428CrossRefGoogle Scholar
  20. Kim SJ, Lee SR (2014) Protective effect of melatonin against transient global cerebral ischemia-induced neuronal cell damage via inhibition of matrix metalloproteinase-9. Life Sci 94:8–16CrossRefGoogle Scholar
  21. Kim YH, Kim YS, Kim BH, Lee KS, Park HS, Lim CH (2019) Remote ischemic preconditioning ameliorates indirect acute lung injury by modulating phosphorylation of IκBα in mice. J Int Med Res 47:936–950CrossRefGoogle Scholar
  22. Kimura H (2014) Production and physiological effects of hydrogen sulfide. Antioxid Redox Signal 20(5):783–793CrossRefGoogle Scholar
  23. Kimura H (2015) Signaling molecules: hydrogen sulfide and polysulfide. Antioxid Redox Signal 22(5):362–376CrossRefGoogle Scholar
  24. Kuksis M, Smith PM, Ferguson AV (2014) Hydrogen sulfide regulates cardiovascular function by influencing the excitability of subfornical organ neurons. PLoS ONE 9(8):e105772CrossRefGoogle Scholar
  25. Kumar M, Sandhir R (2018) Hydrogen sulfide in physiological and pathological mechanisms in brain. CNS Neurol Disord Drug Targets 17:654–670CrossRefGoogle Scholar
  26. Lertratanangkoon K, Scimeca JM, Wei JN (1999) Inhibition of glutathione synthesis with propargylglycine enhances N-acetylmethionine protection and methylation in bromobenzene-treated Syrian hamsters. J Nutr 129(3):649–656CrossRefGoogle Scholar
  27. Li XH, Deng YY, Li F, Shi JS, Gong QH (2016) Neuroprotective effects of sodium hydrosulfide against β-amyloid-induced neurotoxicity. Int J Mol Med 38(4):1152–1160CrossRefGoogle Scholar
  28. Lin Y, Zeng H, Gao L, Gu T, Wang C, Zhang H (2017) Hydrogen sulfide attenuates atherosclerosis in a partially ligated carotid artery mouse model via regulating angiotensin converting enzyme 2 expression. Front Physiol 8:782CrossRefGoogle Scholar
  29. Liu H, Deng Y, Gao J, Liu Y, Li W, Shi J, Gong Q (2015) Sodium hydrosulfide attenuates beta-amyloid-induced cognitive deficits and neuroinflammation via modulation of MAPK/NF-κB pathway in rats. Curr Alzheimer Res 12(7):673–683CrossRefGoogle Scholar
  30. Mullenheim J, Molojavyi A, Preckel B, Thamer V, Schlack W (2001) Thiopentone does not block ischemic preconditioning in the isolated rat heart. Can J Anaesth 48:784CrossRefGoogle Scholar
  31. Okuno S, Nakase H, Sakaki T (2001) Comparative study of 2,3,5-triphenyltetrazolium chloride (TTC) and hematoxylin-eosin staining for quantification of early brain ischemic injury in cats. Neurol Res 23(6):657–661CrossRefGoogle Scholar
  32. Panza E, De Cicco P, Armogida C, Scognamiglio G, Gigantino V, Botti G, Germano D, Napolitano M, Papapetropoulos A, Bucci M, Cirino G, Ianaro A (2015) Role of the cystathionine γ lyase/hydrogen sulfide pathway in human melanoma progression. Pigment Cell Melanoma Res 28(1):61–72CrossRefGoogle Scholar
  33. Patel S, Fedinec AL, Liu J, Weiss MA, Pourcyrous M, Harsono M, Parfenova H, Leffler CW (2018) Hydrogen sulfide mediates the vasodilator effect of endothelin-1 in the cerebral circulation. Am J Physiol Heart Circ Physiol.  https://doi.org/10.1152/ajpheart.00451.2018 Google Scholar
  34. Pernow J, Wang QD (1997) Endothelin in myocardial ischaemia and reperfusion. Cardiovasc Res 33(3):518–526CrossRefGoogle Scholar
  35. Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P (1993) Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 87(3):893–899CrossRefGoogle Scholar
  36. Randhawa PK, Jaggi AS (2016) Gadolinium and ruthenium red attenuate remote hind limb preconditioning-induced cardioprotection: possible role of TRP and especially TRPV channels. Naunyn Schmiedebergs Arch Pharmacol 389(8):887–896CrossRefGoogle Scholar
  37. Rodriguez R, Santiago-Mejia J, Gomez C, San-Juan ER (2005) A simplified procedure for the quantitative measurement of neurological deficits after forebrain ischemia in mice. J Neurosci Methods 147:22–28CrossRefGoogle Scholar
  38. Rubanyi GM, Polokoff MA (1994) Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev 46:325–415Google Scholar
  39. Serafim KG, Navarro SA, Zarpelon AC, Pinho-Ribeiro FA, Fattori V, Cunha TM, Alves-Filho JC, Cunha FQ, Casagrande R, Verri WA Jr (2015) Bosentan, a mixed endothelin receptor antagonist, inhibits superoxide anion-induced pain and inflammation in mice. Naunyn Schmiedebergs Arch Pharmacol 388(11):1211–1221CrossRefGoogle Scholar
  40. Shen Y, Shen Z, Luo S, Guo W, Zhu YZ. The cardioprotective effects of hydrogen sulfide in heart diseases: from molecular mechanisms to therapeutic potential. Oxid Med Cell Longev 2015:925167Google Scholar
  41. Song K, Wang F, Li Q, Shi YB, Zheng HF, Peng H, Shen HY, Liu CF, Hu LF (2014) Hydrogen sulfide inhibits the renal fibrosis of obstructive nephropathy. Kidney Int 85(6):1318–1329CrossRefGoogle Scholar
  42. Stipanuk MH, Beck PW (1982) Characterization of the enzymic capacity for cysteine desulphhydration in liver and kidney of the rat. Biochem J 206(2):267–277CrossRefGoogle Scholar
  43. Szabo C, Papapetropoulos A (2017) International union of basic and clinical pharmacology. CII: pharmacological modulation of H2S levels: H2S donors and H2S biosynthesis inhibitors. Pharmacol Rev 69(4):497–564CrossRefGoogle Scholar
  44. Szabo C, Ransy C, Módis K, Andriamihaja M, Murghes B, Coletta C, Olah G, Yanagi K, Bouillaud F (2014) Regulation of mitochondrial bioenergetic function by hydrogen sulfide. Part I. Biochemical and physiological mechanisms. Br J Pharmacol 171(8):2099–2122CrossRefGoogle Scholar
  45. Teng X, Yuan X, Tang Y, Shi J (2015) Protective effects of remote ischemic preconditioning in isolated rat hearts. Int J Clin Exp Med 8(8):12575–12583Google Scholar
  46. Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1(2):848–858CrossRefGoogle Scholar
  47. Wan L, Cheng Y, Luo Z, Guo H, Zhao W, Gu Q, Yang X, Xu J, Bei W, Guo J (2015) Neuroprotection, learning and memory improvement of a standardized extract from Renshen Shouwu against neuronal injury and vascular dementia in rats with brain ischemia. J Ethnopharmacol 165:118–126CrossRefGoogle Scholar
  48. Wei HJ, Li X, Tang XQ (2014) Therapeutic benefits of H2S in Alzheimer’s disease. J Clin Neurosci 21(10):1665–1669CrossRefGoogle Scholar
  49. Wiklund L, Martijn C, Miclescu A, Semenas E, Rubertsson S, Sharma HS (2012) Central nervous tissue damage after hypoxia and reperfusion in conjunction with cardiac arrest and cardiopulmonary resuscitation: mechanisms of action and possibilities for mitigation. Int Rev Neurobiol 102:173–187CrossRefGoogle Scholar
  50. Wojciechowska M, Zarębiński M, Pawluczuk P, Gralak-Łachowska D, Pawłowski L, Loska W, Goszczyńska M, Flis K, Cudnoch-Jędrzejewska A (2018) Remote ischemic preconditioning in renal protection during elective percutaneous coronary intervention. Adv Exp Med Biol.  https://doi.org/10.1007/5584_2018_282 Google Scholar
  51. Wu L, Feng XT, Hu YQ, Tang N, Zhao QS, Li TW, Li HY, Wang QB, Bi XY, Cai XK (2015) Global gene expression profile of the hippocampus in a rat model of vascular dementia. Tohoku J Exp Med 237(1):57–67CrossRefGoogle Scholar
  52. Xiao A, Li J, Liu T, Liu Z, Wei C, Xu X, Li Q, Li J (2016) L-cysteine enhances nutrient absorption via a cystathionine-β-synthase-derived H2 S pathway in rodent jejunum. Clin Exp Pharmacol Physiol 43(5):562–568CrossRefGoogle Scholar
  53. Xu Z, Prathapasinghe G, Wu N, Hwang SY, Siow YL, Ohm K (2009) Ischemia-reperfusion reduces cystathionine-beta-synthase-mediated hydrogen sulfide generation in the kidney. Am J Physiol Renal Physiol 297:F27–F35CrossRefGoogle Scholar
  54. Ya B, Zhang L, Zhang L, Li Y, Li L (2012) 5-hydroxymethyl-2-furfural prolongs survival and inhibits oxidative stress in a mouse model of forebrain ischemia. Neural Regen Res 7(22):1722–1728Google Scholar
  55. Ya BL, Li HF, Wang HY, Wu F, Xin Q, Cheng HJ, Li WJ, Lin N, Ba ZH, Zhang RJ, Liu Q, Li YN, Bai B, Ge F (2017) 5-HMF attenuates striatum oxidative damage via Nrf2/ARE signaling pathway following transient global cerebral ischemia. Cell Stress Chaperones 22(1):55–65CrossRefGoogle Scholar
  56. Yang J, Liu C, Du X, Liu M, Ji X, Du H, Zhao H (2018) Hypoxia inducible factor 1α plays a key role in remote ischemic preconditioning against stroke by modulating inflammatory responses in rats. J Am Heart Assoc.  https://doi.org/10.1161/JAHA.117.007589 Google Scholar
  57. Zhang Y, Liu X, Yan F, Min L, Ji X, Luo Y (2012) Protective effects of remote ischemic preconditioning in rat hindlimb on ischemia-reperfusion injury. Neural Regen Res 7(8):583–587Google Scholar
  58. Zhang M, Gu WW, Hong XY (2018) Involvement of endothelin 1 in remote preconditioning-induced cardioprotection through connexin 43 and Akt/GSK-3β signaling pathway. Sci Rep 8(1):10941CrossRefGoogle Scholar
  59. Zheng F, Han J, Lu H, Cui C, Yang J, Cui Q, Cai J, Zhou Y, Tang C, Xu G, Geng B (2018) Cystathionine beta synthase-hydrogen sulfide system in paraventricular nucleus reduced high fatty diet induced obesity and insulin resistance by brain-adipose axis. Biochim Biophys Acta Mol Basis Dis 1864(10):3281–3291CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Neurology, China-Japan Union HospitalJilin UniversityChangchunChina
  2. 2.Department of EndocrinologyThe People’s Hospital of Jilin ProvinceChangchunChina
  3. 3.Department of Radiology, China-Japan Union HospitalJilin UniversityChangchunChina

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