Hyperbaric Oxygen Treatment: Effects on MitochondrialFunction and Oxidative Stress

Review: Hyperbaric Oxygen Treatment: Effects on Mitochondrial Function and Oxidative Stress

Nofar Schottlender ^1,2 , Irit Gottfried ¹ and Uri Ashery ^1,2,*

The study reviews the effects of hyperbaric oxygen treatment (HBOT) on mitochondrial function and oxidative stress, discussing its potential therapeutic implications for various diseases.

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Hyperbaric Oxygen Treatment Overview ​

Hyperbaric oxygen treatment (HBOT) involves administering 100% oxygen at pressures greater than 1 ATA, significantly increasing the amount of dissolved oxygen in the blood. ​ This treatment has implications for mitochondrial function and oxidative stress, potentially offering therapeutic benefits for various diseases.

Effects of HBOT on Mitochondrial Function ​

HBOT can enhance mitochondrial activity and integrity, particularly with long-term treatment protocols. ​

• HBOT increases dissolved oxygen levels in tissues, improving mitochondrial function. ​
• Short-term treatments (1-5 sessions) may reduce mitochondrial activity and integrity. ​
• Long-term treatments (20-60 sessions) show significant improvements in mitochondrial parameters. ​
• Studies indicate that HBOT can enhance ATP production and reduce apoptosis signaling in various disease models. ​
• Mitochondria are the primary site for ROS production, and HBOT can modulate this process. ​

Understanding Oxidative Stress Mechanisms

Oxidative stress arises from an imbalance between free radicals and antioxidants, leading to cellular damage. ​

• Mitochondria are a major source of reactive oxygen species (ROS) during aerobic metabolism. ​
• ROS can cause damage to DNA, proteins, and lipids, contributing to various diseases. ​
• Complexes I and III of the electron transport chain are key sites for ROS production. ​
• Short-term HBOT may initially elevate ROS levels, but long-term treatment enhances antioxidant defenses. ​

HBOT Protocols and Their Outcomes ​

Different HBOT protocols yield varying effects on mitochondrial function and oxidative stress. ​

• Treatment pressures range from 1.5 ATA to 2.5 ATA, with durations from 1 to 4 hours. ​
• Studies show that 1-5 treatments often lead to reduced mitochondrial function, while 20-60 treatments improve it. ​
• Specific studies report increased ATP levels and reduced apoptosis in models of traumatic brain injury and neurodegenerative diseases. ​
• The balance between ROS production and antioxidant activity is crucial for therapeutic outcomes. ​

Role of Antioxidants in HBOT ​

HBOT activates antioxidant pathways, which help mitigate oxidative stress. ​

• Nrf2 is a key transcription factor activated by HBOT, promoting the expression of antioxidant genes. ​
• Long-term HBOT leads to increased levels of antioxidant enzymes, aiding in cellular protection. ​
• The interplay between ROS and antioxidants determines the extent of oxidative stress experienced during treatment. ​

Hyperoxic–Hypoxic Paradox in HBOT ​

Intermittent fluctuations between hyperoxia and apparent hypoxia during HBOT enhance cellular responses. ​

• The hyperoxic-hypoxic paradox activates transcription factors like HIF1α and SIRT1, promoting cell survival and mitochondrial biogenesis. ​
• These fluctuations mimic hypoxic conditions, stimulating protective cellular mechanisms.
• HIF1α and SIRT1 play critical roles in neuroprotection and metabolic regulation during HBOT. ​

Clinical Implications and Safety of HBOT ​

HBOT is generally safe when administered under controlled conditions, but precautions are necessary. ​

• Treatment is typically limited to pressures below 3 ATA to minimize risks of oxygen toxicity. ​
• Monitoring and pre-therapy evaluations are essential to ensure patient safety.
• The therapeutic benefits of HBOT are supported by evidence of improved mitochondrial function and reduced oxidative stress in various conditions. ​

Oxidative Stress and Disease Associations ​

Oxidative stress is linked to various diseases, including cancer, diabetes, and neurodegenerative disorders, affecting metabolic rates and contributing to pathophysiology. ​ Elevated reactive oxygen species (ROS) production from hyperglycemia disrupts insulin gene expression and promotes vascular inflammation. ​

• Oxidative stress is associated with cancer, diabetes, and neurodegenerative diseases. ​
• Hyperglycemia increases ROS production, inhibiting PDX-1 and compromising insulin expression. ​
• ROS interacts with transcription factors, leading to endothelial dysfunction and vascular inflammation. ​

Hyperbaric Oxygen Therapy (HBOT) Effects

HBOT shows varying effects on oxidative stress and mitochondrial activity, with short-term treatments potentially harmful and longer treatments beneficial. ​ Clinical trials indicate that HBOT can improve cognitive functions and quality of life in patients with neurodegenerative diseases. ​

• Short-term HBOT (1-5 sessions) may have negative effects, while long-term (20-30 sessions) shows benefits. ​
• HBOT can enhance antioxidant enzyme activity and reduce oxidative stress markers. ​
• Clinical trials demonstrate cognitive improvement in Alzheimer's and mild cognitive impairment patients. ​

Mitochondrial Function and Immune Response ​

Mitochondrial function is crucial for immune responses, with ROS playing a role in eliminating pathogens and regulating T cell activation. ​ Increased ROS levels enhance immune cell activation, while antioxidants can inhibit this process. ​

• Mitochondrial ROS helps macrophages eliminate bacteria and parasites. ​
• ROS induces T cell activation and proliferation through IL-2 secretion. ​
• Antioxidants can inhibit T cell expansion and NF-κB activation in immune cells. ​

Neurodegenerative Diseases and Oxidative Stress ​

Neurodegenerative diseases like Alzheimer's and Huntington's are characterized by increased oxidative stress and mitochondrial dysfunction. ​ Studies suggest that antioxidant therapies may alleviate symptoms and improve outcomes in these conditions. ​

• Alzheimer's disease shows higher oxidative stress markers in regions with amyloid-β aggregates. ​
• Antioxidant enzymes can mitigate neuronal death and improve motor function in Huntington's disease models. ​
• HBOT has shown promise in reducing oxidative stress and improving cognitive function in animal models. ​

Mechanisms of HBOT in Disease Treatment

HBOT's mechanism involves inducing oxidative stress initially, followed by increased antioxidant defenses with prolonged treatment. ​ This paradoxical effect highlights the importance of mitochondrial equilibrium in disease management. ​

• Initial HBOT sessions may increase oxidative stress, but subsequent sessions enhance antioxidant defenses. ​
• The hyperoxic-hypoxic paradox (HHP) stimulates antioxidant enzyme production. ​
• Maintaining mitochondrial equilibrium is vital for treating diseases associated with oxidative stress. ​