Brain and Cognitive Functions

Molecular Hydrogen Research on Brain and Cognitive Functions

Molecular hydrogen in the treatment of acute and chronic neurological conditions: mechanisms of protection and routes of administration
Oxidative stress caused by reactive oxygen species is considered a major mediator of tissue and cell injuries in various neuronal conditions, including neurological emergencies and neurodegenerative diseases. Molecular hydrogen is well characterized as a scavenger of hydroxyl radicals and peroxynitrite. Recently, the neuroprotective effects of treatment with molecular hydrogen have been reported in both basic and clinical settings. Here, we review the effects of hydrogen therapy in acute neuronal conditions and neurodegenerative diseases. Hydrogen therapy administered in drinking water may be useful for the prevention of neurodegenerative diseases and for reducing the symptoms of acute neuronal conditions.
Molecular hydrogen inhalation attenuates postoperative cognitive impairment in rats
Postoperative cognitive decline is a major clinical problem with high morbidity and mortality after surgery. Many studies have found that molecular hydrogen (H2) has significant neuroprotection against acute and chronic neurological injury by regulating inflammation and apoptosis. In this study, we hypothesized that H2 treatment could ameliorate the development of cognitive impairment following surgery. Adult male rats were subjected to stabilized tibial fracture operation under anesthesia. Two percent of H2 was inhaled for 3 h beginning at 1 h after surgery. Separate cohorts of rats were tested for cognitive function with fear conditioning and the Y-maze test, or euthanized to assess blood-brain barrier integrity, and systemic and hippocampal proinflammatory cytokine and caspase-3 activity. Surgery-challenged animals showed significant cognitive impairment evidenced by a decreased percentage of freezing time and an increased number of learning trials on days 1, 3, and 7 after operation, which were significantly improved by H2 treatment. Furthermore, H2 treatment significantly ameliorated the increase in serum and hippocampal proinflammatory cytokines tumor necrosis factor-α, interleukin-1β, interleukin-6, and high-mobility group protein 1 in surgery-challenged animals. Moreover, H2 treatment markedly improved blood-brain barrier integrity and reduced caspase-3 activity in the hippocampus of surgery-challenged animals. These findings suggest that H2 treatment could significantly mitigate surgery-induced cognitive impairment by regulating inflammation and apoptosis
Molecular hydrogen protects against oxidative stress-induced SH-SY5Y neuroblastoma cell death through the process of mitohormesis
Inhalation of molecular hydrogen (H2) gas ameliorates oxidative stress-induced acute injuries in the brain. Consumption of water nearly saturated with H2 also prevents chronic neurodegenerative diseases including Parkinson’s disease in animal and clinical studies. However, the molecular mechanisms underlying the remarkable effect of a small amount of H2 remain unclear. Here, we investigated the effect of H2 on mitochondria in cultured human neuroblastoma SH-SY5Y cells. H2 increased the mitochondrial membrane potential and the cellular ATP level, which were accompanied by a decrease in the reduced glutathione level and an increase in the superoxide level. Pretreatment with H2 suppressed H2O2-induced cell death, whereas post-treatment did not. Increases in the expression of anti-oxidative enzymes underlying the Nrf2 pathway in H2-treated cells indicated that mild stress caused by H2 induced increased resistance to exacerbated oxidative stress. We propose that H2 functions both as a radical scavenger and a mitohormetic effector against oxidative stress in cells.
Complexity of Stomach-Brain Interaction Induced by Molecular Hydrogen in Parkinson's Disease Model Mice
Molecular hydrogen (H2), as a new medical gas, has protective effects in neurological disorders including Parkinson's disease (PD). In our previous report, the neuroprotective effect of drinking water with saturated H2 (H2 water) in PD mice might be due to stomach-brain interaction via release of gastric hormone, ghrelin. In the present study, we assessed the effect of H2-induced ghrelin more precisely. To confirm the contribution of ghrelin in H2 water-drinking PD model mice, ghrelin-knock out (KO) mice were used. Despite the speculation, the effect of H2 water was still observed in ghrelin-KO PD model mice. To further check the involvement of ghrelin, possible contribution of ghrelin-induced vagal afferent effect was tested by performing subdiaphragmatic vagotomy before treating with H2 water and administration of MPTP (1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine). The protective effect of H2 water was still observed in the vagotomized mice in substantia nigra, suggesting that stimulation of vagal afferent nerves is not involved in H2-induced neuroprotection. Other neuroprotective substitutes in ghrelin-KO mice were speculated because H2-induced neuroprotection was not cancelled by ghrelin receptor antagonist, D-Lys3 GHRP-6, in ghrelin-KO PD model mice, unlike in wild-type PD model mice. Our results indicate that ghrelin may not be the only factor for H2-induced neuroprotection and other factors can substitute the role of ghrelin when ghrelin is absent, raising intriguing options of research for H2-responsive factors.

Therapeutic Approach to Neurodegenerative Diseases by Medical Gases: Focusing on Redox Signaling and Related Antioxidant Enzymes
The brain consumes 20 to 50% of total body oxygen consumption even though it only accounts for 2% of the body weight. Meaning that brain function is highly dependent on a consistent supply of oxygen. Since 2-5% of oxygen consumed by cells is converted into reactive oxygen species (ROS) as a byproduct of cellular respiration, the brain most likely undergoes the most ROS damage. Hydrogen can prevent oxidative stress damage which may be beneficial for neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and ALS.

Hydrogen-rich saline improves memory function in a rat model of amyloid-beta-induced Alzheimer’s disease by reduction of oxidative stress
Alzheimer’s disease affects 5% of the population older than 65 years. There is an enormous medical need for novel therapeutic strategies that can alleviate the underlying causes of Alzheimer’s disease. In this study, it was observed that molecular hydrogen-rich saline improved learning and memory functions due to molecular hydrogen’s properties as an anti-neuroinflammatory and antioxidant.

Therapeutic Effects of Hydrogen in Animal Models of Parkinson’s Disease
The main pathological feature of Parkinson’s disease was the loss of neurons in the substantia nigra. A growing body of evidence suggests that oxidative stress is closely related to the onset and progression of both Parkinson’s Disease and Alzheimer’s Disease. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) was found to induce PD-like pathology by neurotoxic mechanism of mitochondrial impairment. This causes oxidative damage and neurodegeneration. Overall, it seems through the evidence so far that molecular hydrogen is an effective antioxidant that can take care of oxidative stress that causes neurodegeneration. Molecular hydrogen is a promising therapeutic modality for Parkinson’s disease and other neurodegenerative diseases and it should be studied under clinical settings.

Drinking Hydrogen Water Ameliorated Cognitive Impairment in Senescence-Accelerated Mice
Molecular hydrogen has been reported to have neuroprotective effects due to its antioxidant properties. According to this study, treatment with molecular hydrogen water for 30 days prevented age-related declines in cognitive function, and also elevated antioxidant activity. Drinking molecular hydrogen water for 18 weeks also slowed neurodegeneration in the hippocampus.

Consumption of Molecular Hydrogen Prevents the Stress-Induced Impairments in Hippocampus-Dependent Learning Tasks during Chronic Physical Restraint in Mice
Oxidative stress is widely accepted as a contributor to decreased brain function. Antioxidants to prevent oxidative stress in the brain have been the focus of much research throughout the years. However, most antioxidants are not able to cross the blood-brain-barrier to neutralize oxidative stress in the brain. Molecular hydrogen is an antioxidant that can easily pass through the blood-brain-barrier due to its small size and gaseous form. Molecular hydrogen gas inhalation is not practical for prevention of oxidative stress in the brain during high stress situations, which is why this study examined the effectiveness of molecular hydrogen rich water in delivering molecular hydrogen to the brain. Molecular hydrogen water suppressed accumulation of oxidative stress markers in the mice that were tested. Hydrogen water also helped mice with learning tasks compared to mice that were given control water.
Hydrogen-rich pure water prevents superoxide formation in brain slices of vitamin C-depleted SMP30/GNL knockout mice
This study showed that a significant 27.2% less superoxide formed in the molecular hydrogen group subjected to ischemia-reperfusion than the control water group. Superoxide is a precursor of the dangerous hydroxyl radical. If superoxide is not taken care of quickly by superoxide dismutase, it may eventually convert into a hydroxyl radical. The decrease in superoxide shows that molecular hydrogen may be stimulating the activity of the superoxide dismutase enzyme.
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