Redox Effects Of Molecular Hydrogen And Its Therapeutic Efficacy in The Treatment Of Neurodegenerative Diseases Part 1

Abstract: 

Oxidative stress (OS) and neuroinflammatory stress affect many neurological disorders. Despite the clinical significance of oxidative damage in neurological disorders, still, no effective and safe treatment methods for neurodiseases are available. With this, molecular hydrogen (H2 ) has been recently reported as an antioxidant and anti-inflammatory agent to treat several oxidative stress-related diseases. 

Oxidative stress is a topic that has attracted much attention in recent years and has been widely studied in the fields of biology and medicine. Oxidative stress refers to the process of abnormal changes in the internal and external environment of cells due to the presence of large amounts of free radicals or peroxides. With the changes in human lifestyles and the increasing environmental pollution, the impact of oxidative stress is increasing.

Fortunately, however, research shows that oxidative stress is not entirely negative. Moderate oxidative stress promotes normal cell and body function and is associated with improved memory. Many studies have shown that individuals who are exposed to high oxidative stress for a long time, such as the elderly and patients with certain diseases, are indeed at risk for memory decline. However, for healthy people, moderate oxidative stress is beneficial for improving memory and learning abilities.

Oxidative stress can affect the function of neurons in the brain in a variety of ways. First, oxidative stress promotes connections between neurons, promoting information transmission and cognitive abilities. Second, moderate oxidative stress can increase the number of neural stem cells in the brain, thereby promoting the persistence of memory and learning. In addition, oxidative stress can also increase the levels of some neurotransmitters in the brain, such as dopamine and norepinephrine, which are closely related to learning and memory.

In summary, moderate oxidative stress is beneficial to memory and learning abilities. Although oxidative stress may cause some negative effects, we should pay attention to and grasp the positive effects of moderate oxidative stress. In life, we can effectively control the level of oxidative stress through a healthier lifestyle, diet, and exercise, thereby better protecting and improving our memory and learning abilities. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thus enhancing the connectivity and function of neural networks. These effects can help improve memory, learning, and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases.

Click know supplements to improve memory

In animal and human clinical trials, the routes for H2 administration are mainly categorized into three types: H2 gas inhalation, H2 water dissolving, and H2 -H2-dissolved saline injection. This review explores some significant progress in research on H2 use in neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, neonatal disorders of the brain, and other NDs (retinal ischemia and traumatic brain injury). 

Even though most neurological problems are not currently curable, these studies have shown the therapeutic potential for the prevention, treatment, and mitigation of H2 administration. Several possible H2 --effectors, including cell signaling molecules and hormones, which prevent OS and inflammation, will also be addressed. However, more clinical and other related studies are required to evaluate the direct H2 target molecule.

Keywords: molecular hydrogen; inflammation; neuroprotection; neurological disorder; oxidative stress; antioxidant.

1. Introduction

Neurodegenerative diseases (NDs) are groups of various aging disorders that generally lead to a gradual death and increase in neuronal cells, leading in affected persons to compromised motor and memory function [1]. 

The exact mechanism for the pathogenesis of NDs remains largely undefined; however, emerging evidence suggests that oxidative stress (OS) plays an important function in the pathogenesis of numerous brain-related disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), cerebral ischemia, and other brain injuries [2–4]. 

Our cells need to maintain moderate levels of reactive oxygen species (ROS) to carry out normal biological functions. However, severe production of ROS is responsible for the cause of oxidative damage that may lead to apoptosis [5]. This excessive production of ROS appears to be a possible cause of structural and functional modifications of cellular biomolecules, including proteins, deoxyribonucleic acid (DNA), and lipids, and thus eventually confines neuronal function and survival and is commonly observed in the brains of patients with neurodegenerative conditions [3,4]. 

The central nervous system (CNS) utilizes large amounts of oxygen to perform physiological processes, resulting in the generation of abundant levels of free radicals [5]. Endogenous antioxidant systems, such as those comprising superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione, play an important role in the rescue of brain cells from OS and preserve the correct redox balance in the brain tissue, by stimulating antioxidative defense mechanisms for counterbalance ROS. 

These enzymatic antioxidants are chain-breaking antioxidants that can scavenge radical species [6]. Manganese-containing SOD decreases the superoxide radical anion produced during the electron transport chain in the mitochondrial matrix, whereas CAT and/or GPx play key roles in decomposing hydrogen peroxide to water and oxygen [6,7]. 

Various studies have reported decreased levels of antioxidative enzyme activities, such as CAT and SOD, in neurological diseases including PD [8,9]. Interestingly, one study showed that impairment of SOD activity leads to possible pathogenesis related to OS in PD and AD [10]. Furthermore, research has shown that reticence of CAT activity results in elevated cytotoxicity and increased ROS, representing an essential role of CAT in maintaining oxidative balance [11]. 

Emerging evidence highlights and corroborates the role of OS in the pathogenesis of NDs [2–4]. As a result, in recent years, researchers have been interested in evaluating the role of antioxidants in preventing and alleviating these diseases. It is a well-accepted fact that natural antioxidants and antioxidative enzymes have a key role in the reduction of cellular ROS [12]. 

Recently, molecular hydrogen (H2) has attracted great attention in the medical field as a nonfunctional gas that is safe and effective and attenuates OS by acting as a radical scavenger for hydroxyl radical (•OH) and peroxynitrite (ONOO-) [13]. 

Various studies have highlighted the beneficial effects of H2 in reducing the pathophysiology of various diseases by reducing OS [13,14]. There are numerous convenient and effective routes for administering H2, such as inhalation, oral intake of hydrogen-rich water (HRW), injection of hydrogen-rich saline (HS), and direct incorporation (bath, eye drops, and others) [14,15]. 

H2 has been reported as a therapeutic gas in a rat model of ischemia-reperfusion (IR) brain injury and reported to have a preventive effect on IR injury in optic nerves in a model of brain white matter [16]. Moreover, the protective effect of H2 in drinking water through the antioxidative effects of dopaminergic neurons in the substantia nigra pars compacta (SNpc) has been studied in an animal model [17]. 

Further, interestingly, another study showed that drinking H2-dissolved water (HW) and intermittent H2 exposure prevent PD neurotoxicity [18]. A clinical trial performed by Nagatani and colleagues showed that intravenous administration of HRW was found to be safe for patients suffering from acute cerebral infarction, including those treated with a tissue plasminogen activator [19]. 

Additionally, a study showed that inhalation of H2 gas concealed brain damage-induced middle-cerebral occlusion in rats enhanced cognitive scores, and lessened brain injury in patients with acute cerebral infarction [20]. 

H2 was found to have remedial and ergogenic effects in different clinical and pre-clinical studies on mild cognitive impairment [21,22]. Most brain injuries in our nervous system respond to neuroinflammation, which is distinguished by phenotypical changes in microglia and astrocytes, and excessive production of free radicals, cytokines, and neurotrophins. 

Evidence indicates that regulation of microglial redox status plays an essential role in modulating the neuroinflammatory response [23]. Studies have shown that regular consumption of HW reduces the intensity of acute behavioral outcomes and promotes recovery from neuroinflammation [24]. H2 can reduce the activation of proinflammatory cytokines, microglia, and 8-hydroxy-2-deoxyguanosine (8-OHdG) to reduce oxidative damage and neuroinflammation in the fetal brain in animal models [24,25]. 

In addition, a study showed that HW has a protective effect against neonatal hypoxic-ischemia encephalopathy by decreasing the levels of serum neuron-specific enolase, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) [26]. Therefore, this review article highlights the involvement of OS in NDs and the effect of H2 in the treatment of these diseases.

2. Characteristics of Molecular Hydrogen

H2 works as a moderate but efficient antioxidant [13,27]. Hydrogen is the world's most abundant element, accounting for about 75% of the world's mass. Hydrogen is present in water and organic as well as inorganic compounds. H2 gas is a colorless, odorless, fuel-intensive diatomic gas. There is less than 1 ppm of hydrogen gas in the Earth's atmosphere [28]. 

H2 does not react with most compounds, including oxygen gas, at room temperature. H2 gas is only inflammable at temperatures exceeding 537 ◦C. H2 (4–75%, v/v) is explosive due to the rapid oxidation chain reaction. H2 can be dissolved in water under atmospheric pressure to 0.8 mM (1.6 ppm, w/v) [28]. In recent years, various studies related to H2 have attracted researchers' attention globally, owing to its protective and therapeutic effects [14,15]. Furthermore, hydrogen has a more significant advantage over other gases used for medical purposes, in terms of its toxicity; hydrogen remains non-toxic up to high concentrations and is even used in diving applications [29,30]. 

Studies have found that the effects of hydrogen inhalation are not apparent and do not affect blood pressure or other parameters, such as pH and temperature. Thus, in comparison, hydrogen has fewer side effects than other antioxidants, as it only decreases •OH [13,31].

3. Administration Routes of Hydrogen

H2 may be administered or taken into the body via various routes. These routes may be divided into three types: H2 gas inhalation, drinking HW, and HS injection. H2 gas inhalation is the simplest and most commonly used method since the initial reports regarding the use of H2 [13]. Inhaled H2 diffuses into the lung alveoli and is transported to the entire body. 

This procedure can, however, be uncomfortable and even dangerous, since H2 gas is explosive at concentrations above 4% in air [27]. Therefore, the mixed gas concentration of H2 is usually maintained between 1% and 4%. Inhaling H2 gas improves acute conditions such as ischemia-reperfusion injury (IRI) and several organ graft injuries. HRW is safer and more comfortable than H2 gas inhalation. 

It has been reported that HW ad libitum prevents arteriosclerosis among mice with knockout apolipoprotein E, a model for atherosclerosis that develops spontaneously [32]. Consumption of H2 prevents stress-induced impairments in hippocampus-dependent learning tasks during chronic physical restraint in mice [33]. 

Recently, the inhalation of H2 and consuming HW showed different adjustments to signal and gene expression in mice [34]. Although the process is invasive, the neuroprotective efficacy in the brain following IRI intraperitoneal injection of HS has been similar to that of H2 gas inhalation [35]. In the human gastrointestinal tract, H2 is produced by intestinal bacteria and plays a key role in metabolic pathways. 

It functions as a distinctive antioxidant and prevents cardiovascular disorders [15]. One of the studies showed that gut bacteria play a role in the progression of neurological disorders. In this regard, patients suffering from various CNS disorders were found to have increased intestinal permeability that creates a passage to harmful metabolites from the intestine to the blood which greatly affects the CNS [36]. 

A study showed that oral administration of HW leads to protective effects in rat and mouse models of PD [17]. These findings demonstrate the potential use of HRW for defense against NDs, as well as the possibility of using HRW to treat acute brain disorders, as shown in Figure 1. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway plays a vital role in protecting cells against different stressors and its dysfunction is correlated with decreased tolerance to OS [37]. Nrf2 is an important defense mechanism of the brain against toxins in both, glial and neuronal cells [38,39]. 

The Nrf2 pathway targets various genes for instance heme oxygenase-1 (HO-1), glutathione S-transferase, SOD, CAT, NAD(P)H dehydrogenase(quinone)1, and others, thus, protecting the neurons of the CNS against OS [40,41]. Nrf2 and various antioxidant enzymes may also increase the expression of anti-inflammatory mediators, phase I and II drug-metabolizing enzymes, and mitochondrial pathways [42,43]. 

Recent research studies have shown that Nrf2 plays a defensive action against neurotoxins such as 6-hydroxydopamine and 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), in both, in vitro and in vivo models of PD [44,45]. In this regard, oral administration of HRW has shown a neuroprotective effect against traumatic brain injury (TBI) by activating the Nrf2 signaling pathway. 

Furthermore, similar findings have been reported in various NDs such as PD, AD, IR, and hemorrhagic stroke, and the effects are attributed to the antioxidant properties of HRW [46–48].

4. H2 Acts as an Antioxidant Agent

Hz is highly reactive, protein denaturing, and promotes DNA breakdown. It can selectively reduce OH and ONOO-, causing a widespread reaction with proteins, lipids, and nucleic acids [49]. Based on animal models and clinical observations, an accumulated body of evidence has shown that H can be efficiently used to protect against oxidative damage-associated diseases [50]. 

It decreases the amount of cytotoxic ROS (®OH), successfully defending cells [50]. Other studies demonstrated similar protective effects against lRl in organs, such as the liver, heart, and intestines [51]. In rat acute stroke models1% to 4% H, inhalation alleviates infarction dimensions [52]. H, inhalation prevents critical oxidative damage in 1% to 3% of the cases [53]. 

HRW intake attenuates learning and memory impairment in mice by reducing oxidative damage. Low-level (l, 3 v/100 v)gas respiration reportedly reduces OS, exceptional hypoxia-induced dyslipidemia, cardiomyocyte hypertrophy, and perivascular fibrosis in left ventricular in C57BL/6] mice [54Additionally, the ingestion of HRW triggers the Nrf2/antioxidant protection pathway and antioxidant gene expression to speed up the reduction in oral mucosal impairment in rats [55]. 

Similarly, the findings of another study showed that HRW had a beneficial effect on acute skin wounds in rats caused by radiation [56]. Several substitute pathways are currently being studied as main components of the energy moderating characteristics of Hz, including (1) ghrelin-linked upregulation of ghrelin receptor (GHS-R1α); (2) ghrelin-linked motivation of glucose transporter 1; (3) non-ghrelin linked stimulation of glucose transporter 4; and (4) non-ghrelin linked improved expression of fibroblast growth factor 21 (FGF21), a regulator of energy expenses [57,58]. 

HRW has shown neuroprotective properties in a murine MTTP-induced PD model [45,59,60]. Lin and colleagues reported that HRW reduces OS in patients with chronic hepatitis B and metabolic syndrome [61]. Studies have shown that H2 may have benefited by activating the Nrf2 signaling pathway, thus improving antioxidant activity and reducing OS, apoptosis, and inflammation [46,62]. 

H2 increases the antioxidant activities of enzymes in radiation and TBI through the upregulation of Nrf2 [63]. The basic anti-inflammatory mechanism of H2 can even be used by macrophages via the Nrf2 signaling pathway [64]. Nrf2 is a transcription factor that combines antioxidant response elements to control the expression of antioxidants, protecting the body from injury and inflammations against oxidative damage [65].

5. Anti-Inflammatory Effects of H2 in Different Neurodegenerative Disease Models

Numerous studies have reported the anti-inflammatory action of H2 [63,64,66]. The rapid spread, high penetrability, and absence of clear side effects are some of its advantages. H2 scavenges ROS radicals and is extremely effective in reducing inflammation in numerous tissues and organs, including the heart, brain, and lungs, and is recognized to be a defender against oxidative damage [67,68]. 

HRW has been widely studied for its ability to inhibit inflammatory reactions and alleviate neuronal apoptosis [18,69]. Microglia is likely to cause neuroinflammation in the brain. Activated microglia and ROS produce pro-inflammatory cytokines. One of the studies showed that H2 has a promising effect on prevention and inflammation related to perinatal brain injury in in vitro and in vivo models [70]. 

Furthermore, the same study reported that HW prevents lipopolysaccharide (LPS)-induced production of ROS by microglia and reduces LPS-induced microglial neurotoxicity [70]. Several studies have shown that HS can mitigate intestinal infections such as intestinal IR damage, ulcerative colitis, and colon inflammation [71,72]. 

Moreover, HRW has shown a preventive effect against the superoxide ions formation in vitamin C-depleted SMP30/GNL-knockout mice during hypoxia–rexygenation conditions [73]. Additionally, one of the studies reported that the addition of H2 to hemodialysis solutions had antiinflammatory and anti-hypertensive action against hemodialysis patients, suggesting it is a therapeutic option for uremia patients [74]. In another study, the role of reduction in athletes' muscles was enhanced by using H2 in the case of intensive physical practice [21]. 

Domoki and colleagues reported that 2.1% air ventilation augmented by hydrogen substantially maintained cerebrovascular reactivity to hypercapnia and decreased neuronal damage caused by asphyxia-re-ventilation in a perinatal asphyxia newborn pig model [75]. In addition, HRW prevented endoplasmic stress and upregulated HO-1 expression [64]. HRW also ameliorates cognitive impairment in mice with accelerated senescence [53].

For more information:1950477648nn@gmail.com