Endothelial NOS activation induces the blood–brain barrier disruption via ER stress following status epilepticus

Ko, Ah-Reum; Kim, Ji Yang; Hyun, Hye-Won

doi:10.1016/j.brainres.2015.06.020

Cited by 20 publications

(12 citation statements)

References 50 publications

(59 reference statements)

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“…Following contusive SCI, CHOP deficiency in mice significantly preserves microvascular density and attenuated macrophage infiltration compared to wild type mice 24 . Up-regulation of GRP78 expression participates in status epilepticus induced vasogenic edema formation and BBB breakdown 45 . Evidence also suggest that ER stress in the endothelial cells may be an important causal factor to diabetes-induced vascular complications 46 , and inhibition of ER stress improves coronary artery function in type 2 diabetic mice (T2DM) 47 .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Endoplasmic Reticulum Stress Preserves the Integrity of Blood-Spinal Cord Barrier in Diabetic Rats Subjected to Spinal Cord Injury

Zou

Yin

et al. 2017

Sci Rep

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The blood-spinal cord barrier (BSCB) plays significance roles in recovery following spinal cord injury (SCI), and diabetes mellitus (DM) impairs endothelial cell function and integrity of BSCS. Endoplasmic reticulum (ER) stress occurs in the early stages of SCI and affects prognosis and cell survival. However, the relationship between ER stress and the integrity of BSCB in diabetic rats after SCI remains unclear. Here we observed that diabetic rats showed increased extravasation of Evans Blue (EB) dye, and loss of endothelial cells and pericytes 1 day after SCI compared to non-diabetic rats. Diabetes was also shown to induce activation of ER stress. Similar effects were observed in human brain microvascular endothelial cells. 4-phenylbutyric acid (4-PBA), an ER stress inhibitor lowered the adverse effect of diabetes on SCI, reduced EB dye extravasation, and limited the loss of endothelial cells and pericytes. Moreover, 4-PBA treatment partially reversed the degradation of tight junction and adherens junction both in vivo and in vitro. In conclusion, diabetes exacerbates the disruption of BSCB after SCI via inducing ER stress, and inhibition of ER stress by 4-PBA may play a beneficial role on the integrity of BSCB in diabetic SCI rats, leading to improved prognosis.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Endoplasmic Reticulum Stress Preserves the Integrity of Blood-Spinal Cord Barrier in Diabetic Rats Subjected to Spinal Cord Injury

Zou

Yin

et al. 2017

Sci Rep

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“…NO then disrupts the BBB and increases permeability through tight junction hydrolysis, mediated by metalloproteinases activation. ET-1-ETB signal contributes to increased formation of ROS such as NADPH oxidase, and subsequent astrocytic dysfunction [ 198 ]. Additionally, endothelial glutamate receptors can be activated during SE, which in turn leads to oxidative stress and BBB disruption [ 199 ].…”

Section: Introductionmentioning

confidence: 99%

Astroglial role in the pathophysiology of statusepilepticus: an overview

et al. 2018

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Status epilepticus is a medical emergency with elevated morbidity and mortality rates, and represents a leading cause of epilepsy-related deaths. Though status epilepticus can occur at any age, it manifests more likely in children and elderly people. Despite the common prevalence of epileptic disorders, a complete explanation for the mechanisms leading to development of self-limited or long lasting seizures (as in status epilepticus) are still lacking. Apart from neurons, research evidence suggests the involvement of immune and glial cells in epileptogenesis. Among glial cells, astrocytes represent an ideal target for the study of the pathophysiology of status epilepticus, due to their key role in homeostatic balance of the central nervous system. During status epilepticus, astroglial cells are activated by the presence of cytokines, damage associated molecular patterns and reactive oxygen species. The persistent activation of astrocytes leads to a decrease in glutamate clearance with a corresponding accumulation in the synaptic extracellular space, increasing the chance of neuronal excitotoxicity. Moreover, major alterations in astrocytic gap junction coupling, inflammation and receptor expression, facilitate the generation of seizures. Astrocytes are also involved in dysregulation of inhibitory transmission in the central nervous system and directly participate in ionic homeostatic alterations during status epilepticus. In the present review, we focus on the functional and structural changes in astrocytic activity that participate in the development and maintenance of status epilepticus, with special attention on concurrent inflammatory alterations. We also include potential astrocytic treatment targets for status epilepticus.

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“…Several publications reported that ER stress induction is linked to endothelial dysfunction and can lead to an increased vascular permeability in various disease models515253545556. We previously demonstrated that exposure of brain endothelial cells to Efavirenz induces ER stress and disrupts autophagy25.…”

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confidence: 97%

Antiretroviral Treatment with Efavirenz Disrupts the Blood-Brain Barrier Integrity and Increases Stroke Severity

Bertrand

Dygert

Toborek

2016

Sci Rep

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The introduction of antiretroviral drugs (ARVd) changed the prognosis of HIV infection from a deadly disease to a chronic disease. However, even with undetectable viral loads, patients still develop a wide range of pathologies, including cerebrovascular complications and stroke. It is hypothesized that toxic side effects of ARVd may contribute to these effects. To address this notion, we evaluated the impact of several non-nucleoside reverse transcriptase inhibitors (NNRTI; Efavirenz, Etravirine, Rilpivirine and Nevirapine) on the integrity of the blood-brain barrier, and their impact on severity of stroke. Among studied drugs, Efavirenz, but not other NNRTIs, altered claudin-5 expression, increased endothelial permeability, and disrupted the blood-brain barrier integrity. Importantly, Efavirenz exposure increased the severity of stroke in a model of middle cerebral artery occlusion in mice. Taken together, these results indicate that selected ARVd can exacerbate HIV-associated cerebrovascular pathology. Therefore, careful consideration should be taken when choosing an anti-retroviral therapy regimen.

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Endothelial NOS activation induces the blood–brain barrier disruption via ER stress following status epilepticus

Cited by 20 publications

References 50 publications

Inhibition of Endoplasmic Reticulum Stress Preserves the Integrity of Blood-Spinal Cord Barrier in Diabetic Rats Subjected to Spinal Cord Injury

Inhibition of Endoplasmic Reticulum Stress Preserves the Integrity of Blood-Spinal Cord Barrier in Diabetic Rats Subjected to Spinal Cord Injury

Astroglial role in the pathophysiology of statusepilepticus: an overview

Antiretroviral Treatment with Efavirenz Disrupts the Blood-Brain Barrier Integrity and Increases Stroke Severity

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