Redox Effects Of Molecular Hydrogen And Its Therapeutic Efficacy in The Treatment Of Neurodegenerative Diseases Part 2

6. Effects of Molecular Hydrogen on Animal and Human Models of Neurodegenerative Diseases

PD is caused by the death of dopaminergic neurons at the SNpc of the midbrain and is the second most common ND after AD. PD is caused by two mechanisms: excessive OS and the abnormal ubiquitin-proteasome system [17,76]. 

Dopamine itself is a prooxidant and dopaminergic cells are intended for exposure to high levels of ROS. In the neuronal cell body, an irregular ubiquitin-proteasome system often induces the accumulation of insoluble α-synuclein, resulting in neuronal cell death. 

By stereotactically injecting catecholaminergic neurotoxin 6-hydroxydopamine into the right striatum, a research group created a rat hemiPD model, and H2 was shown to have a positive impact [77]. 

Another study demonstrated a similar prominent effect of HRW on an MPTP-induced mouse model of PD [76]. It is interesting to note that the H2 levels used for MPTP mice were only 5%, the second-lowest in all studies on rodents or humans that had previously been published. AD is the most common ND and is characterized by irregular β-amyloid (Aβ) and tau accumulation, with large aggregates known as senile plaques and neurofibrillary tangles [78]. Various research has demonstrated the effects of H2 in different animal models of AD [17,33,46]. 

One research group reported that the administration of HW prevented cognitive impairment and inhibited OS [33]. At the same time, they observed that HW restored neural proliferation of the dentate gyrus after restraint stress [33]. 

Li and colleagues developed an intra-cerebroventricular injection rat model of Aβ (1–42) AD [79]. With HS treatment, they found that reduced learning and memory impairments and reduced Aβ caused neural inflammation [79]. 

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HS also suppressed lipid peroxidation and inflammatory mediators, such as IL-6 and TNF-α [79]. Furthermore, Wang and colleagues reported that the protective effects of HS may be due to the activation of c-Jun N-terminal Kinase (JNK) and nuclear factor κB (NF-κB) pathways [80]. Additionally, a study in a dementia mouse model reported that administration of HW decreased OS and prevented the decline of memory and cognition while simultaneously increasing the lifespan in the mice. 

A clinical trial result showed that H2 can notably improve cognition in the apolipoprotein E4 genotype carriers [53]. Studies have shown the relationship of apolipoprotein E in anti-inflammatory, antiapoptotic, and antioxidative effects during brain injuries [81]. In Table 1, the effects of H2 on NDs, such as PD, AD, and other brain conditions are listed.

7. Hydrogen Therapy in Neonatal Brain Disorders

Brain disorders are the key factors in the development of autism, cerebral paralysis, mental delay, and various other impairments [99]. Perinatal asphyxia is one of the major causes of neonatal brain damage [99]. Inflammation and OS are major causes of neuronal apoptosis hypoxia-ischemia [100]. Cai and colleagues have reported the reduction of neuronal apoptosis from neonatal hypoxia in rats with H2-gas inhalation [101]. 

Abnormal behavior in rats was improved 5 weeks after hypoxia-ischemia with HS administration in a study [102]. H2 gas reduced neuronal damage caused by the cerebral cortex, hippocampus, basal ganglia, and hypoxia-ischemia brain ventilation in newborn pigs [75]. One study demonstrated that the inhalation of H2 gas extended the after-asphyxia period from 4 h to 24 h in newborn pigs, highlighting the H2 gas translation potential [103]. Administration of H2 in neonates with ischemic brain injury was found to be highly effective in prognostic improvement. 

Mano and colleagues also reported the improvement of hippocampal damage caused by IRI, through maternal HRW administration by 4-hydro-xynonenal and 8-OHdG on day 7 after birth [25]. Furthermore, another study reported that H2 improved fetal mouse brain injury caused by maternal exposure to LPS [70]. H2 administration in different forms, such as HRW, HS, or hydrogen inhalation, exhibits anti-inflammatory and antioxidant effects, as observed in many studies [33,79,80,84]. H2 can also stimulate energy metabolism to reduce neuronal damage. 

For example, it could upregulate the expression of FGF21 [104]. These findings indicate that prenatal H2 administration may be an effective approach for the treatment of inflammatory fetal response syndrome [104]. One study showed that sevoflurane exposure causes abnormal social behavior, similar to autism, in mice [105]. 

With this, Yonamine and colleagues reported that H2 gas treatment eliminates the increased OS caused by sevoflurane in neonatal mice [106]. In addition, co-administration of H2 prevented abnormal maternal behavior later in adulthood resulting from neonatal exposure to sevoflurane, which indicates a considerable H2 gas potential in reducing adverse effects of anesthetic exposure [106,107].

8. Mechanisms of Hydrogen Treatment in Neurodegenerative Diseases

Understanding the mechanisms of action of H2 in NDs is significant to fully explore the use of H2 in clinical therapy. OS and inflammation mainly contribute to the pathogenesis of AD, PD, and other neurodegenerative disorders. AD is the most common ND that causes dementia [10,17,78]. In most cases, AD patients have decreased learning and memory, cognitive impairment, and social and emotional disorders [3,108]. 

Mitochondrial damage is also caused by tau protein, resulting in energy dysfunction, ROS production, and ultimately damage to synaptic properties. Tau protein also causes mitochondrial damage, leading to energy dysfunction, ROS production, and ultimately damage to synaptic properties. The overproduction of Aβ in the brain results in the dysfunction of mitochondrial complexes that contribute to ROS overproduction and adenosine triphosphate (ATP) depletion [80,108,109]. 

ATP is important for axonal transport and neurotransmission and contributes to the maintenance of ion channel function and ion balance, both internally and externally, in cells. The depletion of ATP is, therefore, the reason for mitochondrial damage. In addition, an increase in ROS causes a shift in the poles of the mitochondrial pore that causes ions of calcium to flow into mitochondria, thus aggravating mitochondrial damage [109]. ROS can also affect membrane function, leading to lipid peroxidation, encouraging apoptosis in cells, and a decrease in the number of neurons. 

In short, the pathogenic mechanistic systems of AD are known to include cholinergic function disorder, amyloid cascade, OS, inflammation, excitotoxicity, and steroidal hormone deficiencies [110]. In NDs, pro-inflammatory cytokines, such as NF-κB, IL-1β, IL-6, IL-10, TNF-α, C-C motif chemokine ligand 2 (CCL-2), interferon-γ, and intercellular adhesion molecule-1, are involved in the anti-inflammatory effects of H2 [15,26,43]. The decrease in the nuclear binding domain leucine-rich repeat and pyrin domain-containing protein-3(NLRP3) in AD transgenic mouse models has been shown to inhibit memory impairment and Aβ deposition [111]. 

A study by Ren and colleagues showed that H2 inhibits NLRP3 inflammatory activation in AD brains [112]. Additionally, Lin and colleagues reported that HRW can boost the AMP-activated protein kinase (AMPK). Sirt1-FoxO3a pathways may play a role in antioxidant stress, reduce mitochondrial damage, act as a neuroprotective agent, and neutralize ROS caused by AD [113]. 

Sirt1 may also induce autophagy that plays a neuronal role in many NDs [114]. Autophagy is an essential process to preserve cell homeostasis and, through the promotion of autophagy in AD [114], H2 may also protect cells. Phospho-p38 and JNK participate in cell survival control as members of the mitogen-activated protein kinase (MAPK) [15,80]. Henderson and colleagues reported an improved Bax phosphorylation of the AD brains and mitochondrial translocation caused by OS and p38K [115]. 

The results in many animal models have shown that H2 water can stop phospho-p38 and JNK activation [15,80,116]. Interestingly, Hou and colleagues reported that HRW improves the cognitive function in female AD mice by reducing brain estrogen levels, ERβ, and brain-derived neurotrophic factor (BDNF) expression, but not in males, and without affecting the β-amyloid precursor protein treatment and Aβ clearance [117]. In addition, inflammation and OS were more pronounced in female AD mice than in males. 

This suggests that hydrogen can also be involved in the pathogenesis of AD by affecting the ERβ-BDNF estrogen signaling pathway [117]. MAPK and the signaling pathway of protein kinase C can inhibit AD and neuronal damage [70]. It was also thought that BDNF and tyrosine kinase recipient B were designed to regulate the expression of neuronally related genes. 

Finally, synaptic plasticity, learning, and the ability to remember are enhanced by H2 treatment [70]. In addition, the estrogen ERβ-BDNF signaling pathway was related to the antioxidant and anti-inflammatory effects in AD [118]. In pathological AD prevention, the activation of ERβ signaling also involves ROS scavenging [118]. Therefore, the main mechanisms of action of H2 include anti-inflammatory, antioxidative, and antiapoptotic properties, autophagy regulation, and the hormone signal pathway [15].

9. Studies Related to Hydrogen Therapy in Neurodegenerative Diseases

Numerous studies have investigated the potential use of H2 treatment in various NDs. In addition, HW was observed to increase malondialdehyde and 4-hydroxy-2- nominal, and OS markers enriched by chronic restriction. In addition, an increase in malondialdehyde and 4-hydroxy-2-nonenal and OS markers enriched by chronic restriction was observed by HW. 

At the same time, the decrease in the number of proliferating cells in the dentate gyrus, after restraining stress, was restored [33]. Neurogenesis continues to change in the adult hippocampus, which is important in learning, memory, and plasticity. A reduction in hippocampal neurogenesis may cause cognitive impairments and pathologic tau aggregations, which are characteristic of AD [119]. 

One report stated that HW can reduce memory and learning impairment and Aβ inflammation, and significantly improve memory long-term potentiation (LTP), and synaptic plasticity, which has implications for learning and memory [79]. Moreover, another study revealed that HS protection might be caused by the inhibition of JNK and NF-κB activation [80]. Similarly, one study revealed that age-related impairment of learning capacity and memory in senescence-accelerated mouse-prone 8 strains could be improved in 30-day HW consumption [120]. 

Numerous studies have demonstrated that apolipoprotein E has anti-inflammatory, antioxidant, and anti-apoptotic effects during brain injury [53,81]. However, apolipoprotein E4 is thought to play an active role in the pathological process of AD to promote oxidation, phosphorylation, and Aβ production [121]. Table 2 lists the various experimental studies related to NDs. However, there are still numerous ongoing studies and clinical trials all over the world.

10. Other Neurological Disorders

Numerous studies have shown a high occurrence of CNS disorders, including retinal ischemia [82,88,121]. Topical HS eye drops have been administered regularly during ischemia periods, and the drops have been found to suppress an increment of •OH. Furthermore, HS reduces the number of apoptotic and oxidative cells with retinal stress and prevents retinal dilution with associated activation of Muller glia, astrocytes, and microglia [122]. 

Moreover, it has been reported that H2 protected itself against antimycin A and a cisplatin-causing strain in auditory tissue cultures, suggesting that H2 prevented hair cell destruction, partly by reducing ROS production [123–125]. When the ear is exposed to loud sounds, the over-stimulation of the hair cells leads to ROS development which causes cell death [90,123]. Intraperitoneal HS injection has recently been shown to protect guinea pigs against noise-induced hearing loss [125]. In addition, in developing countries, TBI and spinal cord injury cause most deaths and disabilities. There are an estimated 200–600 injuries per 100,000 people in different regions of CNS injuries [126]. 

Ji and colleagues reported that H2 administration protected the animal TBI model against neuronal cell death [127]. H2 gas inhalation prevents the growth of oxidative products and improves enzyme activity in the brain tissue of endogenous antioxidants (SOD and CAT), resulting in a rat TBI model [127]. Moreover, Dohi and colleagues have reported that the use of HRW inhibited TBI edema and completely blocked the expression of pathologic tau in mice [128]. Additionally, H2 treatments have also been used to prevent sepsis and LPS inflammation in the brain and to protect carbon monoxide rodents from toxicity [52,129].

11. Therapeutic Efficacy of H2 Molecule

H2 has extensive and numerous effects on NDs including PD. Moreover, due to its beneficial efficacy, no adverse effects have been reported to date. The brain can be provided with detectable H2 amounts through the inhalation of H2 gas as well as HS injection [28]. On the other hand, the H2 concentration is too low to detect using a conventional hydrogen sensor after HRW administration. 

Interestingly, HRW has shown better results than H2 gas in an animal PD model [18]. Matsumoto and colleagues reported that HRW increased gastric expression and ghrelin secretion in mouse models [130]. Interestingly, the neurological impact of HRW was negated by a growth hormone secretagogue receptor (GHSR) (ghrelin receptor antagonist) and ghrelin-secretion antagonist [130]. Ghrelin was found to encourage the release of growth hormones and food intake, and GHSRs are manifested in substantia nigra dopaminergic neurons. 

Ghrelin is neuroprotective in PD as it inhibits microglia-related neuroinflammation [131]. Based on these results, higher levels of H2 in HRW are expected to directly affect gastric cells producing ghrelin and regulate intracellular signaling secretions of ghrelin [130]. In addition, one of the studies has shown that HO-1 and its enzyme products are associated with ischemic brain damage. However, a similar study showed that H2 gas inhalation does not improve lung hyperoxia in Nrf2-knockout mice, and inhalation during hyperoxia has been reported by Kawamura and colleagues to increase blood oxygenation, reduce inflammation, and induce the expression of HO-1 in the lung [132]. 

HO-1 functions in carbon monoxide, free ions, and biliverdin production in enzymatic heme, and is monitored in transcription through Nrf2. Therefore, HO-1 is involved in the defense of cells against OS, and it has been hypothesized that HO-1 could be a neuroprotective therapeutic target. HO-1 mutations have been related to a high risk of triggering HO-1 expression [53,55,132]. 

In addition, Iuchi and colleagues have shown that H2 even at lower levels (approximately 1% v/v) modulates the Ca2+ signals and regulates gene expression by changing the production of oxidized phospholipids [133]. As H2 is the smallest and the non-polar molecule, some protein mediators are unlikely to be binding. Further research is needed to identify the direct target molecule of H2. H2 regulates the cell response to OS, inflammation, and apoptosis [27].

Humans are innocuous when exposed to hydrogen. The risk of explosion at concentrations above 4% is a limiting factor in using H2 gas studies. Safer storage technologies, especially hydrides, are being developed [27,134]. The risk of explosion can also be eliminated by the dissolution of H2 in water or normal saline, either orally or intravenously [134].

12. Novel Advantages of H2 Molecule

To date, there is insufficient information about the pharmacodynamics and toxicity of H2. The therapeutic effect of H2 is already recognized in the medical field. However, before recognition as an innocuous and effective remedial gas, numerous issues must be resolved [27,135]. As a valuable treatment agent in clinical medicine, H2 has numerous potential benefits. Its physical characteristics and low molecular mass enable its rapid dispersion into the cytosol, other target cells, and the sub-cellular compartments through the plasma membrane [14,15,27]. 

H2 delivery does not influence physiological parameters including oxygen saturation, temperature, pH, and blood pressure [27,31]. In the biomedical sciences, the outcome of H2 appears to be similar to other types of therapeutic gas families, such as nitric oxide, hydrogen sulfide, and carbon monoxide. H2 was seriously considered only 10 years ago as an unreactive gas; scientists now see H2 as a healing agent and a preferred treatment course [136]. Although existing information on H2 remains insufficient, the promising characteristics of H2 therapy, as established through some pilot studies, are the motivation for future research; appreciation of the activities of H2 could guide us towards new forms of H2 therapy for many conditions and human diseases.

13. Concluding Remarks

Although several NDs are currently incurable, the therapeutic potential action of H2 administration for the prevention, treatment, and mitigation of these disorders is indicated by numerous studies. Although some NDs are currently not curable, several studies indicate the therapeutic action. The potential of H2 administration to prevent, treat, and alleviate certain disorders. To date, no reports of adverse effects of H2 have been illustrated. H2 is relatively easy to implement, inexpensive, and efficient in everyday health practice. However, the optimal route and dose of H2 administration for each disease remain to be established. This review summarizes current evidence on the preventive and therapeutic roles of H2 in different animal models and the human pathologies of OS-related NDs, inflammation, and apoptosis. More studies are required to expand the basic concepts and understanding of H2 for its optimal clinical use.

Author Contributions: Conceptualization, K.J.L.; writing-original draft preparation, M.H.R.; writing-review and editing, J.B. and A.F.; prepared the tables and figures, R.A., S.S., S.H.G., and T.T.T.; visualization, C.H.K.; supervision, K.J.L. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Data Availability Statement: The data presented in this study are available within the article (tables and figures).

Conflicts of Interest: The authors declare no conflict of interest.

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