Oxygen-Glucose Deprivation in Mouse Astrocytes is Associated with Ultrastructural Changes in Connexin 43 Gap Junctions

Beckmann, Arnold; Grißmer, Alexander; Wolf, Sandra; Recktenwald, Johanna; Meier, Carola

doi:10.1016/j.neuroscience.2018.11.043

Cited by 14 publications

(22 citation statements)

References 71 publications

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“…Primary astrocytes were isolated from the brains of newborn C57BL/6J mice (1‐3 days) according to a previous report . After 2 weeks, primary astrocytes were plated in 6‐well culture plates at a density of 1 × 10 6 cells/well.…”

Section: Methodsmentioning

confidence: 99%

dl‐3‐n‐butylphthalide preserves white matter integrity and alleviates cognitive impairment in mice with chronic cerebral hypoperfusion

Han

Zhang

et al. 2019

CNS Neurosci Ther

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Aims Effects of dl‐3‐n‐butylphthalide (NBP) on white matter damage and cognitive impairment in vascular cognitive impairment (VCI) have not been well studied. This study aimed to investigate the effects of NBP treatment on chronic cerebral hypoperfusion‐induced white matter lesions and cognitive dysfunction in mice. Methods Mice were subjected to bilateral common carotid artery stenosis (BCAS) for over 30 days. The cerebral blood flow was detected using a laser Doppler flowmetry. Cognitive functions were assessed by several behavioral tests. We also evaluated the effects of NBP on the blood‐brain barrier (BBB) disruption and reactive astrogliosis, using Evans Blue extravasation, Western blot, CBA, and immunofluorescence in BCAS mice and cultured astrocytes. Results The results indicated that NBP treatment attenuated spatial memory dysfunction while promoted cerebral perfusion and white matter integrity in BCAS mice. Moreover, NBP treatment prevented BBB leakage and damage of endothelial cells, as well as disruption of endothelial tight junctions. Furthermore, NBP administration effectively decreased the number of activated astrocytes and pro‐inflammatory cytokines, as well as the production of MMPs, in BCAS‐induced mice and LPS‐stimulated astrocytes. Conclusion Our results indicated that NBP represents a promising therapy for chronic cerebral hypoperfusion‐induced white matter damage and cognitive impairment.

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Section: Methodsmentioning

confidence: 99%

dl‐3‐n‐butylphthalide preserves white matter integrity and alleviates cognitive impairment in mice with chronic cerebral hypoperfusion

Han

Zhang

et al. 2019

CNS Neurosci Ther

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“…It has been reported that the C-terminal of astrocytic Cx43 could be phosphorylated after ischemic stroke via several protein kinases including protein kinase C (96), mitogen-activated protein kinase (MAPK) (97), pp60Src kinase (98), and casein kinase 1δ (99), inducing Cx43 internalization, further contributing to the uncoupling process of astrocytes (100,101). Interestingly, other studies have found that in vitro hypoxia may lead to the dephosphorylation of the C-terminal of astrocytic Cx43, accompanied by the uncoupling of astrocytes (101,102). This controversy arises because the phosphorylation and dephosphorylation of Cx43 as well as astrocytic uncoupling all occur within a short period after ischemia.…”

Section: Change In Astrocytic Cx43 In Ischemic Strokementioning

confidence: 99%

The Multifaceted Role of Astrocyte Connexin 43 in Ischemic Stroke Through Forming Hemichannels and Gap Junctions

et al. 2020

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Ischemic stroke is a multi-factorial cerebrovascular disease with high worldwide morbidity and mortality. In the past few years, multiple studies have revealed the underlying mechanism of ischemia/reperfusion injury, including calcium overload, amino acid toxicity, oxidative stress, and inflammation. Connexin 43 (Cx43), the predominant connexin protein in astrocytes, has been recently proven to display non-substitutable roles in the pathology of ischemic stroke development and progression through forming gap junctions and hemichannels. Under normal conditions, astrocytic Cx43 could be found in hemichannels or in the coupling with other hemichannels on astrocytes, neurons, or oligodendrocytes to form the neuro-glial syncytium, which is involved in metabolites exchange between communicated cells, thus maintaining the homeostasis of the CNS environment. In ischemic stroke, the phosphorylation of Cx43 might cause the degradation of gap junctions and the opening of hemichannels, contributing to the release of inflammatory mediators. However, the remaining gap junctions could facilitate the exchange of protective and harmful metabolites between healthy and injured cells, protecting the injured cells to some extent or damaging the healthy cells depending on the balance of the exchange of protective and harmful metabolites. In this study, we review the changes in astrocytic Cx43 expression and distribution as well as the influence of these changes on the function of astrocytes and other cells in the CNS, providing new insight into the pathology of ischemic stroke injury; we also discuss the potential of astrocytic Cx43 as a target for the treatment of ischemic stroke.

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“…Oxygen-glucose deprivation is the most common way to imitate hypoxic injury in vitro (Beckmann et al, 2018), and Hypoxic injury generally occurs after TBI (Salehi et al, 2017). Furthermore, OGD is also a recognized method to establish BBB injury model in vitro (Ge et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

Semaphorin 3A Contributes to Secondary Blood–Brain Barrier Damage After Traumatic Brain Injury

Yang

Wang

Fan

et al. 2019

Front. Cell. Neurosci.

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Semaphorin 3A (SEMA3A) is a member of the Semaphorins family, a class of membrane-associated protein that participates in the construction of nerve networks. SEMA3A has been reported to affect vascular permeability previously, but its influence in traumatic brain injury (TBI) is still unknown. To investigate the effects of SEMA3A, we used a mouse TBI model with a controlled cortical impact (CCI) device and a blood–brain barrier (BBB) injury model in vitro with oxygen-glucose deprivation (OGD). We tested post-TBI changes in SEMA3A, and its related receptors (Nrp-1 and plexin-A1) expression and distribution through western blotting and double-immunofluorescence staining, respectively. Neurological outcomes were evaluated by modified neurological severity scores (mNSSs) and beam-walking test. We examined BBB damage through Evans Blue dye extravasation, brain water content, and western blotting for VE-cadherin and p-VE-cadherin in vivo , and we examined the endothelial cell barrier through hopping probe ion conductance microscopy (HPICM), transwell leakage, and western blotting for VE-cadherin and p-VE-cadherin in vitro . Changes in miR-30b-5p were assessed by RT-PCR. Finally, the neuroprotective function of miR-30b-5p is measured by brain water content, mNSSs and beam-walking test. SEMA3A expression varied following TBI and peaked on the third day which expressed approximate fourfold increase compared with sham group, with the protein concentrated at the lesion boundary. SEMA3A contributed to neurological function deficits and secondary BBB damage in vivo . Our results demonstrated that SEMA3A level following OGD injury almost doubled than control group, and the negative effects of OGD injury can be improved by blocking SEMA3A expression. Furthermore, the expression of miR-30b-5p decreased approximate 40% at the third day and 60% at the seventh day post-CCI. OGD injury also exhibited an effect to approximately decrease 50% of miR-30b-5p expression. Additionally, the expression of SEMA3A post-TBI is regulated by miR-30b-5p, and miR-30b-5p could improve neurological outcomes post-TBI efficiently. Our results demonstrate that SEMA3A is a significant factor in secondary BBB damage after TBI and can be abolished by miR-30b-5p, which represents a potential therapeutic target.

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Oxygen-Glucose Deprivation in Mouse Astrocytes is Associated with Ultrastructural Changes in Connexin 43 Gap Junctions

Cited by 14 publications

References 71 publications

dl‐3‐n‐butylphthalide preserves white matter integrity and alleviates cognitive impairment in mice with chronic cerebral hypoperfusion

dl‐3‐n‐butylphthalide preserves white matter integrity and alleviates cognitive impairment in mice with chronic cerebral hypoperfusion

The Multifaceted Role of Astrocyte Connexin 43 in Ischemic Stroke Through Forming Hemichannels and Gap Junctions

Semaphorin 3A Contributes to Secondary Blood–Brain Barrier Damage After Traumatic Brain Injury

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