Novel Role of Molecular Hydrogen: The End of Ophthalmic Diseases?

Abstract

Molecular hydrogen (H₂) is a colorless, odorless, and tasteless gas which displays non-toxic features at high concentrations. H₂ can alleviate oxidative damage, reduce inflammatory reactions and inhibit apoptosis cascades, thereby inducing protective and repairing effects on cells. H₂ can be transported into the body in the form of H₂ gas, hydrogen-rich water (HRW), hydrogen-rich saline (HRS) or H₂ produced by intestinal bacteria. Accumulating evidence suggest that H₂ is protective against multiple ophthalmic diseases, including cataracts, dry eye disease, diabetic retinopathy (DR) and other fields. In particular, H₂ has been tested in the treatment of dry eye disease and corneal endothelial injury in clinical practice. This medical gas has brought hope to patients suffering from blindness. Although H₂ has demonstrated promising therapeutic potentials and broad application prospects, further large-scale studies involving more patients are still needed to determine its optimal application mode and dosage. In this paper, we have reviewed the basic characteristics of H₂, and its therapeutic effects in ophthalmic diseases. We also focus on the latest progress in the administration approaches and mechanisms underlying these benefits.

Keywords: molecular hydrogen; ophthalmic diseases; oxidation stress.

Figure 1

The emerging applications of hydrogen in the treatment of various ophthalmological diseases. Created with BioRender.com.

Figure 2

The fundamental principles underlying the therapeutic effects of H₂ in ophthalmological pathologies. H₂, molecular hydrogen; •OH, hydroxyl radical; ONOO⁻, peroxynitrite; ROS, reactive oxygen species; Nrf2, nuclear factor erythroid 2-related factor 2; CAT, catalase; GPX1, glutathione peroxidase 1; GR, glutathione reductase; ASK1, apoptosis signal-regulating kinase 1; P38MAPK, p38 mitogen activated protein kinase; NOX, NADPH Oxidases; TNF-α, tumor necrosis factor alpha; IL, interleukin; NF-κB, nuclear factor kappaB; TGF-β, transforming growth factor-beta; MIP 1, macrophage inflammatory protein 1.LTC4, leukotriene C4; AA, arachidonic acid; STEAP3, six-transmembrane epithelial antigen of the prostate 3; SLC11A2, solute carrier family 11 member 2; DMT1, divalent metal transporter 1; H₂O₂, hydrogen peroxide; PL, phospholipid; PLOOH, phospholipid hydroperoxides; NLRP3, NOD-like receptor family pyrin domain containing 3; RAS, rat sarcoma; ERK1/2, extracellular signal-related kinases 1 and 2; JNK, Jun N-terminal kinase; BCL-2, B cell lymphoma protein-2; PI3K, phosphatidylinositol 3-kinases; GSK3β, glycogen synthase kinase-3beta. Created with BioRender.com.

Figure 3

The mechanism of oxidative stress and its damage to DNA, lipids and proteins. (1) •OH and ONOO⁻ production mechanism. (2) Damage of chromosome and mitochondrial DNA by •OH and •NO₂ and its possible consequences. (3) The α-carbon site of amino acid residues can form stable carbon-centered radicals with hydroxyl radicals and react with O₂ to form alkyl peroxyl groups. Peroxyl radicals can be removed via an elimination reaction that releases HO₂• and generates an imine, which subsequently undergoes hydrolysis and thus gives rise to backbone fragmentation. In addition, peroxyl radicals can extract hydrogen atoms from another species to produce hydroperoxide. The subsequent decomposition of these hydroperoxides to radicals can also result in backbone fragmentation via an alkoxyl–radical-mediated process. (4) LH is a lipid with allylic hydrogens, which are present in polyunsaturated fatty acids, including arachidonic acid. The reaction of •OH and LH leads to lipid peroxidation and eventually causes autophagy and apoptosis. LH, luteinizing hormone; CAT, catalase; L•, an alkoxyl radical; LOO•, peroxyl radical; LOOH, a lipid hydroperoxide; QH•−, ubisemiquinone; •OH, hydroxyl radical; H₂O₂, hydrogen peroxide; O₂^•−, superoxide; ONOO⁻, peroxynitrite; •NO, nitric oxide; HO₂•, hydroperoxyl radical; ETC, electron transport chain; NOX4, NADPH oxidase 4; ONOOH, peroxynitrous acid; MAPKs, mitogen-activated protein kinases; JNK, Jun N-terminal kinase; ERK, extracellular signal-regulated kinase; PKC, protein kinase C; AMPK, adenosine monophosphate-activated protein kinase; mTOR, mammalian target of rapamycin; IKK, IκB kinase; NF-κb, nuclear factor κB. Created with BioRender.com.

Figure 4

Common routes of H₂ administration in ophthalmology. H₂, molecular hydrogen. Created with BioRender.com.