Professor Mami is mainly engaged in the research of the protective effect of hydrogen on Parkinson's disease, so most of them put forward the views on the rapid direct antioxidant and long-term indirect effects of hydrogen in treating diseases based on his own research. If Professor Ota is the first scholar to discover the biological effects of hydrogen, Professor Nakao will extend his research to the depths, and Professor Mami is the scholar who has systematically thought about the nature of hydrogen effects. Therefore, reading Professor Mami's articles, especially review articles, is very important to gain insight into the latest views on hydrogen effects. However, some of Professor Mami's views are too focused on his own research evidence, and the research and thinking of other scholars is not comprehensive enough. For example, the perception of the effect of small doses of hydrogen, the indirect effects of inflammation, and some opinions on the long-term effects, all have this trace. Therefore, it is still not considered as everyone in the field of hydrogen biology, or that everyone in this field has not yet appeared. Hydrogen biology calls for academic leaders to lead. In a recent review, the description of the acute and chronic effects of the hydrogen effect focused on the analysis of the obvious delayed effect of the neuroprotective effect after the use of hydrogen. This is a typical pre-adaptation research model. If it can be confirmed in more models, various omics and molecular biology studies can be carried out specifically for normal animals treated with hydrogen, which is useful for finding the long-awaited hydrogen effect. The molecular basis of this brings important clues.
5.1. The acute protective effect of hydrogen
The most prominent acute protective effect of hydrogen is considered to be the antioxidant effect. This antioxidant effect produces protection against various oxidative damages such as cerebral ischemia reperfusion injury. This protective effect is also used in the rapid protection of Parkinson’s disease models. Can reflect. Moreover, oxidative damage does play an important role in the occurrence and development of Parkinson's disease. For example, the neurotransmitter dopamine is a pro-oxidant substance, and dopamine can promote the production of free radicals. Intracerebral injection of neuroindependent 6-OHDA can specifically cause oxidative damage and death of dopamine neurons. Using hydrogen water one week before surgery can almost completely avoid this damage process, and animals will not produce Parkinson's behavior. Even if you drink hydrogen water 3 days after the operation, although the symptoms cannot be completely eliminated, Parkinson's behavior can still be effectively inhibited, indicating that hydrogen can not only prevent the occurrence of Parkinson, but also treat this disease. Hydrogen water treatment was performed 48 hours before the toxin injection, and the tyrosine hydroxylase activity representing dopaminergic neurons in the animal brain did not increase, indicating that the protective effect of hydrogen on dopamine neurons had a delayed protective effect.
MPTP is another neurotoxin that induces Parkinson's disease. This toxin has very good fat solubility and easily crosses the blood-brain barrier, so it does not require direct injection into the brain. It can be injected into the blood to create an animal model. After entering the brain, MPTP Can be converted into MPP+, dopamine neurons have a very high affinity for this MPP+, because dopamine channels can be used as the transporter of this toxin, MPP+ entering neurons can enter the cell mitochondria, destroy mitochondrial respiratory function, and inhibit respiration The enzyme activity of complex I and inhibition of the enzyme activity of complex I can lead to a decrease in ATP production and an increase in free radical production, which leads to oxidative damage and cell necrosis, and induces Parkinson's disease manifestations. 3-4 consecutive acute injections of 20 mg/kg within 2 hours, chronic continuous subcutaneous injection, or continuous intraperitoneal microdialysis injection of MPTP can all be used as a chronic preparation method for Parkinson’s disease. MPTP can induce an increase in 8-hydroxyguanine in cells, which is a marker of DNA oxidative damage, and it can also induce an increase in 4-HNE, which is a marker of lipid peroxidation. After the animals drank hydrogen water, the above-mentioned signs in the substantia nigra dopamine nerve cells were significantly reduced, indicating that the hydrogen water has a protective effect on DNA and lipid peroxidation damage. Dissolving hydrogen in physiological saline to prepare a hydrogen-containing injection can also be used as a means of giving hydrogen, which has a protective effect on brain damage such as cerebral ischemia and senile dementia. Breathing hydrogen can also effectively protect brain damage after brain trauma and reduce oxidative damage. Brain trauma can cause damage to the blood-brain barrier of the brain, brain edema and neurological dysfunction. Intraperitoneal injection of hydrogen saline can produce a dose-dependent protective effect on the above changes. This shows that hydrogen saline has potential application prospects for brain trauma. In addition, studies have found that hydrogen saline has a protective effect on brain cell apoptosis, autophagy and necrosis caused by carbon monoxide poisoning, as well as light-induced retinal nerve damage.
These effects are all related to the anti-oxidation of hydrogen, or can be explained from the perspective of anti-oxidation. However, there is also academic controversy over the antioxidant effect of hydrogen itself, and there is no reasonable explanation for the phenomenon of short-term use of hydrogen to produce long-term protective effects.
5.2. Chronic protection
It is very puzzling why hydrogen therapy can produce long-term effects in a short time. Professor Mami believes that the anti-inflammatory effect of hydrogen may be part of the reason. If there is a time-dependent effect, it is a very important question for how long the protective effect remains after drinking hydrogen water (a typical pre-adaptation idea). To study this problem, scientists used an animal model of acute Parkinson's disease induced by MPTP injection 1, 3 and 7 days after drinking hydrogen water continuously for 7 days to observe whether there is still a protective effect. According to the characteristics of the gas, it is impossible to continue to exist in the body after stopping for more than 1 day (theoretically, it can't exist in 1 hour). So if this effect still exists, its effect is definitely not a direct effect of hydrogen, but an indirect effect. Using this method, a more accurate study of the nature of the role of hydrogen can be obtained, because it can be observed what changes occur in animal tissues when there is no disease, and this change may be the nature or molecular basis of the role of hydrogen. Within 7 days of waiting for the test after MPTP injection, because the hydrogen water was not continued to be drunk, hydrogen gas could not be detected in the brain, indicating that the hydrogen gas did not continue to stay in the brain.
Figure 2 Days of drinking H2 water to show neuroprotection in MPTP-induced Parkinson's disease model mice. (A) Experimental protocol showing how many days of drinking H2 water are necessary to show neuroprotection in substantia nigra(SN) before MPTP-injection. The brains were subjected to to analyses 7 days after MPTP-injection. (B) Average number of tyrosine hydroxylase(TH)-positivedopaminergic neurons in SN parscompacta (SNpc), measured in 20 μm coronalsections (n=4–6).
But the neuroprotective effect still exists. If drinking hydrogen water in advance can produce neuroprotection, how long can this neuroprotection last? In other words, when will the neuroprotective effect disappear after stopping drinking hydrogen water? To answer this question, scientists studied the acute Parkinson’s disease animal model induced by MPTP injection at 1, 3, and 7 days after stopping drinking hydrogen water and found that this protective effect was completely maintained after stopping drinking hydrogen water for 3 days. The protective effect still exists, but the effect has been reduced to 1/3 of the original (no statistical difference). The difference was not statistically significant after 7 days of stopping (seems to be effective).
Figure 3 Days of drinking non-H2 water after 7 days of H2 water to show disappearance of neuroprotection in MPTP-induced PD modelmice. (A) Experimental protocol showing how many days the H2 water-induced neuroprotection was kept. After 7 days of H2 water consumption , 1, 3 and 7 days of non-H2 water (control water) was given, then MPTP was injected. The brains were subjected to analyses 7 days after MPTP- injection. (B) Average number of TH-positive dopaminergic neurons in SNpc, measuredin 20 μm coronal sections(n=4–6).
This preventive effect of hydrogen was also found in the optic nerve ischemia animal model NodaM, Fujita K, Hamner MA, Yamafuji M, Akimoto N, et al. (2012) Molecular hydrogenprotects against central nervous system white matter ischemic injury. SfN 42ndannual meeting 660.14. These phenomena indicate that there is obviously an indirect molecular basis for the treatment of diseases by hydrogen, and genetic and protein levels should be analyzed for these treatments to find possible agents for the treatment of diseases by hydrogen.
Of course, it may also be regulated by enzyme activity to affect the activity of signal transduction pathways, thereby exerting the effect of controlling inflammation. It may also affect the expression of endogenous antioxidant related genes and activate the endogenous antioxidant system to exert antioxidant and anti-inflammatory effects.
Is hydrogen an adrenal agonist?
Mami's team has published papers on the indirect effects of hydrogen. They proposed that hydrogen water can produce neuroprotective effects because hydrogen can promote the secretion of a hormone in gastric cells. This hormone is ghrelin. Studies have proven this hormone. It has a neuroprotective effect. Their research found that drinking hydrogen water for 4 consecutive days can promote the secretion of this hormone (this may indicate that drinking hydrogen water for at least 4 consecutive days, otherwise it will be difficult to exert its effect). Ghrelin is a hormone that promotes the secretion of growth hormone by binding to GHS-R receptors in the body. GHS-R receptors are also expressed on substantia nigra dopamine nerve cells. Studies have also found that ghrelin can protect dopamine nerve cells through this receptor. This effect is related to the inhibition of mitochondrial energy metabolism (UCP2 pathway).
Studies have found that β1 adrenergic receptors can stimulate ghrelin gene expression and secretion, and the neuroprotective effect of hydrogen gas can be affected by the β1 adrenergic receptor blocker atenolol or ghrelin receptor blocker D-Lys3 GHRP-6 (Figure 4). This is also a new explanation for the protective effect of hydrogen. The basis is that hydrogen activates the β1 adrenal receptors in the stomach and promotes the synthesis and release of ghrelin. This hormone enters the brain, activates the receptors on dopamine neurons, and protects dopamine neurons. Damaged by toxins.
Some people have experienced increased heart rate after drinking hydrogen water, or the adrenal receptors in the heart of these patients were stimulated by hydrogen. This study suggests that β1 adrenal receptors may be the molecular target of hydrogen in the body. However, it seems difficult to understand the many biological effects of hydrogen.