Methylene Blue Reduces Neuronal Apoptosis and Improves Blood-Brain Barrier Integrity After Traumatic Brain Injury

Shen, Jun; Yang, Xinyu; Li, Qifeng; Gao, Yalong; Yuan, Lili; Zhang, Jianning

doi:10.3389/fneur.2019.01133

Cited by 29 publications

(25 citation statements)

References 33 publications

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“…Most likely, this effect was achieved due to the unique properties of MB, which can act as an alternative electron carrier [52]. It has been repeatedly shown that MB improves memory in various experimental models [53][54][55][56][57]. At the same time, we showed that at a concentration of 50 mg/kg/day, MB did not significantly increase the cognitive parameters of mice.…”

Section: Plos Onementioning

confidence: 56%

Effect of long-term methylene blue treatment on the composition of mouse gut microbiome and its relationship with the cognitive abilities of mice

et al. 2020

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In recent years, methylene blue (MB) has attracted considerable interest as a potential drug for the treatment of methemoglobinemia and neurodegenerative diseases. MB is active against microorganisms from various taxonomic groups. However, no studies have yet been conducted on the effect of MB on the intestinal microbiome of model animals. The aim of this work was to study the effect of different concentrations of MB on the mouse gut microbiome and its relationship with the cognitive abilities of mice. We showed that a low MB concentration (15 mg/kg/day) did not cause significant changes in the microbiome composition. The Bacteroidetes/Firmicutes ratio decreased relative to the control on the 2nd and 3rd weeks. A slight decrease in the levels Actinobacteria was detected on the 3rd week of the experiment. Changes in the content of Delta, Gamma, and Epsilonproteobacteria have been also observed. We did not find significant alterations in the composition of intestinal microbiome, which could be an indication of the development of dysbiosis or other gut dysfunction. At the same time, a high concentration of MB (50 mg/kg/day) led to pronounced changes, primarily an increase in the levels of Delta, Gamma and Epsilonproteobacteria. Over 4 weeks of therapy, the treatment with high MB concentration has led to an increase in the median content of Proteobacteria to 7.49% vs. 1.61% in the control group. Finally, we found that MB at a concentration of 15 mg/kg/day improved the cognitive abilities of mice, while negative correlation between the content of Deferribacteres and cognitive parameters was revealed. Our data expand the understanding of the relationship between MB, cognitive abilities, and gut microbiome in respect to the antibacterial properties of MB.

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Section: Plos Onementioning

confidence: 56%

Effect of long-term methylene blue treatment on the composition of mouse gut microbiome and its relationship with the cognitive abilities of mice

et al. 2020

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“…BBB is considered a therapeutic target for TBI (Abrahamson and Ikonomovic 2020 ; Jing et al 2020 ; Kempuraj et al 2017 ; Shen et al 2019 ; Thal and Neuhaus 2014 ). Endothelial cells are connected by many tight junction proteins that form BBB and regulate the rate of microvascular permeability in the brain.…”

Section: Discussionmentioning

confidence: 99%

Acute Traumatic Brain Injury-Induced Neuroinflammatory Response and Neurovascular Disorders in the Brain

et al. 2020

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Acute traumatic brain injury (TBI) leads to neuroinflammation, neurodegeneration, cognitive decline, psychological disorders, increased blood-brain barrier (BBB) permeability, and microvascular damage in the brain. Inflammatory mediators secreted from activated glial cells, neurons, and mast cells are implicated in the pathogenesis of TBI through secondary brain damage. Abnormalities or damage to the neurovascular unit is the indication of secondary injuries in the brain after TBI. However, the precise mechanisms of molecular and ultrastructural neurovascular alterations involved in the pathogenesis of acute TBI are not yet clearly understood. Moreover, currently, there are no precision-targeted effective treatment options to prevent the sequelae of TBI. In this study, mice were subjected to closed head weight-drop-induced acute TBI and evaluated neuroinflammatory and neurovascular alterations in the brain by immunofluorescence staining or quantitation by enzyme-linked immunosorbent assay (ELISA) procedure. Mast cell stabilizer drug cromolyn was administered to inhibit the neuroinflammatory response of TBI. Results indicate decreased level of pericyte marker platelet-derived growth factor receptor-beta (PDGFR-β) and BBB-associated tight junction proteins junctional adhesion molecule-A (JAM-A) and zonula occludens-1 (ZO-1) in the brains 7 days after weight-drop-induced acute TBI as compared with the brains from sham control mice indicating acute TBI-associated BBB/ tight junction protein disruption. Further, the administration of cromolyn drug significantly inhibited acute TBI-associated decrease of PDGFR-β, JAM-A, and ZO-1 in the brain. These findings suggest that acute TBI causes BBB/tight junction damage and that cromolyn administration could protect this acute TBI-induced brain damage as well as its long-time consequences.

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“…Evens blue (EB) dye extravasation was used to evaluate BBB permeability, as previously described ( 40 ). Briefly, mice were injected with 100 μl of 4% EB, and then perfused with phosphate buffered saline.…”

Section: Methodsmentioning

confidence: 99%

“…The TUNEL staining procedure was then performed as previously described (40). TUNEL and immunofluorescence staining of neuronal nuclei (NeuN) were combined to evaluate neuronal apoptosis.…”

Section: Tunel Assaymentioning

confidence: 99%

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Losartan Treatment Could Improve the Outcome of TBI Mice

Xiong

Gao

et al. 2020

Front. Neurol.

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Traumatic brain injury frequently leads to serious mortality and physical disability, yet effective treatments remains insufficient. TBI always leads to a series of secondary brain injuries including neuronal apoptosis, continuous inflammation, endoplasmic reticulum stress, and disruption of the blood-brain barrier. Sartans that block angiotensin II type 1 receptors are strongly neuroprotective, neurorestorative and anti-inflammatory. However, whether losartan, a FDA-approved and widely used drug for regulating blood pressure, is beneficial for improving the prognosis of TBI need more evidence. Through a controlled cortical impact injury mice model, we confirmed that losartan treatment could ameliorate CCI-induced secondary brain injury. We found that losartan treatment decreased brain lesion volume, neuronal apoptosis and ER stress protein ATF4 and eIF2α. Moreover, our results showed that losartan also improved neurological and motor function. It is worth pointing out that losartan increased the expression of tight junction proteins ZO-1 and alleviated brain edema and blood brain barrier leakage. Additionally, losartan inhibited pro-inflammatory factor TNF-α and improve anti-inflammatory factor IL-10. Taken together, our data demonstrated that losartan could improve the prognosis of TBI and may be a promising therapeutic method for mitigating TBI.

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Methylene Blue Reduces Neuronal Apoptosis and Improves Blood-Brain Barrier Integrity After Traumatic Brain Injury

Cited by 29 publications

References 33 publications

Effect of long-term methylene blue treatment on the composition of mouse gut microbiome and its relationship with the cognitive abilities of mice

Effect of long-term methylene blue treatment on the composition of mouse gut microbiome and its relationship with the cognitive abilities of mice

Acute Traumatic Brain Injury-Induced Neuroinflammatory Response and Neurovascular Disorders in the Brain

Losartan Treatment Could Improve the Outcome of TBI Mice

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