Role of NADPH Oxidases in Blood–Brain Barrier Disruption and Ischemic Stroke

Hernandes, Marina S.; Xu, Qian; Griendling, Kathy K.

doi:10.3390/antiox11101966

Cited by 9 publications

(3 citation statements)

References 99 publications

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“…The disruption of the BBB by ischemia-reperfusion injury could cause BMECs damage, eventually leading to apoptosis [62]. Apoptosis is the predominant form of cellular demise following stroke.…”

Section: Discussionmentioning

confidence: 99%

Acupuncture Extended the Thrombolysis Window by Suppressing Blood–Brain Barrier Disruption and Regulating Autophagy–Apoptosis Balance after Ischemic Stroke

Zhang,

Lu,

et al. 2024

Brain Sciences

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Background: Ischemic stroke (IS) is one of the leading causes of death and disability worldwide. The narrow therapeutic window (within 4.5 h) and severe hemorrhagic potential limits therapeutic efficacy of recombinant tissue type plasminogen activator (rt-PA) intravenous thrombolysis for patients. Xingnao Kaiqiao (XNKQ) acupuncture is an integral part of traditional Chinese medicine, specifically designed to address acute ischemic stroke by targeting key acupoints such as Shuigou (GV26) and Neiguan (PC6). In this study, we explored the therapeutic potential of XNKQ acupuncture in extending the time window for thrombolysis and interrogated the molecular mechanisms responsible for this effect. Methods: The effect of extending the thrombolysis window by acupuncture was evaluated via TTC staining, neuronal score evaluation, hemorrhagic transformation assay, and H&E staining. RNA sequencing (RNA-seq) technology was performed to identify the therapeutic targets and intervention mechanisms of acupuncture. Evans blue staining and transmission electron microscopy were used to assess blood–brain barrier (BBB) integrity. Immunofluorescence staining and co-immunoprecipitation were performed to evaluate the level of autophagy and apoptosis and validate their interactions with BBB endothelial cells. Results: Acupuncture alleviated infarction and neurological deficits and extended the thrombolysis window to 6 h. The RNA-seq revealed 16 potential therapeutic predictors for acupuncture intervention, which related to suppressing inflammation and restoring the function of BBB and blood vessels. Furthermore, acupuncture suppressed BBB leakage and preserved tight junction protein expression. The protective effect was associated with regulation of the autophagy–apoptosis balance in BBB endothelial cells. Acupuncture intervention dissociated the Beclin1/Bcl-2 complex, thereby promoting autophagy and reducing apoptosis. Conclusion: XNKQ acupuncture could serve as an adjunctive therapy for rt-PA thrombolysis, aiming to extend the therapeutic time window and mitigate ischemia–reperfusion injury. Acupuncture suppressed BBB disruption by regulating the autophagy–apoptosis balance, which in turn extended the therapeutic window of rt-PA in IS. These findings provide a rationale for further exploration of acupuncture as a complementary candidate co-administered with rt-PA.

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Section: Discussionmentioning

confidence: 99%

Acupuncture Extended the Thrombolysis Window by Suppressing Blood–Brain Barrier Disruption and Regulating Autophagy–Apoptosis Balance after Ischemic Stroke

Zhang,

Lu,

et al. 2024

Brain Sciences

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“…The disruption of junctional proteins by TBI could cause ECs damage, eventually leading to ECs apoptosis. 36 Apoptosis is a form of programmed cell death (PCD) that occurs in multicellular organisms. 37 Under physiological conditions, apoptosis plays an important role in the development by eliminating unnecessary and unhealthy cells.…”

Section: Discussionmentioning

confidence: 99%

Fucoxanthin ameliorates traumatic brain injury by suppressing the blood–brain barrier disruption

Zhang,

Hu,

Bai

et al. 2023

iScience

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“…One of the primary sources generating ROS in the central nervous system (CNS) is NADPH oxidases (NOX) and; therefore, NOX plays a critical role in neuropathology [44,45]. Hippocampal neuronal cells are shown to express NOX [46,47].…”

Section: Pkc/nox Signalling Pathway Is Critical In Cu-induced Ht22 Ce...mentioning

confidence: 99%

Signalling Mechanism in TRPM2-dependent Copper- induced HT22 Cell Death

Rathakrishnan,

Hazanol,

Dali

et al. 2023

J Biochem Microbiol Biotechnol

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Copper (Cu) is one of the critical elements needed by the human body. However, this metal can cause cytotoxicity when present in excess amounts. In this study, we used HT22 hippocampus cells to examine the function of the Ca2+-permeable transient receptor melastatin 2 (TRPM2) channel in Cu-induced neuronal cell death and the underlying mechanisms. Immunocytochemistry, single-cell imaging, acridine orange/propidium iodide (AO/PI) cell death assay and immunofluorescence microscopy were applied to interpret the mechanisms involved in Cu-induced HT22 cell death. Treatment of 30-300 μM Cu induced an increase in the [Ca2+]i in HT22 cells. Further analysis indicates that Cu exposure induced substantial HT22 cell death. Such response on HT22 cells was significantly inhibited by 2-aminoethoxydiphenyl borate (2-APB) and N-(p-amylcinnamoyl)anthranilic acid (ACA), TRPM2 channel inhibitors. Furthermore, Cu-induced HT22 cell death was suppressed by pharmacologically inhibiting poly(ADPR) polymerase (PARP) using PJ-34 and DPQ. It is known that the activation of TRPM2 channel is via the increase of intracellular reactive oxygen species (ROS). A significant concentration-dependent increase in the generation of ROS was observed in HT22 following the treatment with 30-300 μM Cu. Additionally, Cu-induced HT22 cell death was ablated by inhibiting PKC using CTC, a PKC inhibitor and NADPH oxidase (NOX) using DPI, a NOX generic inhibitor and GKT137831, a NOX1/4-specific inhibitor. Overall, our present study provides evidence suggesting that PKC/NOX/ROS/PARP is an important signalling pathway in Cu-induced activation of the TRPM2 channel and increase in the [Ca2+]i which eventually results in the toxicity of HT22 cells. These results provide new insights into the mechanisms of neurological-associated Cu-induced diseases.

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Role of NADPH Oxidases in Blood–Brain Barrier Disruption and Ischemic Stroke

Cited by 9 publications

References 99 publications

Acupuncture Extended the Thrombolysis Window by Suppressing Blood–Brain Barrier Disruption and Regulating Autophagy–Apoptosis Balance after Ischemic Stroke

Acupuncture Extended the Thrombolysis Window by Suppressing Blood–Brain Barrier Disruption and Regulating Autophagy–Apoptosis Balance after Ischemic Stroke

Fucoxanthin ameliorates traumatic brain injury by suppressing the blood–brain barrier disruption

Signalling Mechanism in TRPM2-dependent Copper- induced HT22 Cell Death

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