Shigeo Ohta’s research while affiliated with Juntendo University and other places

Oxidative stress is one of the major causes of most age-dependent neurodegenerative disorders. Neurons accumulate oxidative damage over time due to post-mitotic cells. Thus, modulation of oxidative stress is essential to overcome these disorders. Molecular hydrogen (H2) has great potential for treating various diseases and improving quality of life by exerting multiple functions including anti-oxidation, anti-inflammation, and energy metabolism promotion. Among these functions, H2 activates a transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) to enhance the transcription of transcribe a broad range of anti-stress enzymes, including antioxidant enzymes. There was an elusive contradiction between H2 and Nrf2 because Nrf2 is activated in response to oxidative stress, whereas H2 has a reducing potential. The target molecule for H2 has recently been identified as the oxidized form of Fe-porphyrin conjugated with the -OH group (PrP-Fe(III)-OH). As the initial step, the hydroxyl radical (•OH) oxidizes heme (PrP-Fe(II)) to form PrP-Fe(III)-OH. Then, H2 reacts with PrP-Fe(III)-OH to produce PrP-Fe(III)-H and H2O. In turn, Fe(III) with H has the potential to act as an electrophile to oxidize Kelch-like ECH-associated protein 1 (Keap1), resulting in activating Nrf2. Thus, when the original highly damaging electrophilicity of •OH is buffered by H2 and its target porphyrin, the electrophilicity provided by •OH can indirectly activate Nrf2 to reduce oxidative stress. Even without lowering the dosage, the effect of alleviated potent is considered to be hormesis-like. This “Therapeutic Brief” propose that the alleviated oxidative potent of •OH functions to activate Nrf2 as hormesis-like. Keywords: Hematin, hydroxyl radical, molecular hydrogen, Nrf2, oxidative stress, porphyrin

(1) Background: Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disorder. Hydrogen gas (H2) is a therapeutic medical gas with multiple functions such as anti-oxidant, anti-inflammation, anti-cell death, and the stimulation of energy metabolism. To develop a disease-modifying treatment for AD through multifactorial mechanisms, an open label pilot study on H2 treatment was conducted. (2) Methods: Eight patients with AD inhaled 3% H2 gas for one hour twice daily for 6 months and then followed for 1 year without inhaling H2 gas. The patients were clinically assessed using the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog). To objectively assess the neuron integrity, diffusion tensor imaging (DTI) with advanced magnetic resonance imaging (MRI) was applied to neuron bundles passing through the hippocampus. (3) Results: The mean individual ADAS-cog change showed significant improvement after 6 months of H2 treatment (−4.1) vs. untreated patients (+2.6). As assessed by DTI, H2 treatment significantly improved the integrity of neurons passing through the hippocampus vs. the initial stage. The improvement by ADAS-cog and DTI assessments were maintained during the follow-up after 6 months (significantly) or 1 year (non-significantly). (4) Conclusions: This study suggests that H2 treatment not only relieves temporary symptoms, but also has disease-modifying effects, despite its limitations.

Introduction: Molecular hydrogen (H2) has emerged as a therapeutic medical gas that exerts multiple functions. H2 inhalation has been approved as safe, and some clinical studies showed that it effectively improved conditions of patients with a variety of disorders such as stroke, heart infarction, chronic obstructive pulmonary disease, cancer, and COVID-19. Urinary and fecal incontinences are unavoidable symptoms of advanced Alzheimer's disease (AD) dementia. In particular, fecal incontinence increases the level of confusion for patients and caretakers suffer from increased workloads. Materials and Methods: To assess the integrity of the neurons related to AD, the bundles of neurons passing through the hippocampus were visualized by modified diffusion tensor imaging (DTI) technology using advanced magnetic resonance imaging (MRI) Results: A 79-year-old woman with advanced AD continued to inhale 3% H2 gas containing 21% oxygen twice daily for 1 hour and maintained clinical observations for 2 years. After the long period of inhalation of H2 gas, the patient went to the bathroom by herself for adequate excretion. She remained to be able to go to the bathroom for her bowel movements in time, afterwards. After the long-term inhalation of H2 gas, her MRI of the brain to generate DTI images with an anisotropic (FA) value of 0.2 (FA = 0.2) showed improved integrity of the hippocampal neurons along with these clinical improvements. Conclusion: This case report casts the question on the current understanding that the advanced and severe AD patients will never improve.

Background: Molecular hydrogen (H2) acts as a therapeutic antioxidant. Inhalation of H2 gas (1-4%) was effective for the improvement of cerebral infarction in multiple animal experiments. Thus, for actual applications, a randomized controlled clinical study is desired to evaluate the effects of inhalation of H2 gas. Here, we evaluate the H2 treatment on acute cerebral infarction. Methods: Through this randomized controlled clinical study, we assessed the safety and effectiveness of H2 treatment in patients with cerebral infarction in an acute stage with mild- to moderate-severity National Institute of Health Stroke Scale (NIHSS) scores (NIHSS = 2-6). We enrolled 50 patients (25 each in the H2 group and the control group) with a therapeutic time window of 6 to 24 hours. The H2 group inhaled 3% H2 gas (1 hour twice a day), and the control group received conventional intravenous medications for the initial 7 days. The evaluations included daily vital signs, NIHSS scores, physical therapy indices, weekly blood chemistry, and brain magnetic resonance imaging (MRI) scans over the 2-week study period. Results: The H2 group showed no significant adverse effects with improvements in oxygen saturation. The following significant effects were found: the relative signal intensity of MRI, which indicated the severity of the infarction site, NIHSS scores for clinically quantifying stroke severity, and physical therapy evaluation, as judged by the Barthel Index. Conclusions: H2 treatment was safe and effective in patients with acute cerebral infarction. These results suggested a potential for widespread and general application of H2 gas.