The efficacy of hydrogen in the treatment of neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease

【Abstract】

Neurodegenerative diseases (NDs) are a collective term for a group of aging diseases that are usually triggered by neuronal cell death, commonly manifesting as impaired motor and memory function [1].

Recent research evidence suggests that oxidative stress (OS) plays an important role in the pathogenesis of many brain-related diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), cerebral ischemia, and other brain injuries [2-4].

Our cells must maintain moderate levels of oxidation in order to maintain normal physiological function
.
However, when this level exceeds a certain level, oxidative stress (OS) is caused, which leads to oxidative damage leading to apoptosis [5].

The body has an endogenous antioxidant system, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione, which maintain the body's oxidative balance, scavenge free radicals and other substances that cause oxidative stress, and protect nerve cells[6].

When this balance mechanism is disrupted, oxidative stress occurs, causing various neurodegenerative diseases
.
For example, when SOD activity is disrupted, it activates pathogenesis associated with oxidative stress (OS) in Parkinson's disease (PD) and Alzheimer's disease (AD) [7].

In recent years, researchers have been evaluating the role
of antioxidants in preventing and alleviating neurodegenerative diseases.
Recently, molecular hydrogen (H2) has attracted great attention in the medical field as a safe and effective medical gas by scavenging free radicals such as hydroxyl radicals (OH) and peroxynitrite (ONOO-) and reducing oxidative stress (OS) levels [8].

【Application of hydrogen in medicine】

Various studies have highlighted the positive effects of hydrogen by reducing oxidative stress (OS) levels [9].

There are many convenient and effective routes of hydrogen administration, such as hydrogen inhalation, oral hydrogen-rich water (HRW), hydrogen-rich saline (HS) injection, and direct action on the affected area (e.
g.
, shower, eye drops, etc.
) [10].

Beneficial effect of hydrogen on different acute neuronal diseases

Hydrogen has been reported to have a therapeutic effect on the ischemia-reperfusion (IR) brain injury model in rats, and has a preventive effect on the IR injury of the optic nerve in the white matter model [11].
Drinking hydrogen-rich water (HW) or inhaling hydrogen can reduce levels of neurotoxins that cause Parkinson's disease (PD) [12]; Hydrogen can reduce brain damage in patients with acute cerebral infarction [13].

Other research findings, such as regular drinking of hydrogen-rich water, can reduce the harm of acute stress (mental disorders caused by vigorous, unusual mental stimulation, life events or persistent difficulties) and promote the recovery of neuroinflammation [14]; Hydrogen reduces oxidative damage and neuroinflammation in the fetal brain by reducing the activation of pro-inflammatory cytokines, microglia, and 8-hydroxy-2-deoxyguanosine (8-OHdG); Hydrogen-rich water has a protective effect
against neonatal hypoxic-ischaemic encephalopathy by reducing serum levels of neuron-specific enolase enzyme (NSE), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α).

In terms of
security.
Inhalation of hydrogen does not affect physiological indicators such as blood pressure, body pH, body temperature, etc.
, and there are almost no side effects, as it only acts
with free radicals such as • OH.

[Effect of hydrogen on human neurodegenerative disease models]

Hydrogen scavenges ROS free radicals and is extremely effective in reducing inflammation in many tissues and organs, including the heart, brain, and lungs [16].
Hydrogen-rich water has been widely studied for its ability to inhibit inflammatory responses and reduce neuronal apoptosis [17].

Parkinson's disease (PD) is caused by the mass death of dopaminergic neuron cells in the brain and is the second most degenerative neurodegenerative disease after Alzheimer's disease
(AD).
It is caused by two mechanisms, one is excessive oxidative stress (OS) and the other is abnormalities
in the ubiquitin-proteasome system.
The ubiquitin-proteasome system (UPS) is the main pathway of intracellular protein degradation, participating in the degradation of more than 80% of intracellular proteins [18].

Dopamine itself is a pro-oxidant, and when dopaminergic cells are exposed to high levels of ROS, in neuronal cells, the abnormal ubiquitin-proteasome system often induces the accumulation of insoluble α-synuclein, which eventually leads to neuronal cell death, and hydrogen can reverse this effect
.

Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by irregular aggregation of β-amyloid (Aβ) and tau [19].

Various studies have demonstrated the positive role of
hydrogen in different Alzheimer's disease (AD) models.
For example, hydrogen-rich water can prevent cognitive impairment and reduce oxidative stress (OS) levels [20], while hydrogen water has been observed to alleviate hippocampal dentate gyrus nerve proliferation inhibition after binding stress; In intraventricular injection of Aβ(1-42) senile dementia animal models, learning and memory impairment, Aβ reduction, and neuroinflammation were found to be reduced by hydrogen-containing saline treatment, while hydrogen water was observed to inhibit lipid peroxidation and inflammatory mediators, such as IL-6 and TNF-α [21].

This protective effect of hydrogen is due to the activation of the c-Jun n-terminal kinase (JNK) and nuclear factor κB (NF-κB) pathway [22].

A study of mouse models of dementia found that hydrogen reduced oxidative stress (OS) levels, prevented memory and cognitive decline, and increased lifespan
in mice.

Tests of the effects of hydrogen on various diseases

【Therapeutic effect of hydrogen on autism, cerebral palsy, and mental retardation】

Brain lesions are a key factor in the development of autism, cerebral palsy, mental retardation, and various other disorders [23].

Perinatal asphyxia is one of the leading causes of neonatal brain injury, and hydrogen inhalation can reduce neuronal apoptosis caused by hypoxia in newborns [24].

Hydrogen also stimulates energy metabolism to reduce neuronal damage
.
For example, it can upregulate the expression of FGF21 [25].

One study showed that the use of sevoflurane caused abnormal social behaviors similar to autism in mice [26], while hydrogen gas treatment eliminated the increase in oxidative stress caused by sevoflurane in mice, thereby improving autism-related symptoms
.

【Therapeutic effect of hydrogen on other neurological diseases】

Numerous studies have shown a high incidence of central nervous system disorders, such as retinal ischemia [27].

The use of hydrogen-containing eye drops inhibits the increase of OH, reduces the damage to the retina caused by apoptosis caused by oxidative stress (OS), and protects Müller's cells (which play an important role in maintaining the structure and function of the retina), astrocytes, microglia, etc.
from oxidative stress (OS
).

When the sound is too loud, it will cause overstimulation of ear hair cells, resulting in oxidative stress and causing cell death [28].

In animal model tests, the injection of hydrogen-containing saline can protect animals from hearing loss
caused by noise.

In developing countries, traumatic brain injury and spinal cord injury cause a large number of deaths and disabilities
every year.
Hydrogen protects neuronal cell death caused by brain trauma because inhalation of hydrogen prevents the production of oxidative stress (OS) products and increases the enzymatic activity of endogenous antioxidants (SOD and CAT) in brain tissue, providing a protective effect [29].

In addition, hydrogen therapy can also prevent brain sepsis and LPS inflammation [30].

【Research Conclusion】

Although several neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), cannot be cured, a large number of studies have shown that hydrogen has a significant role in the prevention, treatment, and symptom relief of
these diseases.
To date, there have been no reports of significant side effects of hydrogen therapy, which is relatively easy to implement, inexpensive and effective
in routine treatment.

However, the optimal approach and dose of hydrogen therapy for each disease are different, and different treatment regimens need to be adopted according to different diseases and different symptoms to achieve their optimal clinical application
.

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