The Molecular Biological Mechanism of Hydrogen Therapy and Its Application in Spinal Cord Injury

Figures & data

Figure 1 Molecular action mechanism of hydrogen in biology.

Figure 2 Advantages of hydrogen therapy in treating spinal cord injury.

Figure 3 Methods of hydrogen delivery.

Table 1 Basic Research of Hydrogen in the Treatment of Spinal Cord Injury

Cells/Animals	Treatments	Duration	Effects	Biomarkers Evaluated	References
BV2 cell/Sprague‒Dawley rats	Ferromagnetic fluid hydrogel for slow release of hydrogen	8 weeks post injury	Reducing the expression of activated microglia and proinflammatory factors in SCI rats through the NF-κB pathway. Significantly promotes axonal directed regeneration and functional recovery after spinal cord injury	IL-1β↓, IL-6↓, iNOS↓, TNF-α↓, P-P65↓, P-IκB↓	[102]
Bone mesenchymal stem cell/Sprague‒Dawley rats	Hydrogen-Rich Cell Culture Medium/Hydrogen-Rich Saline	28 days post injury	Hydrogen can repair spinal cord injury by reducing inflammatory response and oxidative stress at the injury site and enhancing the migration and proliferation of bone marrow mesenchymal stem cells	TNF-α↓, IL-1β↓, IL-6↓, MDA↓, SOD↑	[101]
Sprague‒Dawley rats	Hydrogen-Rich Saline	7 days post injury	The levels of IL-6 and TNF-α were significantly decreased in hydrogen-rich saline treated group after SCI, and apoptosis was also significantly reduced	TNF-α↓, IL-6↓	[113]
Sprague‒Dawley rats	Hydrogen gas inhalation	140 minutes	Hydrogen inhalation exerts a concentration-dependent protective effect on the spinal cord, and GLT-1 is involved in this protective effect	GLT-1↓	[103]
Sprague‒Dawley rats	Hydrogen-Rich Saline	7 days from surgery	Hydrogen-rich saline can dose-dependently decrease morphine tolerance, reduce proinflammatory cytokine expression, inhibit astrocyte activation, reduce GLT-1 and GS nitration, and inhibit membrane transport of NMDA receptors	TNF-α↓, IL-1β↓, IL-6↓, GLT-1↓, GS nitration↓, NMDA receptors↓	[106]
Primary spinal cord neuron, C57BL/6 mice	Hydrogen gas inhalation	42 days post injury	Hydrogen can reduce the production of ROS and inhibit neuronal apoptosis by oxidative stress, restoring the construction and function of mitochondria in spinal cord injury. Cox8b, Cox6a2, Cox7a1, Hspb7, and Atp2a1 were identified as potential target genes for hydrogen treatment	Cox8b↓, Cox6a2↓, Cox7a1↓, Hspb7↓, Atp2a1↓	[43]
Wistar rats	Hydrogen-Rich Saline	42 days post injury	Hydrogen rich saline can promote the recovery of testicular biological function through antioxidant, anti-inflammatory, and antiapoptotic effects after spinal cord injury	HO-1↓, MFN-2↑	[114]
Sprague‒Dawley rats	Hydrogen-Rich Saline	2 weeks post injury	Injecting hydrogen rich saline within 2 weeks after injury can effectively promote the repair of acute spinal cord injury, which is achieved by alleviating tissue damaging oxidative stress, inflammation and apoptosis	CGRP↑, caspase-3↓, SOD↑, MDA↓	[44]
Astrocytes/Sprague‒Dawley rats	Hydrogen-Rich Saline	2 weeks post injury	Hydrogen could suppress reactive astrogliosis after contusive SCI and reduce the release of proinflammatory cytokines produced by active astrocytes related to oxidative injury	ROS↓, STAT3↓, p-STAT3↓, GFAP↓, TNF-α↓, IL-1β↓, IL-6↓,	[70]
New Zealand white rabbits	Hydrogen-Rich Saline	72 hours after reperfusion	Hydrogen therapy for spinal cord ischemia‒reperfusion injury by activating the mitoKATP channel and reducing oxidative stress, inflammatory cytokines, and apoptosis	mitoKATP	[105]
Sprague‒Dawley rats	Hydrogen-Rich Saline	72 hours post injury	Hydrogen-rich saline reduced acute spinal cord contusion injury, possibly by reduction of oxidative stress and elevation of BDNF	BDNF↑, MDA↓, MPO↓, caspase-3↓	[115]
New Zealand white rabbits	Hydrogen gas inhalation	72 hours after reperfusion	Hydrogen therapy is beneficial to spinal cord I/R damage by reducing oxidative stress, inflammatory response, and apoptosis	TNF-α↓, HMGB1↓, SOD↑, CAT↑, MDA↓, 8-iso-PGF2α↓	[104]

Abbreviations: Akt, Protein Kinase B; AMPK, Adenosine 5‘-monophosphate-activated protein kinase; ATP, adenosine triphosphate; Bax, BCL2-Associated X; BBB, Basso, Beattie & Bresnahan locomotor rating; Bcl-2, B-cell lymphoma-2; BDNF, Brain-derived neurotrophic factor; CAT, Catalase; CO, Carbon monoxide; Cox6a2, Cytochrome c oxidase subunit 6A2; Cox7a1, Cytochrome c oxidase subunit 7A1; Cox8b, Cytochrome c oxidase subunit 8B; cP-LA2, Cytosolic Phospholipase A2; DNA, DeoxyriboNucleic Acid; DNMT, DNA methyltransferase; ERK, extracellular signal-regulated kinase; ERK, Extracellular regulated protein kinases; FcεRI, IgE High Affinity Receptors; GLT-1, Glutamate transporter-1; GS, Glutamine synthetase; GSDMD, Gasdermin D; GSH-Px, Glutathione peroxidase; GSK-3β, Glycogen synthase kinase-3 beta; HIF1, hypoxia inducible factor-1; HMGB-1, High-mobility group box protein 1; HO-1, oxygenase-1; H₂S, Hydrogen sulfide; Hspb7, Heat Shock Protein Beta 7; ICAM-1, Intercellular adhesion molecule 1; IGF-1, Insulin-like growth factor 1; IL-10, Interleukin-10; IL-1β, Interleukin-1 beta; IL-6, Interleukin-6; JNK, c-Jun amino acid terminal kinase; LC3, Microtubule-associated protein light chain 3; MAPK, Mitogen Activated Protein Kinase; MCP-1, Macrophage chemoattractant protein 1; MDA, malonaldehyde; MPO, Myeloperoxidase; mTOR, Mechanistic Target Of Rapamycin; NAD, Nicotinamide adenine dinucleotide; NF-κB, Nuclear factor-κB; NLRP3, NOD-like receptor thermal protein domain associated protein 3; NMDA, N-Methyl-d-aspartic acid; NO, Nitric Oxide; Nrf2, Nuclear factor E2 related factor 2; PI3K, Phosphatidylinositol 3-kinase; PINK1, PTEN induced putative kinase 1; PLCγ1, Phospholipase C Gamma 1; PLCγ2, Phospholipase C Gamma 2; ROS, Reactive oxygen species; SCI, Spinal cord injury; SOD, superoxide dismutase; STAT3, Signal transducer and activator of transcription; Syk, Spleen Tyrosine Kinase; TGF-β, Transforming growth factor-β; TLR-4, Toll-like receptor 4; TNF-α, Tumor necrosis factor-α; TREM-2, Recombinant Triggering Receptor Expressed On Myeloid Cells 2; HO, hydroxyl radicals; 3-NT, 3-nitrotyrosine; 8-iso-PGF2α, 8-iso-prostaglandin F2alpha.

Figure 4 Protective effect of hydrogen on spinal cord injury and its possible molecular mechanism.

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