Mdivi-1 alleviates brain damage and synaptic dysfunction after intracerebral hemorrhage in mice

Zhang, Yunge; Rui, Tongyu; Luo, Chengliang; Li, Qianqian

doi:10.1007/s00221-021-06089-6

Cited by 15 publications

(11 citation statements)

References 36 publications

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“…[43] Recently, dynamic mitochondrial network shifts towards mitochondrial fission after ICH have been observed in an increasing number of studies, as evidenced by increased expression of Drp1 and mitochondrial fragmentation, indicating that excessive mitochondrial fission is a major contributor to the development of ICH. [6,7,11] In the present study, we found HKL could alleviate mitochondrial fission via balancing Drp1 phosphorylation in ICH, as manifested by reduced Ser616 phosphorylation but increased Ser637 phosphorylation. Moreover, HKL inhibited Drp1 recruitment towards mitochondria and increased ATP levels.…”

Section: Discussionsupporting

confidence: 56%

“…[ 4 , 5 ] An increasing body of evidence suggests that disruption of this dynamic balance is manifested by increased mitochondrial fission and fragmentation in brain injury after ICH. [ 6 , 7 ] Dynamin-related protein 1 (Drp1) is a GTPase considered an essential modulator for mitochondrial fission. The balance between Drp1 and the Ser-616/Ser-637 phosphorylation ratio reflects Drp1 activity.…”

Section: Introductionmentioning

confidence: 99%

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Honokiol attenuates mitochondrial fission and cell apoptosis by activating Sirt3 in intracerebral hemorrhage

Zheng

Gao

Zhao

et al. 2023

Chinese Medical Journal

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Background: Sirtuin-3 (Sirt3) has been documented to protect against mitochondrial dysfunction and apoptosis. Honokiol (HKL) is a Sirt3 pharmacological activator with reported neuroprotective effects in multiple neurological disorders. The present study aimed to explore the neuroprotective effects of HKL and the role of Sirt3 following intracerebral hemorrhage (ICH). Methods: An in vivo ICH model in rats was established by injecting autologous blood into the right basal ganglia. PC12 cells were stimulated with hemin. For the in vivo investigation, the modified Neurological Severity Scores and the Morris water maze test were performed to assess neurological deficits. Hematoxylin–Eosin and Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining were employed to evaluate the histopathology and apoptosis. Immunohistochemical staining was used to investigate the expression of Sirt3. Adenosine triphosphate (ATP) levels were quantified to assess mitochondrial dysfunction. Cell counting kit-8, lactate dehydrogenase assay, and flow cytometry were used to analyze cell vitality and apoptosis in vitro. Immunofluorescence staining was performed to observe mitochondrial morphology and dynamin-related protein 1 (Drp1) localization to mitochondria. Western blot was applied to quantify the expression of Sirt3, Bax, Bcl-2, cleaved-caspase-3, Drp1, phosphorylation of Drp1 at serine-616, and phosphorylation of Drp1 at serine-637 in vivo and in vitro. Results: HKL treatment alleviated neurological deficits, attenuated the histopathological damage and cell apoptosis, and restored the decreased ATP levels in ICH rats. HKL improved cell survival rate, reduced cell apoptosis, and inhibited mitochondrial fission in PC12 cells. Moreover, both in vivo and in vitro models showed increased phosphorylation of Drp1 at Ser616, and reduced phosphorylation of Drp1 at Ser637. Meanwhile, immunofluorescence co-localization analysis revealed that hemin increased the overlap of Drp1 and mitochondria in PC12 cells. The phosphorylation and mitochondrial translocation of Drp1 were effectively reversed by HKL treatment. Importantly, the selective Sirt3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine suppressed these effects. Conclusion: Our findings demonstrated that HKL ameliorated ICH-induced apoptosis and mitochondrial fission by Sirt3, suggesting that HKL has immense prospects for the treatment of ICH.

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Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Honokiol attenuates mitochondrial fission and cell apoptosis by activating Sirt3 in intracerebral hemorrhage

Zheng

Gao

Zhao

et al. 2023

Chinese Medical Journal

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“…Mitochondrial division inhibitor 1 (Mdivi-1) could improve TBI-induced injuries to the BBB and relieve cell death by suppressing mitophagy, as well as mitochondrial division [105]. Another study reported that mitophagy was protective against TBI-induced brain damage, while Mdivi-1 had the opposite effect in TBI rats and aggravated brain damage [106]. In light of this, we speculated that the diverse roles of mitophagy on TBI-induced damage might be related to the extent of mitophagy.…”

Section: Oxidative Stress and Mitophagymentioning

confidence: 99%

“…Apoptosis, one of programmed cell death (PCD), leads to shrinkage, chromosome condensation, and DNA fragmentation [115]. Mdivi-1, which explicitly suppresses mitophagy, can activate apoptotic markers caspase-3 and caspase-9, indicating that mitophagy significantly reduces TBI-induced cell apoptosis [106]. Mdivi-1 was also found to decrease LC puncta and TUNEL-positive cells, implying that Mdivi-1 inhibition on autophagy may be associated with the antiapoptotic effect in TBI [116].…”

Section: Cell Death and Mitophagymentioning

confidence: 99%

Mitophagy and Traumatic Brain Injury: Regulatory Mechanisms and Therapeutic Potentials

Luan

Jiang

Luan

et al. 2023

Oxidative Medicine and Cellular Longevity

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Traumatic brain injury (TBI), a kind of external trauma-induced brain function alteration, has posed a financial burden on the public health system. TBI pathogenesis involves a complicated set of events, including primary and secondary injuries that can cause mitochondrial damage. Mitophagy, a process in which defective mitochondria are specifically degraded, segregates and degrades defective mitochondria allowing a healthier mitochondrial network. Mitophagy ensures that mitochondria remain healthy during TBI, determining whether neurons live or die. Mitophagy acts as a critical regulator in maintaining neuronal survival and healthy. This review will discuss the TBI pathophysiology and the consequences of the damage it causes to mitochondria. This review article will explore the mitophagy process, its key factors, and pathways and reveal the role of mitophagy in TBI. Mitophagy will be further recognized as a therapeutic approach in TBI. This review will offer new insights into mitophagy’s role in TBI progression.

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“…On the contrary, pharmacological inhibition of Drp1 using mitochondrial division inhibitor 1 (mdivi‐1) can alleviate neurological deficits and synaptic dysfunction associated with intracerebral haemorrhage (Zhang, Rui, et al, 2021). Notably, a synergistic protective effect of mitochondria‐targeted antioxidant SS31 and Mdivi1 was reported against Aβ induced cell death in neurons (Reddy et al, 2018).…”

Section: Drp1 Function In the Brainmentioning

confidence: 99%

Mechanistic and therapeutic role of Drp1 in the pathogenesis of Alzheimer's disease

Bera

Lavanya

Reshmi

et al. 2022

Eur J of Neuroscience

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Alzheimer's disease (AD), a progressive neurodegenerative disorder, has emerged as the most common form of dementia in the elderly. Two major pathological hallmarks have been identified for AD: extracellular amyloid plaques and intracellular neurofibrillary tangles (NFT). Recently, dynaminrelated protein 1 (Drp1) was recognized to contribute significantly towards the pathogenesis of AD. Drp1 is primarily located in the cytosol, from where it translocates to the mitochondrial outer membrane and drives the mitochondrial fission via GTP hydrolysis. Drp1 interacts with Aβ and phosphorylated tau, leading to excessive mitochondrial fragmentation, which in turn results in synaptic dysfunction, neuronal damage and cognitive decline. Several studies suggest an increase in the level of Drp1 in the post-mortem brain specimen collected from the AD patients and murine models of AD. Interestingly, heterozygous deletion of Drp1 in the transgenic murine model of AD ameliorates the mitochondrial dysfunction, improving learning and memory. The current review article discusses the possible mechanistic pathways by which Drp1 can influence the pathogenesis of AD. Besides, it will describe various inhibitors for Drp1 and their potential role as therapeutics for AD in the future.

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Mdivi-1 alleviates brain damage and synaptic dysfunction after intracerebral hemorrhage in mice

Cited by 15 publications

References 36 publications

Honokiol attenuates mitochondrial fission and cell apoptosis by activating Sirt3 in intracerebral hemorrhage

Honokiol attenuates mitochondrial fission and cell apoptosis by activating Sirt3 in intracerebral hemorrhage

Mitophagy and Traumatic Brain Injury: Regulatory Mechanisms and Therapeutic Potentials

Mechanistic and therapeutic role of Drp1 in the pathogenesis of Alzheimer's disease

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