Application of hydrogen and hydrogen water in the treatment of macular degeneration, retinopathy, glaucoma, cataract, etc.

We present you a translated from English medical report published in 2016, which presents the collected scientific data on the therapeutic action of hydrogen gas (H2) in Ophthalmology. At the end of the article we have placed a link to the official English text. The figures you will encounter as you read indicate a specific study on patients, the results of which were used in the report. At the end of the official English document you will find a complete list of links to the numbered clinical studies in question. The benefits of taking water enriched with hydrogen gas (hydrogen water) to protect and support vision are already well known. This scientific publication discusses the therapeutic effects of the direct application of hydrogen water and hydrogen gas-enriched saline on the eye. Despite the length of the text, we assure you that the reading is worthwhile. Especially if you have impaired vision. By the titles of the different parts of the report you can easily find the information about a specific eye disease.

The potential use of hydrogen as a successful therapeutic strategy against eye diseases.

Abstract

Hydrogen, one of nature's most well-known molecules, has numerous medical applications due to its ability to selectively neutralize cytotoxic free radicals and alleviate dangerous inflammation. Hydrogen exerts protective effects on a variety of reactive oxygen species (ROS)-related diseases, including those caused by transplantation and intestinal graft injury, chronic inflammation, ischemia/reperfusion injury, etc. Particularly in the eye, hydrogen has been used to counter multiple ocular pathologies in ophthalmic models. Here we systematically review the ophthalmic uses of hydrogen and discuss the underlying mechanisms of hydrogen-induced beneficial effects. We believe that the protective effects of hydrogen, as evidenced by these groundbreaking studies, will enrich our pharmacological knowledge of this natural element and shed light on the discovery of a new therapeutic strategy against ocular diseases.

Introduction

Reactive oxygen species/free radicals (ROS) are a group of highly reactive molecules that are generated during energy-generating biochemical reactions and cellular functions.1 -3 Among these, physiological ROS are recognized as necessary signaling molecules in their own right. (H2MEDICAL: Medics note that there are free radicals that are both necessary and beneficial to the body.) They are capable of oxidizing phosphatases, kinases, and other vital proteins and thus effectively modulating metabolism and the immune system.4 Nonetheless, cytotoxic ROS subtypes, such as hydroxyl radicals (- OH) and peroxynitrite (ONOO-) , degrade the mitochondrial membrane and trigger the release of cytochrome-c, which further activates the downstream apoptotic cascade.5 This leads to the need to promptly eliminate cytotoxic ROS without losing other physiologically useful ROS that are intrinsically linked to biological processes.

In general, enzymatic and nonenzymatic antioxidants build up endogenous antioxidant defenses to selectively neutralize cytotoxic ROS. However, if oxidative stress consistently accumulates in the eye and protection by endogenous antioxidants is insufficient to neutralize excess ROS or maintain cellular homeostasis, this excessive oxidative stress leads to deleterious effects and ultimately causes cell death.6,7 Thus far, data collected suggest that the etiology of multiple ocular diseases, including cataracts, glaucoma, age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy (DR), and multiple traumatic injuries,8 are directly related to ROS damage. Therefore, the administration of highly effective antioxidants is necessary and logical to inhibit the progression of ocular pathologies and protect the eyes from oxidative damage (Figure 1). The beneficial effects induced by the application of antioxidants for the treatment of ocular diseases are inspiring.9,10 However, several factors hinder the therapeutic topical application of these exogenous scavengers, such as low membrane permeability of the eye and high toxic side effects. Furthermore, these drawbacks would limit the application of these therapies to a narrow window of therapeutic dose.

Hydrogen, a colorless, tasteless, and odorless diatomic gas, was initially recognized as a medical therapeutic substance in 1975.12 Subsequently, Ohsawa and his associates. 13 identified hydrogen-induced protective effects in a rat model of cerebral infarction in 2007 and highlighted the discovery of hydrogen as a gaseous free radical scavenging agent.Hydrogen-induced therapeutic effects have since been reported on a wide range of diseases, including transplant-induced intestinal graft injury, cognitive deficits, inflammatory diseases, Parkinson's disease, metabolic syndromes, and ischemia-reperfusion (I/R) injury in brain, liver, myocardium, intestine, and kidney.14-22

Hydrogen can exert antioxidant and antiapoptotic activity through selective neutralization of cytotoxic ROS, such as - OH and ONOO-. Meanwhile, signaling ROS playing metabolic roles, such as superoxide and hydrogen peroxide, are far less affected.13 Unlike other antioxidants with strong redox reactivity, hydrogen does not disrupt physiological oxidation reactions nor does it impair basic defense mechanisms. Recently, it has been confirmed that hydrogen can regulate the expression levels of several endogenous antioxidant enzymes, including superoxide dismutase, glutathione peroxidase, glutathione reductase, and glutathione transferase.23,24 These advantages suggest that the administration of hydrogen therapy may act as a safe and effective strategy against ROS-related disorders without causing side effects.

Hydrogen can permeate through membranes and diffuse into cell organelles (e.g., mitochondria and nuclear DNA) and thus gain access to the intracellular source of cytotoxic ROS.13,24 Based on the favorable distribution characteristic, hydrogen is very effective in reducing the level of cytotoxic ROS that damage nuclear DNA and mitochondria. Hydrogen inhalation has been found to be more effective than "Edaravone," an approved strong antioxidant in Japan, in ameliorating the effects caused by ischemia oxidative damage in neurons.25 In addition, hydrogen is considered an anti-inflammatory agent because it significantly reduces circulating levels of multiple inflammatory cytokines, such as chemokine (C-C motif), C-cell ligand 2 (CCL2), interleukin (IL)-1β, IL-6, and tumor necrosis factor-α.26-28, Hydrogen particularly enhances the accumulation of activated microglia, which indicates inflammation and remodeling

Hydrogen is administered by inhalation to the subject using a ventilator circuit or nasal cannula.30-32 Further study indicates that hydrogen can be taken dissolved in water or in its solubilized form, via hydrogen-rich saline (HRS). These are mobile and easy to control and administer methods of intake.24,33,34 More importantly, higher concentrations of hydrogen can be achieved dissolved in water or incorporated into saline. So far, both in vitro and in vivo studies have confirmed that the antioxidant properties of HRS can reduce the incidence of ROS-related diseases. HRS can be administered orally or as peritoneal or intravenous injections.

The main guideline and goal of potential clinical practice is to ensure safe hydrogen delivery and accurate performance analysis. The tissue compatibility of hydrogen is satisfactory because it is an endogenous substance that is continuously produced in the human gut.40 From a safety perspective, hydrogen outperforms many other antioxidants because it does not exhibit toxicity even at high concentrations. Hydrogen inhalation is already used to prevent decompression sickness in divers and provides good safety profiles

Hydrogen can modulate several biological functions and exhibits antioxidant and anti-inflammatory effects. Hydrogen's ability to neutralize free radicals, especially hydroxyl radicals, as well as other harmful ROS, can be used to treat or prevent ocular disorders associated with oxidative stress. In clinical practice, the ophthalmic use of hydrogen remains an almost unknown field. A series of pioneering experiments, based on laboratory evidence, have verified the valuable potential for developing hydrogen into a therapeutic agent against ocular diseases (Figure 2). Here, we summarize the current use of hydrogen in ophthalmic experiments and discuss its potential clinical applicability (Table 1).

Potential therapeutic effects in retinal degeneration

Retinal degeneration (RD) is a heterogeneous group of inherited retinal dystrophies characterized by progressive photoreceptor apoptosis.41-43 Current therapeutic strategies against RD include gene therapy, nutritional supplementation, antiapoptotic therapy, retinal transplantation, retinal prostheses, and stem cell therapy. However, the therapeutic effects of the aforementioned approaches remain unsatisfactory due to the complex etiology and chronic cycle of pathological progression.44,45 ROS has been shown to play a key role in caspase-independent photoreceptor apoptosis in PD.46 This idea is further supported by the fact that multiple antioxidants have been successful in effectively suppressing photoreceptor degeneration in models of PD.47 -49 Given the potent free radical scavenging ability of hydrogen, it is reasonable to suggest that exogenous hydrogen supplementation may alleviate oxidative stress in PD and act as a therapeutic strategy to delay or prevent photoreceptor degeneration.

Overexposure to light can induce the formation and accumulation of ROS in the retinas and ultimately lead to photoreceptor apoptosis.43,49 The pathologic mechanism of light-induced DR is in part similar to that of PD. Therefore, this highly reproducible model has been widely used in pathological and therapeutic studies of human RD. So far, two independent studies have found that a saturated hydrogen solution protects the retina from light-induced damage by attenuating oxidative stress.51 In more detail, electron microscope investigations have found that hydrogen treatment protects photoreceptor cell organelles against light-induced damage. To some extent, these microstructural results confirm that hydrogen can penetrate membranes and then enter the nucleus and mitochondria. Moreover, the concentration of malondialdehyde in the retina, a putative marker for lipid peroxidation, was significantly reduced by hydrogen therapy, indicating that the protective effects of hydrogen are due to its antioxidant properties.50 These encouraging findings, based on phototoxicity models, verify the efficacy of hydrogen in halting photoreceptor degeneration and the development of a new therapeutic agent to prevent retinal damage in age-related macular degeneration or retinitis pigmentosa. In the long term, delaying the onset and progression of RD through clinical hydrogen therapy and establishing an effective administrative protocol are the focus of future research.

Potential therapeutic effects against diabetic retinopathy (DR)

DR is the leading cause of blindness in the workforce of developed countries and also acts as a significant cause of blindness in the adult population.52 The overall prevalence of retinopathy among patients with diabetes is approximately 26%. Both clinical and experimental studies have shown that DR is closely associated with oxidative stress: ROS-induced biochemical changes can cause both structural and functional abnormalities in the microvasculature of diabetic retinas, leading to blood-retinal barrier breakdown.53,54 The blood-retinal barrier is critical for the separation of retinal neuronal elements from the circulation and the protection of the retina from circulating inflammatory cells and cytotoxic elements.55 Therefore, ROS is considered a major contributor to DR pathology. A new study sought to investigate the effect of hydrogen-enriched HRS saline on streptozotocin-induced mouse model of DR. HRS was found to inhibit caspase activity, reduce retinal apoptosis, and decrease vascular permeability.56 In addition, HRS therapy attenuated retinal parenchymal thickening. Another study also demonstrated the action of HRS in ameliorating streptozotocin-induced DR and found that the blood-retinal barrier was effectively preserved.57

ROS can regulate vascular endothelial growth factor (VEGF) expression levels and enhance VEGF receptor activity through complex signaling network effects. A pioneering study based on a hyperoxia-induced mouse model found that HRS counteracted CNV and reduced VEGF expression by inhibiting oxidative stress.60 Therefore, the anti-VEGF property is considered as another functional protective action of hydrogen gas. These preliminary studies suggest that hydrogen acts as a successful method to further clinical treatment of DR. A randomised, double-blind, placebo-controlled, crossover study has already found that the addition of HRS improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance.61 These effects of hydrogen may be applied to the treatment of diabetic complications, particularly DR, in which metabolic derangement plays a key role.

The potential therapeutic effects against traumatic optic neuropathy

Traumatic optic neuropathy is one of the most devastating causes of permanent visual loss and total blindness. After traumatic injury, such as optic nerve crush, prominent signs of apoptosis of retinal ganglion cells (RGCs) are found in the injured retinas. 62 Oxidative stress is considered a pathological factor that mediates the posttraumatic apoptotic process of RGCs. 63 A pioneering study found that hydrogen promoted survival of RGCs and improved recovery of visual function in a mouse model of optic nerve atrophy.64 Furthermore, terminal deoxynucleotidyl transferase dUTP labeling and malondialdehyde staining assays suggest that neuroprotective effects are mediated by suppression of cell death induced by cytotoxic free radicals. These instrumental findings highlight the possibility of using hydrogen as an effective agent against traumatic optic neuropathy in clinical practice.

Potential therapeutic effects against cataract

Cataract is the leading cause of blindness worldwide and affects up to 80% of the human population over the age of 70 years.65 Its prevalence is increasing in many countries due to the growth of the aging population. Currently, the only effective treatment for cataracts is surgical removal and replacement with an artificial intraocular lens.66 However, an initial study has shown that hydrogen acts as an alternative therapy for cataract patients.23 It has been shown that hydrogen can slow cataract formation and restore antioxidant capacity in a selenite cataract model by maintaining the activity of multiple enzymatic and nonenzymatic antioxidants. Malondialdehyde accumulation in the lens of selenite-treated rat was also effectively suppressed, indicating that hydrogen eventually prevents lens membrane oxidation. According to classical theories, ROS is a crucial etiological contributor to cataract occurrence: oxidative stress leads to a surge of deleterious biochemical reactions in the lens, including crosslinking and aggregation of lens proteins, peroxidation of membrane lipids, apoptosis of lens epithelial cells, and the eventual formation and progression of cataracts.67 In view of hydrogen's potent ability to eliminate free radicals (ROS), it is prudent to further investigate its therapeutic effects on cataract pathology in clinical settings.

Potential therapeutic effects against corneal alkali damage

Accidental alkali burn is a terrible trauma to the eye that leads to acute inflammation and secondary pathologic corneal neovascularization. The balance between angiogenic and antiangiogenic factors determines the fate of corneal neovascularization as well as prognostic vision.68,69 Previously available therapies to prevent the onset of corneal neovascularization, such as antiangiogenic drugs, argon laser photocoagulation, photodynamic therapy, and limbal stem cell transplantation, among others, ROS activate nuclear factor kappa B (NF-kB) transcription factor, which is then translocated into the nucleus to induce the expression of inflammatory cytokines such as VEGF, monocyte chemotactic protein-1 (MCP-1), IL, and tumor necrosis factor- α.70 These cytokines not only cause corneal neovascularization but also activate inflammatory cells that further exacerbate inflammation. Therefore, ROS should be considered a key trigger for pathologic corneal neovascularization and the inflammatory response after the burn. This hypothesis was confirmed by an animal study: ROS can directly lead to pathological corneal neovascularization by activating the NF-kB pathway in the mouse cornea after burn-induced injury.71 More importantly, topical application of a hydrogen-enriched solution significantly reduced angiogenesis in these corneas. Hydrogen water irrigation was found to significantly inhibit phosphorylation of NF-kB and reduce the level of VEGF protein. These encouraging findings suggest that oxidative stress at the onset of corneal injury can be strongly reduced. Hydrogen may become a potent treatment against angiogenesis in corneal alkali burn.

Potential therapeutic effects against glaucoma

Transient elevation of intraocular pressure is known to cause ischemia/reperfusion (I/R) injury to the retina and leads to necrosis and apoptosis of retinal neurons.72,73 These pathologic features closely resemble those of acute angle-closure glaucoma. The underlying mechanisms of I/R damage are closely related to free radical (ROS) formation, which has been recognized as contributing to the pathogenesis of glaucomatous neurodegeneration.74 Encouragingly, it has been shown that endogenous supplementation with antioxidant enzymes or potent antioxidants can delay or prevent ischemia/reperfusion injury in many mammalian retinas.75,76 In a recent mouse-model-based study, continuous administration of hydrogen-enriched eye drops immediately increased vitreous hydrogen concentration and suppressed I/R-induced oxidant stress, leading to a reduction in retinal neuronal apoptosis.39 Furthermore, hydrogen treatment was confirmed to prevent the activation of microglia that leads to ongoing neurodegeneration in injured retinas. Another study aimed at investigating the antiapoptotic mechanism of hydrogen-rich saline(HRS) therapy found that HRS reduced retinal I/R damage by inhibiting poly ADP-ribose polymerase 1, a nuclear enzyme involved in the regulation of multiple pathophysiological cellular procedures, including DNA oxidation and caspase-3-mediated apoptosis.77 These antiapoptotic and anti-inflammatory properties lead to continued further testing of the therapeutic effects of hydrogen against glaucomatous pathologies in future clinical practice.

Glutamate-induced excitotoxicity is another intraocular pressure-independent factor contributing to apoptosis of RGCs in glaucoma.78 Administration of HRS reduces excitotoxic glutamate damage and improves retinal recovery in guinea pigs.38 These beneficial results can be attributed to suppression of glial cells and promotion of glutamate clearance. These underlying mechanisms add to our knowledge of hydrogen as a novel therapeutic agent in the treatment of glaucoma.

Conclusion

The therapeutic medical gas hydrogen may act as a reasonable approach to treat oxidative stress-related disease. Hydrogen is a promising gaseous agent that has come to the forefront of therapeutic research in the last few years. It can selectively reduce cytotoxic ROS and exert organ-protective effects by regulating oxidative stress and inflammation. Hydrogen is so mild that it does not disrupt metabolic redox reactions and does not interfere with the action of necessary free radicals involved in cell signaling. As highlighted earlier, the effectiveness and safety of hydrogen in improving ocular pathologies have been verified through a series of experiments. The pioneering experiments reviewed in this report ignite the hope of discovering a new, easy and universal therapeutic agent against ocular diseases. Future hydrogen therapy should strive to establish well-defined application guidelines and define precise indications for clinical practice.

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Link to the original scientific report and references in English: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878665/

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