Dataset Information

Ozone reduces ischemic damage after a stroke by regulating the autophagy of astrocytes.

ABSTRACT:

Background

Stroke is a common and damaging disease of brain tissue, and has high morbidity, disability, and mortality rates. Ozone (O₃) is an isomer of oxygen and can be applied to ozonate the isolated blood in specific containers outside the body and return it to the body. O₃ can also alter the activity and function of multiple cellular components, thus affecting blood viscosity and altering hemodynamics. However, the question of whether O₃ has clinical value in the treatment of stroke requires further investigation. This study sought to evaluate the protective effect and possible mechanism of O₃ in brain injury after stroke.

Methods

First, oxygen-glucose deprivation/reoxygenation (OGD/R)-induced human glioblastoma cell (A172) and middle cerebral artery occlusion (MCAO) rat models were established. Second, the levels of the associated ribonucleic acids and proteins were analyzed using reverse-transcription real-time-quantitative polymerase chain reaction, Western Blot, or immunofluorescence assays. Third, the concentration of glutamate and lactate dehydrogenase (LDH) were assessed using enzyme-linked immunoassays.

Results

The results showed that glial fibrillary acidic protein was upregulated in the OGD/R A172 cells. O₃ decreased LDH and increased glutamate levels in the OGD/R A172 cells, which suggests that O₃ reduced brain damage in the in vitro stroke model. We also showed that O₃ attenuated brain infarction in the in-vivo stroke model. Further, we found that O₃ alleviated stroke-induced brain damage by reducing the apoptosis of astrocytes. Further, the B-cell lymphoma 2 inhibitor propofol alleviated stroke-induced brain damage.

Conclusions

Thus, O₃ notably alleviated stroke-induced brain damage by inhibiting the apoptosis of astrocytes in the OGD/R-induced human glioblastoma cell and MACO rat models.

SUBMITTER: Huang N

PROVIDER: S-EPMC9929848 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Ozone reduces ischemic damage after a stroke by regulating the autophagy of astrocytes.

Huang Ni N Gao Duangui D Zhou Shi S Huang Zhi Z

Annals of translational medicine 20230101 2

<h4>Background</h4>Stroke is a common and damaging disease of brain tissue, and has high morbidity, disability, and mortality rates. Ozone (O<sub>3</sub>) is an isomer of oxygen and can be applied to ozonate the isolated blood in specific containers outside the body and return it to the body. O<sub>3</sub> can also alter the activity and function of multiple cellular components, thus affecting blood viscosity and altering hemodynamics. However, the question of whether O<sub>3</sub> has clinical ...[more]

PMID: 36819516

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Project description:BackgroundStroke 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.MethodsHydrogen peroxide (H2O2) 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.ResultsThe findings demonstrated that ozone mitigated H2O2-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 H2O2. 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.ConclusionsThese 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.

Project description:Cyclooxygenase (COX)-2 and matrix metalloproteinase (MMP)-9 are two crucial mediators contributing to blood-brain barrier (BBB) damage during cerebral ischemia. However, it is not known whether MMP-9 activation is involved in COX-2-mediated BBB disruption in ischemic stroke. In this study, we hypothesized that genetic deletion or pharmacological inhibition of COX-2 reduces BBB damage by reducing MMP-9 activity in a mouse model of ischemic stroke. Male COX-2 knockout (COX-2-/-) and wild-type (WT) mice were subjected to 60 min of middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion. Genetic deletion of COX-2 or post-ischemic treatment with CAY10404, a highly selective COX-2 inhibitor, significantly reduced BBB damage and hemorrhagic transformation, as assessed by immunoglobulin G (IgG) extravasation and brain hemoglobin (Hb) levels, respectively. Immunoblotting analysis showed that tight junction proteins (TJPs) zonula occludens (ZO)-1 and occludin as well as junctional adhesion molecule-A (JAM-A) and the basal lamina protein collagen IV were dramatically reduced in the ischemic brain. Stroke-induced loss of these BBB structural proteins was significantly attenuated in COX-2-/- mice. Similarly, stroke-induced loss of ZO-1 and occludin was significantly attenuated by CAY10404 treatment. Ischemia-induced increase in MMP-9 protein levels in the ipsilateral cerebral cortex was significantly reduced in COX-2-/- mice. Stroke induced a dramatic increase in MMP-9 enzymatic activity in the ischemic cortex, which was markedly reduced by COX-2 gene deficiency or pharmacological inhibition with CAY10404. Levels of myeloperoxidase (MPO, an indicator of neutrophil infiltration into the brain parenchyma), neutrophil elastase (NE), and lipocalin-2 (LCN2, also known as neutrophil gelatinase-associated lipocalin), measured by western blot and specific ELISA kits, respectively, were markedly increased in the ischemic brain. Increased levels of markers for neutrophil infiltration were significantly reduced in COX-2-/- mice compared with WT controls following stroke. Altogether, neurovascular protective effects of COX-2 blockade are associated with reduced BBB damage, MMP-9 expression/activity and neutrophil infiltration. Our study shows for the first time that MMP-9 is an important downstream effector contributing to COX-2-mediated neurovascular damage in ischemic stroke. Targeting the COX-2/MMP-9 pathway could represent a promising strategy to reduce neuroinflammatory events in order to preserve the BBB integrity and ameliorate ischemic stroke injury.

Dataset Information

Ozone reduces ischemic damage after a stroke by regulating the autophagy of astrocytes.

Background

Methods

Results

Conclusions

Publications

Ozone reduces ischemic damage after a stroke by regulating the autophagy of astrocytes.

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