Skip to main content
Log in

Hydrogen-Rich Saline is Cerebroprotective in a Rat Model of Deep Hypothermic Circulatory Arrest

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Deep hypothermic circulatory arrest (DHCA) has been widely used in the operations involving the aortic arch and brain aneurysm since 1950s; but prolonged DHCA contributes significantly to neurological deficit which remains a major cause of postoperative morbidity and mortality. It has been reported that hydrogen exerts a therapeutic antioxidant activity by selectively reducing hydroxyl radical. In this study, DHCA treated rats developed a significant oxidative stress, inflammatory reaction and apoptosis. The administration of HRS resulted in a significant decrease in the brain injury, together with lower production of IL-1β, TNF-α, 8-OHdG and MDA as well as decreased activity of NOS while increased activity of SOD. The apoptotic index as well as the expressions of caspase-3 in brain tissue was significantly decreased after treatment. HRS administration significantly attenuated the severity of DHCA induced brain injury by mechanisms involving amelioration of oxidative stress, down-regulation of inflammatory factors and reduction of apoptosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

DHCA:

Deep hypothermic circulatory arrest

8-OH-dG:

8-Hydroxydeoxyguanosine

ELISA:

Enzyme-linked immunosorbent assay

EMSA:

Electromobility Shift Analysis

HRS:

Hydrogen-rich saline

IL-1β:

Interleukin-1β

MDA:

Malondialdehyde

NF-κB:

Nuclear factor-κB

NOS:

Nitric oxide synthase

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SIRS:

Systemic inflammatory response syndrome

SOD:

Superoxide dismutase

TNF-α:

Tumor necrosis factor-α

References

  1. Ergin MA, O’Connor J, Guinto R, Griepp RB (1982) Experience with profound hypothermia and circulatory arrest in the treatment of aneurysms of the aortic arch Aortic arch replacement for acute arch dissections. J Thorac Cardiovasc Surg 84:649–655

    PubMed  CAS  Google Scholar 

  2. Niazi SA, Lewis FJ (1957) Profound hypothermia in the monkey with recovery after long periods of cardiac standstill. J Appl Physiol 10:137–138

    PubMed  CAS  Google Scholar 

  3. Crawford ES, Svensson LG, Coselli JS, Safi HJ, Hess KR (1989) Surgical treatment of aneurysm and/or dissection of the ascending aorta, transverse aortic arch, and ascending aorta and transverse aortic arch. Factors influencing survival in 717 patients. J Thorac Cardiovasc Surg 98:659–673; discussion 673–654

    Google Scholar 

  4. Ergin MA, Uysal S, Reich DL, Apaydin A, Lansman SL, McCullough JN, Griepp RB (1999) Temporary neurological dysfunction after deep hypothermic circulatory arrest: a clinical marker of long-term functional deficit. Ann Thorac Surg 67:1887–1890; discussion 1891–1884

    Google Scholar 

  5. Harrington DK, Bonser M, Moss A, Heafield MT, Riddoch MJ, Bonser RS (2003) Neuropsychometric outcome following aortic arch surgery: a prospective randomized trial of retrograde cerebral perfusion. J Thorac Cardiovasc Surg 126:638–644

    Article  PubMed  CAS  Google Scholar 

  6. Parks DA, Granger DN (1988) Ischemia-reperfusion injury: a radical view. Hepatology 8:680–682

    Article  PubMed  CAS  Google Scholar 

  7. Summers ST, Zinner MJ, Freischlag JA (1993) Production of endothelium-derived relaxing factor (EDRF) is compromised after ischemia and reperfusion. Am J Surg 166:216–220

    Article  PubMed  CAS  Google Scholar 

  8. Betteridge DJ (2000) What is oxidative stress? Metabolism 49:3–8

    Article  PubMed  CAS  Google Scholar 

  9. Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K, Katayama Y, Asoh S, Ohta S (2007) Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med 13:688–694

    Article  PubMed  CAS  Google Scholar 

  10. Sato Y, Kajiyama S, Amano A, Kondo Y, Sasaki T, Handa S, Takahashi R, Fukui M, Hasegawa G, Nakamura N, Fujinawa H, Mori T, Ohta M, Obayashi H, Maruyama N, Ishigami A (2008) Hydrogen-rich pure water prevents superoxide formation in brain slices of vitamin C-depleted SMP30/GNL knockout mice. Biochem Biophys Res Commun 375:346–350

    Article  PubMed  CAS  Google Scholar 

  11. Nagata K, Nakashima-Kamimura N, Mikami T, Ohsawa I, Ohta S (2009) Consumption of molecular hydrogen prevents the stress-induced impairments in hippocampus-dependent learning tasks during chronic physical restraint in mice. Neuropsychopharmacology 34:501–508

    Article  PubMed  CAS  Google Scholar 

  12. Sun Q, Cai J, Zhou J, Tao H, Zhang JH, Zhang W, Sun XJ (2010) Hydrogen-rich saline reduces delayed neurologic sequelae in experimental carbon monoxide toxicity*. Crit Care Med

  13. Cai J, Kang Z, Liu WW, Luo X, Qiang S, Zhang JH, Ohta S, Sun X, Xu W, Tao H, Li R (2008) Hydrogen therapy reduces apoptosis in neonatal hypoxia-ischemia rat model. Neurosci Lett 441:167–172

    Article  PubMed  CAS  Google Scholar 

  14. Buchholz BM, Kaczorowski DJ, Sugimoto R, Yang R, Wang Y, Billiar TR, McCurry KR, Bauer AJ, Nakao A (2008) Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury. Am J Transplant 8:2015–2024

    Article  PubMed  CAS  Google Scholar 

  15. Zheng X, Mao Y, Cai J, Li Y, Liu W, Sun P, Zhang JH, Sun X, Yuan H (2009) Hydrogen-rich saline protects against intestinal ischemia/reperfusion injury in rats. Free Radic Res 43:478–484

    Article  PubMed  CAS  Google Scholar 

  16. Chen H, Sun YP, Hu PF, Liu WW, Xiang HG, Li Y, Yan RL, Su N, Ruan CP, Sun XJ, Wang Q (2009) The effects of hydrogen-rich saline on the contractile and structural changes of intestine induced by ischemia-reperfusion in Rats. J Surg Res

  17. Hayashida K, Sano M, Ohsawa I, Shinmura K, Tamaki K, Kimura K, Endo J, Katayama T, Kawamura A, Kohsaka S, Makino S, Ohta S, Ogawa S, Fukuda K (2008) Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury. Biochem Biophys Res Commun 373:30–35

    Article  PubMed  CAS  Google Scholar 

  18. Sun Q, Kang Z, Cai J, Liu W, Liu Y, Zhang JH, Denoble PJ, Tao H, Sun X (2009) Hydrogen-rich saline protects myocardium against ischemia/reperfusion injury in rats. Exp Biol Med (Maywood) 234:1212–1219

    Article  CAS  Google Scholar 

  19. Chen C, Chen Q, Mao Y, Xu S, Xia C, Shi X, Zhang JH, Yuan H, Sun X (2010) Hydrogen-rich saline protects against spinal cord injury in rats. Neurochem Res 35:1111–1118

    Article  PubMed  CAS  Google Scholar 

  20. Gharib B, Hanna S, Abdallahi OM, Lepidi H, Gardette B, De Reggi M (2001) Anti-inflammatory properties of molecular hydrogen: investigation on parasite-induced liver inflammation. C R Acad Sci III 324:719–724

    PubMed  CAS  Google Scholar 

  21. Ohsawa I, Nishimaki K, Yamagata K, Ishikawa M, Ohta S (2008) Consumption of hydrogen water prevents atherosclerosis in apolipoprotein E knockout mice. Biochem Biophys Res Commun 377:1195–1198

    Article  PubMed  CAS  Google Scholar 

  22. Cai J, Kang Z, Liu K, Liu W, Li R, Zhang JH, Luo X, Sun X (2009) Neuroprotective effects of hydrogen saline in neonatal hypoxia-ischemia rat model. Brain Res 1256:129–137

    Article  PubMed  CAS  Google Scholar 

  23. Pulsinelli WA, Brierley JB (1979) A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 10:267–272

    Article  PubMed  CAS  Google Scholar 

  24. Milani H, Lepri ER, Giordani F, Favero-Filho LA (1999) Magnesium chloride alone or in combination with diazepam fails to prevent hippocampal damage following transient forebrain ischemia. Braz J Med Biol Res 32:1285–1293

    Article  PubMed  CAS  Google Scholar 

  25. Hua F, Ma J, Li Y, Ha T, Xia Y, Kelley J, Williams DL, Browder IW, Schweitzer JB, Li C (2006) The development of a novel mouse model of transient global cerebral ischemia. Neurosci Lett 400:69–74

    Article  PubMed  CAS  Google Scholar 

  26. Zhou ML, Zhu L, Wang J, Hang CH, Shi JX (2007) The inflammation in the gut after experimental subarachnoid hemorrhage. J Surg Res 137:103–108

    Article  PubMed  CAS  Google Scholar 

  27. Schmidt-Kastner R, Freund TF (1991) Selective vulnerability of the hippocampus in brain ischemia. Neuroscience 40:599–636

    Article  PubMed  CAS  Google Scholar 

  28. Carden DL, Granger DN (2000) Pathophysiology of ischaemia-reperfusion injury. J Pathol 190:255–266

    Article  PubMed  CAS  Google Scholar 

  29. Chen F, Castranova V, Shi X, Demers LM (1999) New insights into the role of nuclear factor-kappaB, a ubiquitous transcription factor in the initiation of diseases. Clin Chem 45:7–17

    PubMed  CAS  Google Scholar 

  30. Hang CH, Chen G, Shi JX, Zhang X, Li JS (2006) Cortical expression of nuclear factor kappaB after human brain contusion. Brain Res 1109:14–21

    Article  PubMed  CAS  Google Scholar 

  31. Hesse DG, Tracey KJ, Fong Y, Manogue KR, Palladino MA Jr, Cerami A, Shires GT, Lowry SF (1988) Cytokine appearance in human endotoxemia and primate bacteremia. Surg Gynecol Obstet 166:147–153

    PubMed  CAS  Google Scholar 

  32. Church LD, Cook GP, McDermott MF (2008) Primer: inflammasomes and interleukin 1beta in inflammatory disorders. Nat Clin Pract Rheumatol 4:34–42

    Article  PubMed  CAS  Google Scholar 

  33. Dogan A, Rao AM, Baskaya MK, Rao VL, Rastl J, Donaldson D, Dempsey RJ (1997) Effects of ifenprodil, a polyamine site NMDA receptor antagonist, on reperfusion injury after transient focal cerebral ischemia. J Neurosurg 87:921–926

    Article  PubMed  CAS  Google Scholar 

  34. Kumar A, Mittal R, Khanna HD, Basu S (2008) Free radical injury and blood-brain barrier permeability in hypoxic-ischemic encephalopathy. Pediatrics 122:722–727

    Article  Google Scholar 

  35. Kasai H (1997) Analysis of a form of oxidative DNA damage, 8-hydroxy-2’-deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis. Mutat Res 387:147–163

    Article  PubMed  CAS  Google Scholar 

  36. Kaminsky DA, Mitchell J, Carroll N, James A, Soultanakis R, Janssen Y (1999) Nitrotyrosine formation in the airways and lung parenchyma of patients with asthma. J Allergy Clin Immunol 104:747–754

    Article  PubMed  CAS  Google Scholar 

  37. Beckman JS, Crapo JD (1997) The role of nitric oxide in limiting gene transfer: parallels to viral host defenses. Am J Respir Cell Mol Biol 16:495–496

    PubMed  CAS  Google Scholar 

  38. Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516

    Article  PubMed  CAS  Google Scholar 

  39. Maher P, Salgado KF, Zivin JA, Lapchak PA (2007) A novel approach to screening for new neuroprotective compounds for the treatment of stroke. Brain Res 1173:117–125

    Article  PubMed  CAS  Google Scholar 

  40. Fukuda K, Asoh S, Ishikawa M, Yamamoto Y, Ohsawa I, Ohta S (2007) Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress. Biochem Biophys Res Commun 361:670–674

    Article  PubMed  CAS  Google Scholar 

  41. Kajiya M, Sato K, Silva MJ, Ouhara K, Do PM, Shanmugam KT, Kawai T (2009) Hydrogen from intestinal bacteria is protective for Concanavalin A-induced hepatitis. Biochem Biophys Res Commun 386:316–321

    Article  PubMed  CAS  Google Scholar 

  42. Kajiya M, Silva MJ, Sato K, Ouhara K, Kawai T (2009) Hydrogen mediates suppression of colon inflammation induced by dextran sodium sulfate. Biochem Biophys Res Commun 386:11–15

    Article  PubMed  CAS  Google Scholar 

  43. Karin M (1999) The beginning of the end: IkappaB kinase (IKK) and NF-kappaB activation. J Biol Chem 274:27339–27342

    Article  PubMed  CAS  Google Scholar 

  44. Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257

    Article  PubMed  CAS  Google Scholar 

  45. Choi DW, Rothman SM (1990) The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci 13:171–182

    Article  PubMed  CAS  Google Scholar 

  46. Olney JW, Ho OL, Rhee V, DeGubareff T (1973) Letter: neurotoxic effects of glutamate. N Engl J Med 289:1374–1375

    Article  PubMed  CAS  Google Scholar 

  47. Ditsworth D, Priestley MA, Loepke AW, Ramamoorthy C, McCann J, Staple L, Kurth CD (2003) Apoptotic neuronal death following deep hypothermic circulatory arrest in piglets. Anesthesiology 98:1119–1127

    Article  PubMed  Google Scholar 

  48. Kuroda S, Siesjo BK (1997) Reperfusion damage following focal ischemia: pathophysiology and therapeutic windows. Clin Neurosci 4:199–212

    PubMed  CAS  Google Scholar 

  49. Matchett GA, Fathali N, Hasegawa Y, Jadhav V, Ostrowski RP, Martin RD, Dorotta IR, Sun X, Zhang JH (2009) Hydrogen gas is ineffective in moderate and severe neonatal hypoxia-ischemia rat models. Brain Res 1259:90–97

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by grant from the National Natural Science Foundation of China (No. 30972969). We sincerely thank Dr. Geng-bao Feng and Miss Kang-li Hui for their excellent technical assistance. We also sincerely thank Dr. Bing Guan for his assistance with pathology analysis and Dr. Yi Li for language editing.

Conflict of interest

All authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Xuejun Sun or Hua Jing.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shen, L., Wang, J., Liu, K. et al. Hydrogen-Rich Saline is Cerebroprotective in a Rat Model of Deep Hypothermic Circulatory Arrest. Neurochem Res 36, 1501–1511 (2011). https://doi.org/10.1007/s11064-011-0476-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-011-0476-4

Keywords

Navigation