Breaking the Barrier in Stroke: What Should we Know? A Mini-Review

Borlongan, Cesario V.; Rodrigues, Antonio A.; Oliveira, Maria Carolina

doi:10.2174/138161212802002670

Cited by 29 publications

(19 citation statements)

References 43 publications

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“…Although complement inhibitor biologics (whether targeted or systemic) have limited ability to cross the BBB and may thus have limited application in several neurodegenerative diseases, this is of less concern for ischemic stroke. During the acute phase of ischemic stroke, both ischemia and reperfusion insults are associated with a breach of BBB integrity which lasts for several days after injury, both in human and experimental models . This will allow access of complement inhibitory proteins to the ischemic brain.…”

Section: Injury Site‐specific Targeting Of Complement Modulationmentioning

confidence: 99%

“…During the acute phase of ischemic stroke, both ischemia and reperfusion insults are associated with a breach of BBB integrity which lasts for several days after injury, both in human and experimental models. 69 This will allow access of complement inhibitory proteins to the ischemic brain. The temporary disruption to the BBB also highlights a potential advantage of a site-targeted inhibitor in that once it has gained access, the inhibitor will have an increased half-life at the target site.…”

Section: General Considerations Of Site-targeted and Systemic Complmentioning

confidence: 99%

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Injury site‐specific targeting of complement inhibitors for treating stroke

Alawieh

Tomlinson

2016

Immunological Reviews

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Summary Cumulative evidence indicates a role for the complement system in both pathology and recovery after ischemic stroke. Here, we review the current understanding of the dual role of complement in post-stroke injury and recovery, and discuss the challenges of anti-complement therapies. Most complement directed therapeutics currently under investigation or development systemically inhibit the complement system, but since complement is important for immune surveillance and is involved in various homeostatic activities, there are potential risks associated with systemic inhibition. Depending on the target within the complement pathway, other concerns are high concentrations of inhibitor required, low efficacy and poor bioavailability. To overcome these limitations, approaches to target complement inhibitors to specific sites have been investigated. Here we discuss targeting strategies, with a focus on strategies developed in our lab, to specifically localize complement inhibition to sites of tissue injury and complement activation, and in particular to the post-ischemic brain. We discuss various injury site-specific targeted complement inhibitors as potential therapeutic agents for the treatment of ischemic stroke treatment, as well as their use as investigate tools for probing complement-dependent pathophysiological processes.

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Section: Injury Site‐specific Targeting Of Complement Modulationmentioning

confidence: 99%

Section: General Considerations Of Site-targeted and Systemic Complmentioning

confidence: 99%

Injury site‐specific targeting of complement inhibitors for treating stroke

Alawieh

Tomlinson

2016

Immunological Reviews

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“…Diminished blood-brain barrier (BBB) function is an integral feature of neurological disorders such as stroke [1], neurodegenerative diseases [2], traumatic brain injury [3] and neural infections [4]. A likely correlated aspect of the BBB breakdown associated with these pathologies is the production and release of multiple classes of proinflammatory cytokines from cells within the neurovascular unit and periphery (e.g.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Blood-Brain Barrier Phenotype by Proinflammatory Cytokines Involves NADPH Oxidase-Dependent ROS Generation: Consequences for Interendothelial Adherens and Tight Junctions

et al. 2014

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Background and ObjectivesBlood-brain barrier (BBB) dysfunction is an integral feature of neurological disorders and involves the action of multiple proinflammatory cytokines on the microvascular endothelial cells lining cerebral capillaries. There is still however, considerable ambiguity throughout the scientific literature regarding the mechanistic role(s) of cytokines in this context, thereby warranting a comprehensive in vitro investigation into how different cytokines may cause dysregulation of adherens and tight junctions leading to BBB permeabilization.MethodsThe present study employs human brain microvascular endothelial cells (HBMvECs) to compare/contrast the effects of TNF-α and IL-6 on BBB characteristics ranging from the expression of interendothelial junction proteins (VE-cadherin, occludin and claudin-5) to endothelial monolayer permeability. The contribution of cytokine-induced NADPH oxidase activation to altered barrier phenotype was also investigated.ResultsIn response to treatment with either TNF-α or IL-6 (0–100 ng/ml, 0–24 hrs), our studies consistently demonstrated significant dose- and time-dependent decreases in the expression of all interendothelial junction proteins examined, in parallel with dose- and time-dependent increases in ROS generation and HBMvEC permeability. Increased expression and co-association of gp91 and p47, pivotal NADPH oxidase subunits, was also observed in response to either cytokine. Finally, cytokine-dependent effects on junctional protein expression, ROS generation and endothelial permeability could all be attenuated to a comparable extent using a range of antioxidant strategies, which included ROS depleting agents (superoxide dismutase, catalase, N-acetylcysteine, apocynin) and targeted NADPH oxidase blockade (gp91 and p47 siRNA, NSC23766).ConclusionA timely and wide-ranging investigation comparing the permeabilizing actions of TNF-α and IL-6 in HBMvECs is presented, in which we demonstrate how either cytokine can similarly downregulate the expression of interendothelial adherens and tight junction proteins leading to elevation of paracellular permeability. The cytokine-dependent activation of NADPH oxidase leading to ROS generation was also confirmed to be responsible in-part for these events.

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“…During ischemic stroke, cerebral ischemia and subsequent reperfusion result in harmful consequences, including the breakdown of the blood-brain barrier (BBB), which leads to severe neurologic deficits through aggravation of edema formation and brain hemorrhage (Borlongan et al, 2012; Jung et al, 2010; Latour et al, 2004). Acute hyperglycemia increases infarct volume, brain swelling and hemorrhagic transformation in rat models (McBride et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Role of Hypoxia Inducible Factor 1 in Hyperglycemia-Exacerbated Blood-Brain Barrier Disruption in Ischemic Stroke

Zhang

Yan

Shi

2016

Neurobiology of Disease

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Diabetes is a major stroke risk factor and is associated with poor functional recovery after stroke. Accumulating evidence indicates that the worsened outcomes may be due to hyperglycemia-induced cerebral vascular complications, especially disruption of the blood-brain barrier (BBB). The present study tested a hypothesis that the activation of hypoxia inducible factor-1 (HIF-1) was involved in hyperglycemia-aggravated BBB disruption in an ischemic stroke model. Non-diabetic control and Streptozotocin-induced type I diabetic mice were subjected to 90 min transient middle cerebral artery occlusion (MCAO) followed by reperfusion. Our results demonstrated that hyperglycemia induced higher expression of HIF-1α and vascular endothelial growth factor (VEGF) in brain microvessels after MCAO/reperfusion. Diabetic mice showed exacerbated BBB damage and tight junction disruption, increased infarct volume as well as worsened neurological deficits. Furthermore, suppressing HIF-1 activity by specific knock-out endothelial HIF-1α ameliorated BBB leakage and brain infarction in diabetic animals. Moreover, glycemic control by insulin abolished HIF-1α up-regulation in diabetic animals and reduced BBB permeability and brain infarction. These findings strongly indicate that HIF-1 plays an important role in hyperglycemia-induced exacerbation of BBB disruption in ischemic stroke. Endothelial HIF-1 inhibition warrants further investigation as a therapeutic target for the treatment of stroke patients with diabetes.

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Breaking the Barrier in Stroke: What Should we Know? A Mini-Review

Cited by 29 publications

References 43 publications

Injury site‐specific targeting of complement inhibitors for treating stroke

Injury site‐specific targeting of complement inhibitors for treating stroke

Downregulation of Blood-Brain Barrier Phenotype by Proinflammatory Cytokines Involves NADPH Oxidase-Dependent ROS Generation: Consequences for Interendothelial Adherens and Tight Junctions

Role of Hypoxia Inducible Factor 1 in Hyperglycemia-Exacerbated Blood-Brain Barrier Disruption in Ischemic Stroke

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