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Hydrogen, the next neuroprotective agent?

    Adrian Marchidann of Stony Brook University Hospital of the State University of New York recently published a Editorial article in Future Neurol, suggesting that hydrogen is a new concept for the next generation of neuroprotective agents. Hydrogen is the first time to introduce it to everyone. The views belong to the original author and do not represent the words of hydrogen. The original text is free, please search for it yourself.

    Stroke is the most important disease threatening human life in today's world. Approximately 695,000 people in the United States have a stroke each year, of which 610,000 are the first to occur. The treatment strategy for ischemic stroke is to restore blood flow as soon as possible, and the method of restoring blood flow is to use drugs and vascular intervention methods. But the problem of stroke is still serious, because continuing is the most important cause of death and loss of ability. It is estimated that there are now 7.2 million American adults over the age of 20 with a history of stroke. The situation in China is also not optimistic. Stroke and myocardial infarction are the most important causes of death in China. The National Health Action Plan advocated by the state also takes prevention of stroke as an important content.
    Once cerebral ischemia occurs, even if blood flow is restored as soon as possible, brain tissue damage can not be avoided, so protecting nerve cells is an important task in stroke research. Many stroke animal models have shown that some drug molecules have neuroprotective effects, but unfortunately all neuroprotective agents have not successfully entered the clinic. The pathological process of cerebral ischemia is complicated, and it is difficult for a single molecule to successfully block apoptosis and cytotoxic effects at the same time. Another difficulty is that these neuroprotective agents are difficult to spread across the opaque tissue of the ischemic tissue to the target tissue. Potentially successful neuroprotective drugs must be: easy to spread in tissues, have multiple pathological intervention effects, and have few toxic negative effects. Recently, hydrogen neuroprotective effects research has gradually become a new topic that is of interest to many people.
    Ischemia-reperfusion injury is a phenomenon in which the injury is further accelerated after the ischemic tissue restores blood flow. When blood flow is restored for a few seconds to a few minutes, a decrease in mitochondrial function results in a large amount of reactive oxygen species, which is six times faster than normal tissue. Hydroxyl radicals are the most active and most toxic active oxygen, and their oxidative activity is hundreds of times that of hydrogen peroxide.
    The most important reactive oxygen species include singlet oxygen, hydroxyl radicals, superoxide anions, and peroxynitrite. These reactive oxygen species are involved in the waterfall signaling effects of cell death and apoptosis. Peroxynitrite is a product of the reaction of nitric oxide and superoxide anion, which initiates cell necrosis and apoptosis. This is a common pathological phenomenon of inflammatory response, arteriosclerosis, and neurodegenerative processes.
    The reactive oxygen species can undergo a chain reaction to produce new active molecules. There are multiple levels of anti-oxidant systems in the body, such as various antioxidants. Vitamin E protects against lipid peroxidation. Vitamin C and sulfhydryl groups protect the peroxidation process in the cytoplasm. Cholesterol, plasmalogens and carotenoids neutralize singlet oxygen and hydroxyl radicals. The higher the activity of the free radical, the shorter the half-life (life). The site of the antioxidant molecule is important for neutralizing reactive oxygen species. Singlet oxygen can be catalyzed by SOD to form superoxide anion, which can be further converted to hydrogen peroxide, which can be catalyzed by glutathione peroxidase or catalase to water. In the presence of iron and copper ions, hydrogen peroxide can become hydroxyl radicals.
    The concentration of colorless and odorless hydrogen in the Earth's atmosphere is approximately 0.5 ppm. Water electrolysis produces hydrogen and oxygen, and intestinal bacteria digest carbohydrates to produce hydrogen. There is no research evidence that hydrogen is toxic to humans, but too high a concentration of hydrogen will cause hypoxia or even suffocation due to a decrease in the concentration of oxygen.
    The concentration of hydrogen explosion is more than 4.1% (the provisions of the US submarine closed cabin). 49% hydrogen 50% helium 1% oxygen ternary mixture has been used for large depth diving. This high pressure of high pressure hydrogen gas has not found any toxicity of hydrogen indicating that the safety of hydrogen is huge. Hydrogen gas diving is not only safe, but also reduces the occurrence of high-pressure neurological syndrome for up to 72 hours of continuous diving for 27 hours.
    As a neuroprotective agent, hydrogen has many advantages, such as ease of use, ease of manufacture, diffusion across cell membranes, relative inertness, and reaction with only toxic reactive oxygen species. And hydrogen can affect a variety of pathophysiological pathways.
In culturing cells, hydrogen can reduce hydroxyl radicals to protect PC12 without affecting reactive oxygen with signaling. Hydrogen has also been shown to reduce lipid peroxidation, avoid DNA oxidation and reduce glutamate-induced neuronal cell death. Hydrogen also regulates cellular oxidative stress, inflammatory responses, and apoptotic pathways.
Mitochondrial autophagy is an important way to clear abnormal mitochondria and reduce excessive mitochondria production of reactive oxygen species. Hydrogen can increase mitochondrial autophagy by regulating PINK1/Parkin pathway. Nrf2 is the most important transcription factor for intracellular control of the antioxidant system, and hydrogen can increase Nrf2 expression. Hydrogen can also reverse the decrease in SOD and catalase activity in cerebral ischemic tissue.
    The anti-inflammatory effect of hydrogen is to reduce the number of microglia and astrocytes in the damaged brain tissue. Hydrogen increases the number of Treg cells, and some pro-inflammatory factors such as TNF-α, IL-6, IL-1B decrease, while anti-inflammatory Factors such as increased levels of TGF-1β. Hydrogen activates NF-kB and apoptosis-inhibiting molecules that regulate a variety of anti-apoptotic factors.
    Humans use hydrogen very safely, but using more than 4% hydrogen has the risk of burning and explosion, and the treatment of disease must use hydrogen under the premise of ensuring safety. Hydrogen safe preservation technology has always been highly valued in the energy field, and solid storage hydrogen is a typical representative. One way to avoid hydrogen explosion is to dissolve hydrogen in water and ingest hydrogen by drinking, injecting, and bathing. Some people also use intestinal bacteria to produce hydrogen, such as oral lactulose.
The current big challenge is how to translate animal and cytological research into clinical applications. Animal model studies included middle arterial blockade, carotid artery blockade, four-arterial global cerebral ischemia, and resuscitation after cardiac arrest. In the transient forebrain ischemia model, inhalation of 2% hydrogen during reperfusion reduced the volume of cerebral infarction after 1 day and improved the animal behavioral score after 7 days. After spontaneous hydrogen stroke in rats with spontaneous hypertension, the incidence of cerebral hemorrhage and ischemia in the cortex and hippocampus decreased. The effect may be that hydrogen inhibits matrix metalloproteinase activity and protects the integrity of the blood-brain barrier. Hydrogen treatment after cerebral ischemia in gerbils increased the survival rate of animals after 7 days (8.3% to 50%). Some studies have also found that hydrogen has a significant improvement in functional indicators after cardiac arrest.
    In an open-label, non-randomized clinical study, 38 patients received hydrogen or edaravone treatment and found no deterioration in laboratory tests, EEG, and radiation. Drinking neutral hydrogen water does not cause adverse consequences such as genetic mutations, clinical symptoms and laboratory tests. No significant side effects were found at 20 ml/kg per day (about 1200 ml for 60 kg).
    In a clinical trial of 25 patients with cerebral ischemia, 3% hydrogen was inhaled for 1 hour twice a day for 7 consecutive days. The hydrogen level reached the platform after 20 minutes and stopped dropping to 10% after 6-18 minutes of inhalation. Most of the life indicators and blood tests did not change, but the oxygen saturation of the hydrogen treatment group was significantly improved, and the clinical improvement rate was significantly higher than that of the control group.
    Cell, animal, and human studies have shown that hydrogen can be safely used as a neuroprotective agent in the recanalization process, with enough data to summon large-scale, double-blind, placebo studies to confirm and evaluate the effects of hydrogen on acute stroke.
The only author is Adrian Marchidann of the State University of New York at Stony Brook University Hospital.

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