Effects of Mdivi-1 on Neural Mitochondrial Dysfunction and Mitochondria-Mediated Apoptosis in Ischemia-Reperfusion Injury After Stroke: A Systematic Review of Preclinical Studies

Nhu, Nguyen Thanh; Li, Qing; Liu, Yijie; Xu, Jian; Xiao, Shu-Yun; Lee, Shin-Da

doi:10.3389/fnmol.2021.778569

Cited by 45 publications

(23 citation statements)

References 51 publications

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“…When Caspase-3 is stimulated by apoptosis, it is activated and cleaved into cleaved Caspase-3, an essential condition for the initiation of apoptosis (83). Subsequently, cleaved Caspase-3 will decompose the nuclear DNA repair enzymes, resulting in nuclear DNA chromatin condensation and damage, eventually leading to apoptosis (83)(84)(85).…”

Section: Discussionmentioning

confidence: 99%

Para‑hydroxybenzaldehyde against transient focal cerebral ischemia in rats via mitochondrial preservation

et al. 2022

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Gastrodia elata (GE) Blume has been widely used for thousands of years to treat various central and peripheral nervous disorders. P-hydroxybenzaldehyde (PHBA) is a chemical component of GE. However, its role and mechanism in transient focal cerebral ischemia remain unclear. The present study aimed to investigate the protective effect of PHBA on middle cerebral artery occlusion (MCAO) rats. A total of 56 Sprague-Dawley male rats were randomly divided into control, model, PHBA-high dose (PHBA-H) and PHBA-low dose (PHBA-L) groups. The MCAO injury model was replicated in all rats except for the control group. In the control group, only the right common carotid artery was isolated without embolization. After treatment with PHBA, the protective effects (neurological deficit score, cerebral index, weight and cerebral infarct) were analyzed. Western blotting was performed to estimate the protein levels of Bcl-2, Bax and Caspase-3. Apoptotic cells were detected using hematoxylin-eosin staining and TUNEL immunofluorescence assay. Mitochondrial oxidative stress indicators, including reactive oxygen species (ROS), malondialdehyde (MDA) and total superoxide dismutase (T-SOD), while dysfunction indicators, including mitochondrial permeability transition pore (MPTP), ATP and cytochrome C oxidase, were measured using commercial kits. The ultrastructure of mitochondria was observed under an electron microscope. Once the model was successful established, the rats in the MCAO group suffered neurological damage (P<0.001), increased cerebral index (P<0.001), decreased body weight (P<0.001) and had severe cerebral infarction (P<0.001). Moreover, the number of apoptotic cells and the levels of ROS (P<0.001) and MDA (P<0.05) in mitochondria and the protein levels of Bax (P<0.001) and cleaved caspase-3 (P<0.001) were increased. The activities of T-SOD (P<0.001) and cytochrome C oxidase (P<0.001) in the mitochondria, ATP content (P<0.05) and Bcl-2 protein level (P<0.001) decreased, MPTP was stimulated to open and mitochondrial structures were damaged (P<0.001). PHBA treatment resulted in a decrease of the neurological deficit score (PHBA-H 24 h, P<0.001; PHBA-H 6 h and PHBA-L 24 h, P<0.01; PHBA-L 6 h, P<0.05), apoptotic cell number (P<0.001), mitochondrial ROS (P<0.001) and MPTP opening (P<0.001), Bax (P<0.01, P<0.001) and cleaved caspase-3 protein expression (P<0.001) in rats. And the expression of Bcl-2 protein (P<0.001) was increased. In addition, the cerebral index (P<0.05), weight loss (P<0.05), infarction rate (P<0.01) and MDA content (P<0.001) were decrease in the PHBA-H group. The level of ATP (P<0.05) and cytochrome C oxidase (P<0.05) and T-SOD activity (P<0.05) of PHBA-H group rats increased, but no significant difference was observed in the PHBA-L group. Overall, PHBA had a protective effect on transient focal cerebral ischemia in normal rats, regulated the expression of Bcl-2, Bax and cleaved caspase-3 proteins and improved the oxidative stress and dysfunction of mitochondria.

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Section: Discussionmentioning

confidence: 99%

Para‑hydroxybenzaldehyde against transient focal cerebral ischemia in rats via mitochondrial preservation

et al. 2022

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“…Cells treated with DMEM only were used as blank controls, and Dexra was used as a positive control. Finally, we also injected Mdivi-1 (5μM, in DMSO), an inhibitor of mitochondrial division ( Nhu et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Breviscapine remodels myocardial glucose and lipid metabolism by regulating serotonin to alleviate doxorubicin-induced cardiotoxicity

Sun²,

Yang³

et al. 2022

Front. Pharmacol.

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Aims: The broad-spectrum anticancer drug doxorubicin (Dox) is associated with a high incidence of cardiotoxicity, which severely affects the clinical application of the drug and patients’ quality of life. Here, we assess how Dox modulates myocardial energy and contractile function and this could aid the development of relevant protective drugs.Methods: Mice were subjected to doxorubicin and breviscapine treatment. Cardiac function was analyzed by echocardiography, and Dox-mediated signaling was assessed in isolated cardiomyocytes. The dual cardio-protective and anti-tumor actions of breviscapine were assessed in mouse breast tumor models.Results: We found that Dox disrupts myocardial energy metabolism by decreasing glucose uptake and increasing fatty acid oxidation, leading to a decrease in ATP production rate, an increase in oxygen consumption rate and oxidative stress, and further energy deficits to enhance myocardial fatty acid uptake and drive DIC development. Interestingly, breviscapine increases the efficiency of ATP production and restores myocardial energy homeostasis by modulating the serotonin-glucose-myocardial PI3K/AKT loop, increasing glucose utilization by the heart and reducing lipid oxidation. It enhances mitochondrial autophagy via the PINK1/Parkin pathway, eliminates damaged mitochondrial accumulation caused by Dox, reduces the degree of cardiac fibrosis and inflammation, and restores cardiac micro-environmental homeostasis. Importantly, its low inflammation levels reduce myeloid immunosuppressive cell infiltration, and this effect is synergistic with the anti-tumor effect of Dox.Conclusion: Our findings suggest that disruption of the cardiac metabolic network by Dox is an important driver of its cardiotoxicity and that serotonin is an important regulator of myocardial glucose and lipid metabolism. Myocardial energy homeostasis and timely clearance of damaged mitochondria synergistically contribute to the prevention of anthracycline-induced cardiotoxicity and improve the efficiency of tumor treatment.

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“…To test this, vincristine-treated neurons were exposed to the small molecule mdivi-1. Mdivi-1 is largely regarded as a DRP1 inhibitor, and has been utilized in the context of neuronal injury to attenuate traumatic brain injury induced-cell death [20], protect against glutamate excitotoxicity and oxygen-glucose deprivation [21], and reduce cerebral damage caused by ischemia/reperfusion injury [22]. However, the drug has also been shown to inhibit mitochondrial respiratory Complex I [23], the first of five complexes of the electron transport chain.…”

Section: Mdivi-1 Inhibits Vincristine-induced Axon Degenerationmentioning

confidence: 99%

Local production of reactive oxygen species drives vincristine-induced axon degeneration

Gomez-Deza

Slavutsky

Nebiyou

et al. 2022

Preprint

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Chemotherapy-induced peripheral neuropathy (CIPN) is a common and serious consequence of cancer treatment that causes autonomic, motor, and sensory deficits, often resulting in severe pain. CIPN progression frequently leads to reduction or termination of chemotherapy medication in patients, negatively impacting their prognoses. With cancer survival rates improving dramatically, addressing side effects of cancer treatment has become pressing. Furthermore, as much of our knowledge on how CIPN develops derives from rodent studies with uncertain translatability, studying it in human neurons is critical. Here, we use iPSC-derived human neurons to investigate the molecular mechanisms that lead to neurotoxicity induced by vincristine, a common chemotherapeutic used to treat solid tumors. Our results uncover a novel mechanism by which vincristine causes a local increase in mitochondrial proteins that produce reactive oxygen species (ROS) in the axon. Vincristine triggers a cascade of axon pathology leading from elevated axonal ROS levels to mitochondrial dysfunction and SARM1-dependent axon degeneration. Importantly, we show that the neurotoxic effect of increased axonal ROS can be mitigated by the small molecule mdivi-1, identifying a novel therapeutic avenue to treat CIPN.

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Effects of Mdivi-1 on Neural Mitochondrial Dysfunction and Mitochondria-Mediated Apoptosis in Ischemia-Reperfusion Injury After Stroke: A Systematic Review of Preclinical Studies

Cited by 45 publications

References 51 publications

Para‑hydroxybenzaldehyde against transient focal cerebral ischemia in rats via mitochondrial preservation

Para‑hydroxybenzaldehyde against transient focal cerebral ischemia in rats via mitochondrial preservation

Breviscapine remodels myocardial glucose and lipid metabolism by regulating serotonin to alleviate doxorubicin-induced cardiotoxicity

Local production of reactive oxygen species drives vincristine-induced axon degeneration

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