Methylene Blue Reduces Acute Cerebral Ischemic Injury via the Induction of Mitophagy

Yao, Di; He, Yun-Ling; Zhao, Tong; Huang, Xin; Wu, Kui-Wu; Liu, Shuhong; Zhao, Yong-Qi; Fan, Ming; Wu, Liying; Zhu, Lijing

doi:10.2119/molmed.2015.00038

Cited by 72 publications

(57 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Cerebral ischemia and subsequent reperfusion result in cellular organelles damage, which plays a pivotal role in the development of tissue injury after acute ischemic stroke. Ischemia-reperfusion insult generally leads to mitochondrial dysfunction and fragmentation [10, 11]. Consistent with previous finding, we also found mitochondrial fragmentation in N2a cells after 4 h and 12 h reperfusion following 4 h OGD exposure.…”

Section: Discussionsupporting

confidence: 92%

Parkin Protects against Oxygen-Glucose Deprivation/Reperfusion Insult by Promoting Drp1 Degradation

Tang

Tan

et al. 2016

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Ischemic stroke results in severe brain damage and remains one of the leading causes of death and disability worldwide. Effective neuroprotective therapies are needed to reduce brain damage resulting from ischemic stroke. Mitochondria are crucial for cellular energy production and homeostasis. Modulation of mitochondrial function mediates neuroprotection against ischemic brain damage. Dynamin-related protein 1 (Drp1) and parkin play a key role in regulating mitochondrial dynamics. They are potential therapeutic targets for neuroprotection in ischemic stroke. Protective effects of parkin-Drp1 pathway on mitochondria were assessed in a cellular ischemia-reperfusion injury model. Mouse neuroblastoma Neuro2a (N2a) cells were subjected to oxygen-glucose deprivation/reperfusion (OGDR) insult. OGDR induces mitochondrial fragmentation. The expression of Drp1 protein is increased after OGDR insult, while the parkin protein level is decreased. The altered protein level of Drp1 after OGDR injury is mediated by parkin through ubiquitin proteasome system (UPS). Drp1 depletion protects against OGDR induced mitochondrial damage and apoptosis. Meanwhile, parkin overexpression protects against OGDR induced apoptosis and mitochondrial dysfunction, which is attenuated by increased expression of Drp1. Our data demonstrate that parkin protects against OGDR insult through promoting degradation of Drp1. This neuroprotective potential of parkin-Drp1 pathway against OGDR insult will pave the way for developing novel neuroprotective agents for cerebral ischemia-reperfusion related disorders.

show abstract

Section: Discussionsupporting

confidence: 92%

Parkin Protects against Oxygen-Glucose Deprivation/Reperfusion Insult by Promoting Drp1 Degradation

Tang

Tan

et al. 2016

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

show abstract

“…These recent investigations suggested MB protects neuron from I/R insult. Most recent studies show that MB is able to enhance brain function, with mechanisms involving increased autophagy and mitophagy in a rat ischemic stroke model [61,62]. It will be very interesting to further investigate the relationship between mitochondrial function and cognitive behavior, which may be helpful in the understanding of the cognitive improvement effects of MB in brain ischemia.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective and Functional Improvement Effects of Methylene Blue in Global Cerebral Ischemia

et al. 2015

View full text Add to dashboard Cite

Transient global cerebral ischemia (GCI) causes delayed neuronal cell death in the vulnerable hippocampus CA1 subfield, as well as behavioral deficits. Ischemia reperfusion (I/R) produces excessive reactive oxygen species and plays a key role in brain injury. The mitochondrial electron respiratory chain is the main cellular source of free radical generation, and dysfunction of mitochondria has a significant impact on the neuronal cell death in ischemic brain. The aim of the present study is to investigate the potential beneficial effects of methylene blue (MB) in a 4-vessel occlusion (4VO) GCI model on adult male rats. MB was delivered at a dose of 0.5 mg/kg/day for 7 days, through a mini-pump implanted subcutaneously after GCI. We first found that MB significantly improved ischemic neuronal survival in hippocampal CA1 region as measured by cresyl violet staining as well as NeuN staining. We also found that MB has the ability to rescue ischemia-induced decreases of cytochrome c oxidase activity and ATP generation in CA1 region following I/R. Further analysis with labeling of MitoTracker® Red revealed that the depolarization of mitochondrial membrane potential (MMP) was markedly attenuated following MB treatment. In addition, the induction of caspase-3, -8 and -9 activities, and the increased numbers of TUNEL positive cells of CA1 region were significantly reduced by MB application. Correspondingly, Barnes maze tests showed that the deterioration of spatial learning and memory performance following GCI were significantly improved in MB-treatment group compared to ischemic control group. In summary, our study suggests that MB may be a promising therapeutic agent targeting neuronal cell death and cognitive deficits following transient global cerebral ischemia.

show abstract

“…It also is an alternative electron carrier that shuttles electrons between NADH and cytochrome c (cyt c ) so that electrons are rerouted with complex I and III inhibition thereby attenuating ROS overproduction. Its neuroprotective effects have also been attributed to mitophagy (Di et al , 2015), stimulation of HIF-1α (Ryou et al , 2015), and improved cerebral metabolic and hemodynamic function (Lin et al , 2012). MB significantly decreases infarct volume after middle cerebral artery occlusion in animal models (Di et al , 2015; Shen et al , 2013).…”

Section: Pharmacologic Therapiesmentioning

confidence: 99%

“…Its neuroprotective effects have also been attributed to mitophagy (Di et al , 2015), stimulation of HIF-1α (Ryou et al , 2015), and improved cerebral metabolic and hemodynamic function (Lin et al , 2012). MB significantly decreases infarct volume after middle cerebral artery occlusion in animal models (Di et al , 2015; Shen et al , 2013). Given its current use in clinical settings and known side effects, it may easily be a promising translational treatment for the mitochondria dysfunction seen with aging in ischemia (Wen et al , 2011).…”

Section: Pharmacologic Therapiesmentioning

confidence: 99%

Mitochondrial function in hypoxic ischemic injury and influence of aging

Ham

Raju

2017

Progress in Neurobiology

259

200

View full text Add to dashboard Cite

Mitochondria are a major target in hypoxic/ischemic injury. Mitochondrial impairment increases with age leading to dysregulation of molecular pathways linked to mitochondria. The perturbation of mitochondrial homeostasis and cellular energetics worsens outcome following hypoxic-ischemic insults in elderly individuals. In response to acute injury conditions, cellular machinery relies on rapid adaptations by modulating posttranslational modifications. Therefore, post-translational regulation of molecular mediators such as hypoxia-inducible factor 1α (HIF-1α), peroxisome proliferator-activated receptor γ coactivator α (PGC-1α), c-MYC, SIRT1 and AMPK play a critical role in the control of the glycolytic-mitochondrial energy axis in response to hypoxic-ischemic conditions. The deficiency of oxygen and nutrients leads to decreased energetic reliance on mitochondria, promoting glycolysis. The combination of pseudohypoxia, declining autophagy, and dysregulation of stress responses with aging adds to impaired host response to hypoxic-ischemic injury. Furthermore, intermitochondrial signal propagation and tissue wide oscillations in mitochondrial metabolism in response to oxidative stress are emerging as vital to cellular energetics. Recently reported intercellular transport of mitochondria through tunneling nanotubes also play a role in the response to and treatments for ischemic injury. In this review we attempt to provide an overview of some of the molecular mechanisms and potential therapies involved in the alteration of cellular energetics with aging and injury with a neurobiological perspective.

show abstract

Methylene Blue Reduces Acute Cerebral Ischemic Injury via the Induction of Mitophagy

Cited by 72 publications

References 56 publications

Parkin Protects against Oxygen-Glucose Deprivation/Reperfusion Insult by Promoting Drp1 Degradation

Parkin Protects against Oxygen-Glucose Deprivation/Reperfusion Insult by Promoting Drp1 Degradation

Neuroprotective and Functional Improvement Effects of Methylene Blue in Global Cerebral Ischemia

Mitochondrial function in hypoxic ischemic injury and influence of aging

Contact Info

Product

Resources

About