Ozone therapy mitigates parthanatos after ischemic stroke

• Published in: Biological research Vol. 57; no. 1; pp. 71 - 14
• Main Authors: Li, Jiahui, Liu, Xiaolei, Wang, Zengze, Xie, Pengyun, Zhu, Min, Zhong, Hanhui, Luo, Sirui, Tang, Jing, Mo, Guixi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 05.10.2024; BioMed Central; BMC
• Subjects: Adenosine triphosphate; Air pollution; Animals; Antioxidants; Apoptosis; Apoptosis - drug effects; Brain; Ca2; Calcium (intracellular); Calcium - metabolism; Carotid arteries; Cell culture; Cell death; Cerebral ischemia–reperfusion; Chelating agents; Disease Models, Animal; Enzymes; Flow cytometry; Humans; Hydrogen peroxide; Hydrogen Peroxide - metabolism; Immunofluorescence; Ischemia; Ischemic Stroke - drug therapy; Male; Mice; Mice, Inbred C57BL; Neuroprotection; NF-E2-Related Factor 2 - metabolism; Oxidative stress; Oxidative Stress - drug effects; Ozone; Ozone - pharmacology; Ozone - therapeutic use; Parthanatos; Pathophysiology; Peroxisome proliferator-activated receptors; Proteins; Reactive oxygen species; Reactive Oxygen Species - metabolism; Reperfusion; Reperfusion Injury; ROS; Stroke; Veins & arteries; Western blotting; China; United States > US; New Jersey; Germany; Ozone; Ca2; Cerebral ischemia–reperfusion; Parthanatos; ROS
• ISSN: 0717-6287; 0716-9760; 0717-6287
• DOI: 10.1186/s40659-024-00547-5

Stroke is a leading cause of death worldwide, with oxidative stress and calcium overload playing significant roles in the pathophysiology of the disease. Ozone, renowned for its potent antioxidant properties, is commonly employed as an adjuvant therapy in clinical settings. Nevertheless, it remains unclear whether ozone therapy on parthanatos in cerebral ischemia-reperfusion injury (CIRI). This study aims to investigate the impact of ozone therapy on reducing parthanatos during CIRI and to elucidate the underlying mechanism. Hydrogen peroxide (H O ) was utilized to mimic the generation of reactive oxygen species (ROS) in SH-SY5Y cell reperfusion injury in vitro, and an in vivo ischemic stroke model was established. Ozone saline was introduced for co-culture or intravenously administered to mice. Apoptosis and oxidative stress were assessed using flow cytometry and immunofluorescence. Western blotting was utilized to examine the expression of parthanatos signature proteins. The mechanism by which ozone inhibits parthanatos was elucidated through inhibiting PPARg or Nrf2 activity. The findings demonstrated that ozone mitigated H O -induced parthanatos by either upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) or activating peroxisome proliferator-activated receptorg (PPARg). Furthermore, through the use of calcium chelators and ROS inhibitors, it was discovered that ROS directly induced parthanatos and facilitated intracellular calcium elevation. Notably, a malignant feedback loop between ROS and calcium was identified, further amplifying the induction of parthanatos. Ozone therapy exhibited its efficacy by increasing PPARg activity or enhancing the Nrf2 translation, thereby inhibiting ROS production induced by H O . Concurrently, our study demonstrated that ozone treatment markedly inhibited parthanatos in stroke-afflicted mice. Additionally, ozone therapy demonstrated significant neuroprotective effects on cortical neurons, effectively suppressing parthanatos. These findings contribute valuable insights into the potential of ozone therapy as a therapeutic strategy for reducing parthanatos during CIRI, highlighting its impact on key molecular pathways associated with oxidative stress and calcium regulation.