[Alternative Medicine Studies 2011; 1:e11] [page 45]

Hydrogen therapy may be apromising, safe and effectivetreatment for diabetic erectiledysfunction: a hypothesisJun Chen,1 Bin Zhang,1 Mingchao Li,2Tao Qi,1 Zheng Chen,1 Xuejun Sun,3Xiao Chen31Department of Infertility and SexualMedicine, The Third Affiliated Hospital,Sun Yat-Sen University, Guangzhou;2Department of Urology, Tongji Hospital,Tongji Medical College, HuazhongUniversity of Science and Technology,Wuhan; 3Department of Diving Medicine,Second Military Medical University,Shanghai, PR China

Abstract

Inhalation of hydrogen gas has been provento be an effective treatment for ischemia-reper-fusion injury by selectively reducing hydroxyland peroxynitrite radicals. There has been con-siderable evidence of hydrogen’s protectiveeffect against diseases related to oxidativeinjury, such as the ischemia-reperfusion injuryof the brain, liver and heart. More and morestudies suggest that radical oxygen species(ROS) play an important role in the develop-ment of diabetic erectile dysfunction (ED) andantioxidants can markedly decrease the produc-tion of ROS and improve the erectile function.We hypothesize that hydrogen therapy may be apromising, safe and effective treatment for dia-betic ED by reducing the production of ROS.

Introduction

Hydrogen is the lightest and most essentialchemical element, composing nearly 75% ofthe universe’s elemental matter.1 Hydrogen isseldom regarded as an important candidate inmedicine, especially as a therapeutic gas.2However, a recent study showed that hydrogeninhalation exhibited antioxidant and anti-apoptotic activities which protected the brainagainst ischemia-reperfusion injury by selec-tively reducing hydroxyl radical and peroxyni-trite, which are much more reactive than otherROS.3 Other researchers have indicated thathydrogen can also improve myocardial, hepaticischemia-reperfusion injury, neonatal hypox-ia-ischemia, Parkinson’s disease; oxidativestress induced cognitive decline and diabetesmellitus (DM).4-9

Oxidative stress-mediated neurovascular

alteration appears to play an integral role in thedevelopment of erectile dysfunction (ED) indiabetic populations.10,11 NO, the principalmediator of penile erection can react with otherradicals, such as superoxide anions, to produceperoxynitrite and contribute to numerouspathological conditions such as atherosclerosisand generalized reperfusion injury.12,13Hydroxyl radical is generated in biological sys-tems from superoxide anions and hydrogen per-oxide by the Haber-Weiss reaction or fromhydrogen peroxide by the Fenton reaction,14,15which is the strongest of the oxidant speciesand reacts indiscriminately with nucleic acids,lipids and proteins.3 A growing number of stud-ies suggested that radical oxygen species(ROS) play an important role in the develop-ment of diabetic ED and antioxidants canmarkedly decrease the production of ROS andimprove the erectile function. However, nostudy has been conducted to investigate theeffects of hydrogen in the treatment of diabeticED, in which ROS play a pivotal role.

Hydrogen is an important physiological regulatory factor withantioxidant protective effectswhich selectively reduces hydroxylradical and peroxynitrite generation

Hydrogen is the lightest and most abundantof chemical elements, constituting nearly 75%of the universe’s elemental mass.1 It is a color-less, odorless, nonmetallic, tasteless, highlyflammable diatomic gas which is mainly usedin fossil fuel processing and ammonia produc-tion.16 Recent basic and clinical research hasrevealed that hydrogen is an important physio-logical regulatory factor with antioxidant pro-tective effects on cells and organs.17

For both stroke and myocardial infarctionthere are now highly successful approaches torestore blood flow to the ischemic tissue. Sofar, however, research has failed to relieve thispathological cascade of oxidative damage afterreperfusion injury, the burst of reactive oxygenspecies irrevocably drives downstream signal-ing networks that lead to cellular necrosis andapoptosis. In this issue, Ohsawa et al. reportthat highly diffusible hydrogen gas can targetintracellular sources of reactive oxygenspecies and dose-dependently inhibit reperfu-sion-induced oxidative damage. H2 selectivelyreduces hydroxyl radical and peroxynitrite invitro and in vivo, which are much more reac-tive than other ROS.3

A recent study demonstrated that inhalationof H2, at an incombustible level, limited theextent of myocardial infarction resulting frommyocardial ischemia-reperfusion injury, andthereby preserved left ventricular (LV) func-tion in vivo and ex vivo. The anti-oxidantaction of molecular H2 may be explained, atleast partially, by direct ROS scavenging

effect.4 Hydrogen-rich saline improved post-ischemic functional recovery of rat hearts. Theimprovement in post-ischemic functionalrecovery was paralleled by a significant reduc-tion in infarct size, decreased plasma andmyocardium malondialdehyde (MDA) concen-tration, attenuation of cardiac cell apoptosisand DNA oxidative stress in at risk areas(AAR). Histological analysis revealed a sub-stantial decrease in hemorrhage and necrosisas well as a decrease in the number of leuko-cytes within the ischemic zone. This cardiacimprovement may result from radical oxygenspecies (ROS) scavenging effect of molecularH2.5 The inhalation of hydrogen gas was appli-cable for hepatic injury caused byischemia/reperfusion using mice. The portaltriad to the left lobe and the left middle lobe ofthe liver were completely occluded for 90 min,followed by reperfusion for 180 min. Inhalationof hydrogen gas (1-4%) during the last 190 minsuppressed hepatic cell death, and reduced lev-els of serum alanine aminotransferase andhepatic malondialdehyde. The results indicat-ed the potential benefits of inhalation of hydro-

Alternative Medicine Studies 2011; volume 1:e11

Correspondence: Jun Chen, Department ofInfertility and Sexual Medicine, the ThirdAffiliated Hospital of Sun Yat-Sen University,Guangzhou, Guangdong 510630, China. Tel: +86.20.85253235 - Fax: +86.20.87334510. E-mail: jchen121121@hotmail.com Bin Zhang, Department of Infertility and SexualMedicine, the Third Affiliated Hospital of SunYat-Sen University, Guangzhou, Guangdong510630, China. Tel: +86.20.85253235 - Fax: +86.20.87334510. E-mail: doc305@163.com.

Key words: gas medicine, hydrogen therapy, dia-betic erectile dysfunction.

Acknowledgments: this study was supported byNational Natural Sciences Foundation of China(No. 81070487), Doctoral Fund of Ministry ofEducation of China (No.20090171120078),Science and Technology Planning Project ofGuangdong Province, China (2010B031600038),Medical Scientific Research Foundation ofGuangdong Province, China (No. A2009190), theFundamental Research Funds for theCentralUniversities, Asia Pacific Society for SexualMedicine Research Grant (No.2008-2), and PfizerAsia Urology Research Grant (WS570255 ).

Conflict of interest: the authors report no con-flicts of interest.

Received for publication: 4 July 2011.Accepted for publication: 30 August 2011.

This work is licensed under a Creative CommonsAttribution NonCommercial 3.0 License (CC BY-NC 3.0).

©Copyright J. Chen et al., 2011Licensee PAGEPress, ItalyAlternative Medicine Studies 2011; 1:e11doi:10.4081/ams.2011.e11

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gen gas as an applicable method to reduceoxidative stress.6

In Parkinson’s disease, mitochondrial dys-function and the associated oxidative stressare major causes of dopaminergic cell loss inthe substantia nigra. Fu et al. examined effectsof ∼50%-saturated molecular hydrogen indrinking water before and after the stereotac-tic surgery on nigrostrital degeneration in a ratmodel of Parkinson’s disease. Molecular hydro-gen prevented both the development and pro-gression of the nigrostrital degeneration. Pre-and post-treatment with hydrogen preventedthe dopaminergic cell loss. The study suggest-ed that hydrogen water was likely able to retardthe development and progression ofParkinson’s disease by reducing the oxidativestress.7

Chronic physical restraint stress to miceenhanced levels of oxidative stress in the brainand impaired learning and memory.Consumption of hydrogen water ad- libitumthroughout the whole period suppressed theincrease in the oxidative stress and preventedcognitive impairment, whereas hydrogenwater did not improve cognitive ability whenno stress was provided. Thus, continuous con-sumption of hydrogen water reduces oxidativestress in the brain, and prevents the stress-induced decline in learning and memorycaused by chronic physical restraint. Theresults showed that hydrogen water may beapplicable for preventive use in cognitive orother neuronal disorders.8

Oxidative stress is recognized widely asbeing associated with diabetes. Hydrogen-richwater intake was associated with a trend ofdecreased serum concentrations of oxidizedLDL and free fatty acids, and increased plasmalevels of adiponectin and extracellular-super-oxide dismutase. In 4 of 6 patients withimpaired glucose tolerance (IGT), intake ofhydrogen-rich water normalized the oral glu-cose tolerance test, these results suggest thatsupplementation with hydrogen-rich purewater had beneficial effects on lipid and glu-cose metabolism in humans. The results sug-gested that a sufficient supply of this watermay prevent or delay development and progres-sion of type-2 diabetes mellitus and insulinresistance by providing protection againstoxidative stress.9

Reactive oxygen species play animportant role in diabetes-associated erectile dysfunction

ED is defined as the inability to achieve ormaintain erections sufficient for satisfactorysexual intercourse.18 Approximately 52% ofmen between the age of 40 and 70 years sufferfrom ED due to various causes, such as patho-physiological changes in nerves, blood vesi-cles, corporal smooth muscle tissue, and

endothelial cells.12,19 As most of these risk fac-tors for development of ED are inherent to dia-betes mellitus, the current estimates suggestthat as many as 75% of men with diabetes willdevelop some degree of ED at an earlier age.20

Hyperglycemia induced overproduction ofsuperoxide is an initiating event in the activa-tion of pathways involved in the pathogenesisand complications from DM.21,22 Oxidativestress-mediated neurovascular alterationappears to play an integral role in the develop-ment of ED in diabetic populations.10,11 Nitricoxide (NO) is the principal mediator of penileerection.12 Nitrergic nerves and endothelialcells directly release NO in the penis, where itstimulates guanylyl cyclase to produce cGMPand lowers intracellular calcium levels.23 Thistriggers the relaxation of arterial and trabecu-lar smooth muscles leading to arterial dilata-tion, venous constriction, which result in apenile erection.24 The presence of oxygen freeradicals inactivates NO and reduces its physio-logic impact, NO is a free radical and can reactwith other radicals, such as superoxide anions,to produce peroxynitrite and contributes tonumerous pathological conditions such as ath-erosclerosis and generalized reperfusioninjury.13 Peroxynitrite is a highly toxic mole-cule which causes apoptosis, serious damageto cellular mechanisms, including small penileresistance arteries.21,22 High concentrations ofperoxynitrite can produce highly ROS, whichcan initiate a cascade of redox reactions trig-gering apoptosis and evoke cytotoxic effects onendothelial and neuronal cells. Increasedapoptosis and resulting disruption of cellularprocesses in turn lead to reduced expressionlevels of eNOS and nNOS.25 Additionally,increased auto-oxidation of glucose and oxida-tion of low-density lipoproteins have beendescribed in diabetes, which may result in theoverproduction of free radical species, leadingto smooth muscle dysfunction.26

It is postulated that the hydroxyl radical isgenerated in biological systems from superox-ide anion and hydrogen peroxide by the Haber-Weiss reaction or from hydrogen peroxide bythe Fenton reaction.27,28 It is biologicallyimportant to eliminate hydroxyl radicals,because no enzyme detoxifies hydroxyl radi-cals.14,15 Hydroxyl radical is the strongest ofthe oxidant species and reacts indiscriminate-ly with nucleic acids, lipids and proteins.3Hydroxyl radicals play an important role in thediabetes-related ED.29,30

Previous studies indicate that diabetes-induced decreased NO levels in corporealareas could be mainly due to the lack of essen-tial cofactors for NOS activity.31 However, stud-ies involving the systemic and cavernosal vas-culature showed that superoxide-induced inac-tivation, rather than reduced activity of NOS,was the major cause of reduced NO levels.32

A growing number of studies suggest ROS

play an important role in diabetic ED andantioxidants can markedly decrease the pro-duction of ROS and improve the erectile func-tion. A study indicated that non-insulindependent DM caused excessive generation offree radicals, decreased scavenging systems,marked elevation of malondialdehyde, anddecreased glutathione levels in diabetic rats,all of which lead to ED.33 An in vitro study sug-gested that corpus cavernosal vascular smoothmuscle cells (CCSMC) grown in a high glucosemilieu exhibited changes in ROS which weresignificantly increased; after the cells wereexposed to vitamin E for 14 days there was areduction in ROS formation.34 ROS productionwas increased in penile tissue and erectilefunction was decreased in diabetic rats whilethe administration of the antioxidant α-lipoicacid reduced the ROS production and improvedthe erectile function in diabetic ED rats.35Khan et al. reported that overproduction ofsuperoxide anion may play an important rolein the development of diabetic ED. NO- andelectrical field stimulated -mediated cavernos-al smooth muscle relaxation was impaired in arabbit model of diabetes but superoxide dismu-tase (SOD, the enzyme that accelerates thebreakdown of the superoxide anion, O2-toH2O) significantly reversed the impaired relax-ation.36 Bivalacqua et al. reported that super-oxide anion was increased in diabetic rats andthat diabetic rats transfected with AdCMVEC-SOD had reduced corporal superoxide anionlevels and increased cavernosal cGMP levels byincreasing NO bioavailability. Adenoviral genetransfer of EC-SOD could restore erectile func-tion by reducing the production of superoxideanion in diabetic rats.37 Kawakami et al.reported that the superoxide dismutase (SOD)mimetic tempol increased erectile functionthrough modulating oxidative stress-relatedgenes (SOD1, SOD2, GP x 1, CAT, NOS2,NOS3) in diabetic rats.38 Of 84 reactive oxida-tive stress and antioxidant genes 32 were iden-tified specific to diabetic rats compared tohealthy controls. Tempol restored erectilefunction by reducing ROS and decreasingapoptosis in diabetic rats.39 Sildenafil treat-ment, the first-line pharmacotherapy for ED,rapidly and chronically improved vascularrelaxation in diabetic rats by decreasing super-oxide formation and membrane expression ofthe NAD(P)H oxidase subunit gp91phox andRac.40

HypothesisWe hypothesize that hydrogen gas may be a

promising, safe and effective agent for thetreatment of diabetes-related ED by reducinglevels of hydroxyl radicals and peroxynitrite.

Our hypothesis is based on the theory thatmolecular hydrogen can selectively reducehydroxyl radical and peroxynitrite levels invitro and in vivo, as hydroxyl radicals and per-

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oxynitrite are much more reactive than otherROS.3

H2 has a number of advantages: i) it effec-tively neutralizes hydroxyl radicals in livingcells, unlike most known antioxidants, whichare unable to successfully target organelles;3ii) it has favorable distribution characteristics:it can penetrate biomembranes and diffuseinto the cytosol, mitochondria and nucleus;3iii) despite the moderate reduction activity ofH2, its rapid gaseous diffusion might make ithighly effective for reducing cytotoxic radicals.Its ability to protect nuclear DNA and mito-chondria suggests that it could reduce the riskof life style-related diseases and cancer:3 iv) itis likely that H2 is mild enough not to disturbmetabolic oxidation reduction reactions or todisrupt ROS involved in cell signaling-unlikesome antioxidant supplements with strongreductive reactivity, which increase mortality,possibly by affecting essential defensive mech-anisms.3

We will design a study to prove our hypothe-sis. Diabetic ED rats are given H2– saturatedwater for 8 weeks. After 8 weeks, we will meas-ure the production of hydroxyl radicals, perox-ynitrite, and NO, erectile function, liver andkidney function to observe if hydrogen admin-istration improves erectile function withoutside effects through neutralizing hydroxyl rad-icals and peroxynitrite. We will also examinethe production of the ROS involved in cell sig-naling to observe whether hydrogen disruptstheir normal physiological function or not.

The safety of hydrogen for humans isdemonstrated by its application in Hydreliox,an exotic breathing gas mixture of 49% hydro-gen, 50% helium and 1% oxygen, which is usedfor the prevention of decompression sicknessand nitrogen narcosis during very deep techni-cal diving.41 Also no adverse effects have beenfound using drinking hydrogen water in ahuman study.42 A study showed that 20 sub-jects with potential metabolic syndrome con-sumed 1.5-2.0 l/day of H2– saturated water for8 weeks, the treated subjects showed signifi-cant improvements in liver and kidney func-tion,43 which showed that H2 had no toxic sideeffects on liver and kidney and may even pro-tect liver and kidney function. Another studyalso showed that hemodialysis patients treatedwith dialysis solution with H2 for 6 months hadno adverse clinical signs or symptoms.44

Hydrogen gas may be a promising, safe andeffective agent for the treatment of diabetes-related ED by reducing hydroxyl radical andperoxynitrite levels.

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