Blood-brain barrier tight junction permeability and ischemic stroke

Sandoval, Karin E.; Witt, K.

doi:10.1016/j.nbd.2008.08.005

Cited by 840 publications

(758 citation statements)

References 316 publications

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“…Inflammation begins within hours in the postischemic brain,74, 75 resulting in activation of microglial and secretion of inflammatory cytokines within 24 h of infarction 76. These inflammatory cytokines contributes to cerebral edema through disruption of BBB integrity 77. Additionally, through the downregulation of phophorylation of CypA, as demonstrated in our phosphoproteomic results, CN‐105 also maintains BBB integrity, reducing cerebral edema after injury.…”

Section: Discussionmentioning

confidence: 52%

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Kolls

Soderblom

et al. 2017

Ann Clin Transl Neurol

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ObjectiveAt present, the absence of a pharmacological neuroprotectant represents an important unmet clinical need in the treatment of ischemic and traumatic brain injury. Recent evidence suggests that administration of apolipoprotein E mimetic therapies represent a viable therapeutic strategy in this setting. We investigate the neuroprotective and anti‐inflammatory properties of the apolipoprotein E mimetic pentapeptide, CN‐105, in a microglial cell line and murine model of ischemic stroke.MethodsTen to 13‐week‐old male C57/BL6 mice underwent transient middle cerebral artery occlusion and were randomly selected to receive CN‐105 (0.1 mg/kg) in 100 μL volume or vehicle via tail vein injection at various time points. Survival, motor‐sensory functional outcomes using rotarod test and 4‐limb wire hanging test, infarct volume assessment using 2,3,5‐Triphenyltetrazolium chloride staining method, and microglial activation in the contralateral hippocampus using F4/80 immunostaining were assessed at various time points. In vitro assessment of tumor necrosis factor‐alpha secretion in a microglial cell line was performed, and phosphoproteomic analysis conducted to explore early mechanistic pathways of CN‐105 in ischemic stroke.ResultsMice receiving CN‐105 demonstrated improved survival, improved functional outcomes, reduced infarct volume, and reduced microglial activation. CN‐105 also suppressed inflammatory cytokines secretion in microglial cells in vitro. Phosphoproteomic signals suggest that CN‐105 reduces proinflammatory pathways and lower oxidative stress.Interpretation CN‐105 improves functional and histological outcomes in a murine model of ischemic stroke via modulation of neuroinflammatory pathways. Recent clinical trial of this compound has demonstrated favorable pharmacokinetic and safety profile, suggesting that CN‐105 represents an attractive candidate for clinical translation.

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Section: Discussionmentioning

confidence: 52%

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Kolls

Soderblom

et al. 2017

Ann Clin Transl Neurol

View full text Add to dashboard Cite

show abstract

“…Prolonged DM induces thickening of the capillary basement membrane, which then increases BBB permeability because of alterations in the physical dimensions of the meshwork and changes in the normal electrical charge surrounding the pores between endothelial cells 12. A ruptured BBB is permeable to large molecules and facilitates the invasion of inflammatory factors, neurotoxins, and pathogens into the brain 11. BBB disruption occurs in the acute phase after stroke and is among the initial steps that precede many neurological disorders 13.…”

Section: Blood–brain Barrier Disruption In Diabetic Strokementioning

confidence: 99%

“…The TJs create a high endothelial electrical resistance and low paracellular permeability, thereby preventing ion flux and paracellular diffusion across the BBB 26. During ischemic stroke, TJ degradation occurs in a multistep time‐dependent fashion involving a number of interdependent signaling mechanisms 11. During the reperfusion phase of ischemia–reperfusion (I/R) injury, reactive hyperemia and loss of cerebral autoregulation lead to acute opening of the BBB TJs 11.…”

Section: Blood–brain Barrier Disruption In Diabetic Strokementioning

confidence: 99%

“…During ischemic stroke, TJ degradation occurs in a multistep time‐dependent fashion involving a number of interdependent signaling mechanisms 11. During the reperfusion phase of ischemia–reperfusion (I/R) injury, reactive hyperemia and loss of cerebral autoregulation lead to acute opening of the BBB TJs 11. The stability of the TJ is maintained by anchoring TJ proteins (eg, occludin and claudin) and the AJ protein cadherin to the actin cytoskeleton via multiple accessory proteins such as zonula occludens 26, 27.…”

Section: Blood–brain Barrier Disruption In Diabetic Strokementioning

confidence: 99%

“…However, when subjected to hypoxic stress, the actin filaments polymerize into linear stress fibers and the actin–myosin cytoskeleton contracts via myosin light chain phosphorylation, leading to increased cytoskeletal tension, weakening of the junction seals, and increased BBB permeability 27, 28. Stroke decreases TJ transmembrane proteins such as occludin, claudin, zonula occludens, and junction adhesion molecules 11, 26. DM decreases TJ proteins in the parenchymal blood vessels, inducing BBB disruption, and facilitates extravasation of albumin and inflammatory factors into the brain 29.…”

Section: Blood–brain Barrier Disruption In Diabetic Strokementioning

confidence: 99%

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