Hydrogen inhalation, patients with Parkinson’s diseaseScientific Research

Authors:

Hirayama M, Ito M, Minato T, et al.

Published on: 08/12/2018

Inhalation of hydrogen gas elevates urinary 8-hydroxy-2′-deoxyguanine in Parkinson’s disease

Masaaki Hirayama,1 Mikako Ito,2 Tomomi Minato,1 Asako Yoritaka,3 Tyler W. LeBaron,4,5 and Kinji Ohno, MD, PhD2,*

Abstract

Hypoemia is one of the earliest and most common symptoms in Parkinson’s disease (PD). The benefits of hydrogen water on motor deficits have been reported in PD animal models and PD patients, but the effects of hydrogen on PD patients have not been studied. We conducted an 8-week washout study in 20 PD patients in a randomized, double-blind, placebo-controlled, crossover study. Patients inhaled approximately 1.2-1.4% hydrogen-air mixture or placebo for 10 minutes twice a day for 4 weeks. Low-dose hydrogen inhalation did not significantly affect clinical PD parameters, but increased urinary 8-OHdG concentrations by 16%. This increase in 8-OHdG was significantly lower than the over 300% increase in diabetes and more comparable to the increase after vigorous exercise. Although elevated reactive oxygen species are often associated with toxicity and disease, they also play an important role in mediating cytoprotective cellular adaptations in a process known as excitability. Increased hydrogen-induced oxidative stress and its ability to activate Nrf2, the NF-κB pathway, and the heat shock response have been previously reported. Although we did not observe any beneficial effects of hydrogen in our brief experiments, we believe that increased 8-OHdG and other reported hydrogen stress responses may suggest that its beneficial effects are partly or largely mediated by excitatory mechanisms. This study was approved by the Ethics Committee of the Nagoya University Graduate School of Medicine (approval number 2015-0295). This clinical study is registered with the University Hospital’s Medical Information Network (ID UMIN000019082).

Results

A randomized, double-blind, placebo-controlled, crossover study of 20 Parkinson’s disease patients inhaling approximately 1.2-1.4% hydrogen-air mixture or placebo for 10 minutes twice a day for 4 weeks found that OSIT- J (p = 0.77), UPDSR1 (P = 0.84) and UPDRS2 (P = 0.15) were not affected by hydrogen (Table 1). In contrast, 4 weeks of hydrogen inhalation increased urinary 8-OHdG excretion by 16%, which was statistically significant (P=0.02) (Table 1 and Figure 2).

Table 1

Metrics before and after inhalation of true and placebo hydrogen gas for 4 weeks

HydrogenPlacebo
BeforeAfterPBeforeAfterP
OSIT-J4.7±2.04.85±1.90.774.55±2.44.6±2.20.92
UPDRS12.2±1.62.3±1.90.842.7±2.42.4±1.90.41
UPDRS213.7±9.015.9±7.00.1516.6±9.116.8±6.30.93
8-OHdG/Cr (ng/mg Cr)9.5±9.711.0±5.90.029.2±6.99.7±6.80.59

Note: Date are expressed as the mean ± SD. P values are calculated by paired t-test. 8-OHdG: 8-Hydroxy-2′-deoxyguanine; Cr: creatine; UPDRS: Unified Parkinson’s Disease Rating Scale.

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Urinary 8-OHdG/Cr before and after inhalation of true and placebo hydrogen gas for 4 weeks.

Note: (A) Twenty Parkinson’s disease (PD) patients. P value by Student’s paired t-test is indicated. (B) Ten PD patients who inhaled hydrogen first. (C) Ten PD patients who inhaled placebo first. (B, C) No statistical significance by one-way analysis of variance. Date are expressed as the mean ± SE. 8-OHdG: 8-Hydroxy- 2′-deoxyguanine; Cr: creatine.

References

1. Ansari KA, Johnson A. Olfactory function in patients with Parkinson’s disease. J Chronic Dis. 1975;28:493–497. [PubMed] []
2. Doty RL, Singh A, Tetrud J, Langston JW. Lack of major olfactory dysfunction in MPTP-induced parkinsonism. Ann Neurol. 1992;32:97–100. [PubMed] []
3. Tissingh G, Berendse HW, Bergmans P, et al. Loss of olfaction in de novo and treated Parkinson’s disease: possible implications for early diagnosis. Mov Disord. 2001;16:41–46. [PubMed] []
4. Schapira AHV, Chaudhuri KR, Jenner P. Non-motor features of Parkinson disease. Nat Rev Neurosci. 2017;18:509. [PubMed] []
5. Baba T, Takeda A, Kikuchi A, et al. Association of olfactory dysfunction and brain. Metabolism in Parkinson’s disease. Mov Disord. 2011;26:621–628. [PubMed] []
6. Lerner A, Bagic A. Olfactory pathogenesis of idiopathic Parkinson disease revisited. Mov Disord. 2008;23:1076–1084. [PubMed] []
7. Duda JE, Shah U, Arnold SE, Lee VM, Trojanowski JQ. The expression of alpha-, beta-, and gamma-synucleins in olfactory mucosa from patients with and without neurodegenerative diseases. Exp Neurol. 1999;160:515–522. [PubMed] []
8. Tofaris GK, Garcia Reitbock P, Humby T, et al. Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human alpha-synuclein(1-120): implications for Lewy body disorders. J Neurosci. 2006;26:3942–3950. [PMC free article] [PubMed] []
9. Doty RL, Shaman P, Kimmelman CP, Dann MS. University of Pennsylvania Smell Identification Test: a rapid quantitative olfactory function test for the clinic. Laryngoscope. 1984;94:176–178. [PubMed] []
10. Hummel T, Sekinger B, Wolf SR, Pauli E, Kobal G. ‘Sniffin’ sticks’: olfactory performance assessed by the combined testing of odor identification, odor discrimination and olfactory threshold. Chem Senses. 1997;22:39–52. [PubMed] []
11. Saito S, Ayabe-Kanamura S, Takashima Y, et al. Development of a smell identification test using a novel stick-type odor presentation kit. Chem Senses. 2006;31:379–391. [PubMed] []
12. Iijima M, Kobayakawa T, Saito S, et al. Smell identification in Japanese Parkinson’s disease patients: using the odor stick identification test for Japanese subjects. Intern Med. 2008;47:1887–1892. [PubMed] []
13. Braak H, Del Tredici K, Bratzke H, Hamm-Clement J, Sandmann-Keil D, Rub U. Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson’s disease (preclinical and clinical stages) J Neurol. 2002;249:1–5. [PubMed] []
14. Dias V, Junn E, Mouradian MM. The role of oxidative stress in Parkinson’s disease. J Parkinsons Dis. 2013;3:461–491. [PMC free article] [PubMed] []
15. Sato S, Mizuno Y, Hattori N. Urinary 8-hydroxydeoxyguanosine levels as a biomarker for progression of Parkinson disease. Neurology. 2005;64:1081–1083. [PubMed] []
16. Hirayama M, Nakamura T, Watanabe H, et al. Urinary 8-hydroxydeoxyguanosine correlate with hallucinations rather than motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord. 2011;17:46–49. [PubMed] []
17. Ilida A, Nosaka N, Yumoto T, et al. The clinical application of hydrogen as a medical treatment. Acta Med Okayama. 2016;70:331–337. [PubMed] []
18. Fu Y, Ito M, Fujita Y, et al. Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson’s disease. Neurosci Lett. 2009;453:81–85. [PubMed] []
19. Fujita K, Seike T, Yutsudo N, et al. Hydrogen in drinking water reduces dopaminergic neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. PLoS One. 2009;4:e7247. [PMC free article] [PubMed] []
20. Ito M, Hirayama M, Yamai K, et al. Drinking hydrogen water and intermittent hydrogen gas exposure, but not lactulose or continuous hydrogen gas exposure, prevent 6-hydorxydopamine-induced Parkinson’s disease in rats. Med Gas Res. 2012;2:15. [PMC free article] [PubMed] []
21. Yoritaka A, Takanashi M, Hirayama M, Nakahara T, Ohta S, Hattori N. Pilot study of H2 therapy in Parkinson’s disease: a randomized double-blind placebo-controlled trial. Mov Disord. 2013;28:836–839. [PubMed] []
22. Katsumata Y, Sano F, Abe T, et al. The effects of hydrogen gas inhalation on adverse left ventricular remodeling after percutaneous coronary intervention for ST-elevated myocardial infarction-first pilot study in humans. Circ J. 2017;81:940–947. [PubMed] []
23. Ono H, Nishijima Y, Ohta S, et al. Hydrogen gas inhalation treatment in acute cerebral infarction: a randomized controlled clinical study on safety and neuroprotection. J Stroke Cerebrovasc Dis. 2017;26:2587–2594. [PubMed] []
24. Venetsanos AG, Huld T, Adams P, Bartzis JG. Source, dispersion and combustion modelling of an accidental release of hydrogen in an urban environment. J Hazard Mater. 2003;105:1–25. [PubMed] []
25. Sobue S, Yamai K, Ito M, et al. Simultaneous oral and inhalational intake of molecular hydrogen additively suppresses signaling pathways in rodents. Mol Cell Biochem. 2015;403:231–241. [PubMed] []
26. Ishibashi T, Sato B, Rikitake M, et al. Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritis: an open-label pilot study. Med Gas Res. 2012;2:27. [PMC free article] [PubMed] []
27. Yamaguchi Y, Haginaka J, Morimoto S, Fujioka Y, Kunitomo M. Facilitated nitration and oxidation of LDL in cigarette smokers. Eur J Clin Invest. 2005;35:186–193. [PubMed] []
28. Wu LL, Chiou CC, Chang PY, Wu JT. Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics. Clin Chim Acta. 2004;339:1–9. [PubMed] []
29. Dandona P, Thusu K, Cook S, et al. Oxidative damage to DNA in diabetes mellitus. Lancet. 1996;347:444–445. [PubMed] []
30. Okamura K, Doi T, Hamada K, et al. Effect of repeated exercise on urinary 8-hydroxy-deoxyguanosine excretion in humans. Free Radic Res. 1997;26:507–514. [PubMed] []
31. Orhan H, van Holland B, Krab B, et al. Evaluation of a multi-parameter biomarker set for oxidative damage in man: increased urinary excretion of lipid, protein and DNA oxidation products after one hour of exercise. Free Radic Res. 2004;38:1269–1279. [PubMed] []
32. Gomes EC, Silva AN, de Oliveira MR. Oxidants, antioxidants, and the beneficial roles of exercise-induced production of reactive species. Oxid Med Cell Longev. 2012;2012:756132. [PMC free article] [PubMed] []
33. Pedersen BK, Akerstrom TC, Nielsen AR, Fischer CP. Role of myokines in exercise and metabolism. J Appl Physiol (1985) 2007;103:1093–1098. [PubMed] []
34. Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007;13:688–694. [PubMed] []
35. Buxton GV, Greenstock CL, Helman WP, Ross AB. Critical view of rate constants for reactions of hydrated electrons, hydrogen atoms and hydroxyl radicals (•OH/•OH–) in aqueous solution. J Phys Chem Ref Data. 1988;17:513–886. []
36. Christl SU, Murgatroyd PR, Gibson GR, Cummings JH. Production, metabolism, and excretion of hydrogen in the large intestine. Gastroenterology. 1992;102:1269–1277. [PubMed] []
37. Strocchi A, Levitt MD. Maintaining intestinal H2 balance: credit the colonic bacteria. Gastroenterology. 1992;102:1424–1426. [PubMed] []
38. Perman JA, Modler S, Barr RG, Rosenthal P. Fasting breath hydrogen concentration: normal values and clinical application. Gastroenterology. 1984;87(6):1358–1363. [PubMed] []
39. Sone Y, Tanida S, Matsubara K, et al. Everyday breath hydrogen excretion profile in Japanese young female students. J Physiol Anthropol Appl Human Sci. 2000;19:229–237. [PubMed] []
40. Nakao A, Kaczorowski DJ, Wang Y, et al. Amelioration of rat cardiac cold ischemia/reperfusion injury with inhaled hydrogen or carbon monoxide, or both. J Heart Lung Transplant. 2010;29:544–553. [PubMed] []
41. Yun J, Finkel T. Mitohormesis. Cell Metab. 2014;19:757–766. [PMC free article] [PubMed] []
42. Ristow M, Zarse K, Oberbach A, et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A. 2009;106:8665–8670. [PMC free article] [PubMed] []
43. Gomez-Cabrera MC, Salvador-Pascual A, Cabo H, Ferrando B, Vina J. Redox modulation of mitochondriogenesis in exercise. Does antioxidant supplementation blunt the benefits of exercise training? Free Radic Biol Med. 2015;86:37–46. [PubMed] []
44. Aoki K, Nakao A, Adachi T, Matsui Y, Miyakawa S. Pilot study: Effects of drinking hydrogen-rich water on muscle fatigue caused by acute exercise in elite athletes. Med Gas Res. 2012;2:12. [PMC free article] [PubMed] []
45. Han L, Tian R, Yan H, et al. Hydrogen-rich water protects against ischemic brain injury in rats by regulating calcium buffering proteins. Brain Res. 2015;1615:129–138. [PubMed] []
46. Matchett GA, Fathali N, Hasegawa Y, et al. Hydrogen gas is ineffective in moderate and severe neonatal hypoxia-ischemia rat models. Brain Res. 2009;1259:90–97. [PubMed] []
47. Xie Y, Mao Y, Zhang W, Lai D, Wang Q, Shen W. Reactive oxygen species-dependent nitric oxide production contributes to hydrogen-promoted stomatal closure in Arabidopsis. Plant Physiol. 2014;165:759–773. [PMC free article] [PubMed] []
48. Murakami Y, Ito M, Ohsawa I. Molecular hydrogen protects against oxidative stress-induced SH-SY5Y neuroblastoma cell death through the process of mitohormesis. PLoS One. 2017;12:e0176992. [PMC free article] [PubMed] []
49. Spulber S, Edoff K, Hong L, Morisawa S, Shirahata S, Ceccatelli S. Molecular hydrogen reduces LPS-induced neuroinflammation and promotes recovery from sickness behaviour in mice. PLoS One. 2012;7(7):e42078. [PMC free article] [PubMed] []
50. Kawamura T, Wakabayashi N, Shigemura N, et al. Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo. Am J Physiol Lung Cell Mol Physiol. 2013;304:646–656. [PMC free article] [PubMed] []
51. Zhai X, Chen X, Shi J, et al. Lactulose ameliorates cerebral ischemia-reperfusion injury in rats by inducing hydrogen by activating Nrf2 expression. Free Radic Biol Med. 2013;65:731–741. [PubMed] []
52. Li DZ, Zhang QX, Dong XX, Li HD, Ma X. Treatment with hydrogen molecules prevents RANKL-induced osteoclast differentiation associated with inhibition of ROS formation and inactivation of MAPK, AKT and NF-kappa B pathways in murine RAW264.7 cells. J Bone Miner Metab. 2014;32:494–504. [PubMed] []
53. Xie Q, Li XX, Zhang P, et al. Hydrogen gas protects against serum and glucose deprivationinduced myocardial injury in H9c2 cells through activation of the NFE2related factor 2/heme oxygenase 1 signaling pathway. Mol Med Rep. 2014;10:1143–1149. [PubMed] []
54. Song G, Zong C, Zhang Z, et al. Molecular hydrogen stabilizes atherosclerotic plaque in low-density lipoprotein receptor-knockout mice. Free Radic Biol Med. 2015;87:58–68. [PubMed] []
55. Li Y, Li Q, Chen H, et al. Hydrogen gas alleviates the intestinal injury caused by severe sepsis in mice by increasing the expression of heme oxygenase-1. Shock. 2015;44:90–98. [PubMed] []
56. Li Y, Xie K, Chen H, Wang G, Yu Y. Hydrogen gas inhibits high-mobility group box 1 release in septic mice by upregulation of heme oxygenase 1. J Surg Res. 2015;196:136–148. [PubMed] []
57. Huang CS, Kawamura T, Peng X, et al. Hydrogen inhalation reduced epithelial apoptosis in ventilator-induced lung injury via a mechanism involving nuclear factor-kappa B activation. Biochem Biophys Res Commun. 2011;408:253–258. [PubMed] []
58. Zhuang Z, Sun XJ, Zhang X, et al. Nuclear factor-kappaB/Bcl-XL pathway is involved in the protective effect of hydrogen-rich saline on the brain following experimental subarachnoid hemorrhage in rabbits. J Neurosci Res. 2013;91:1599–1608. [PubMed] []
59. Nishiwaki H, Ito M, Negishi S, Sobue S, Ichihara M, Ohno K. Molecular hydrogen upregulates heat shock response and collagen biosynthesis, and downregulates cell cycles: meta-analyses of gene expression profiles. Free Radic Res. 2018;52:434–445. [PubMed] []
References

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