Stroke and the Blood‐Brain Interface

Cipolla, Marilyn J.

doi:10.1002/9783527611225.ch25

Cited by 5 publications

(13 citation statements)

References 155 publications

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“…Its unique features are highly protective of the brain milieu and include continuous, high electrical resistance tight junctions that restrict ion flux, limited transcellular transport, very low hydraulic conductivity and a large number of mitochondrion [119]. In addition, the cerebral microcirculation is in close association with other cell types within the brain, including astrocytes, pericytes and neurons separated by the basal lamina, a specialized extracellular matrix generated by both endothelial cells and astrocytes [120, 121].…”

Section: Microcirculation During I/rmentioning

confidence: 99%

“…BBB disruption can also result from the increased expression and activation of MMPs during ischemia that is increased by pro-inflammatory cytokines such as tumor necrosis factor α (TNFα) [135]. In addition to pro-inflammatory cytokines, other circulating factors are released during I/R that increase BBB permeability and promote vasogenic edema formation, including vascular endothelial growth factor (VEGF), histamine and thrombin [119]. …”

Section: Microcirculation During I/rmentioning

confidence: 99%

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Vascular Protection Following Cerebral Ischemia and Reperfusion

Palomares

Cipolla²

2011

J Neurol Neurophysiol

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Despite considerable research that has contributed to a better understanding of the pathophysiology of stroke, translation of this knowledge into effective therapies has largely failed. The only effective treatment for ischemic stroke is rapid recanalization of an occluded vessel by dissolving the clot with tissue plasminogen activator (tPA). However, stroke adversely affects vascular function as well that can cause secondary brain injury and limit treatment that depends on a patent vasculature. In middle cerebral arteries (MCA), ischemia/reperfusion (I/R) cause loss of myogenic tone, vascular paralysis, and endothelial dysfunction that can lead to loss of autoregulation. In contrast, brain parenchymal arterioles retain considerable tone during I/R that likely contributes to expansion of the infarct into the penumbra. Microvascular dysregulation also occurs during ischemic stroke that causes edema and hemorrhage, exacerbating the primary insult. Ischemic injury of vasculature is progressive with longer duration of I/R. Early postischemic reperfusion has beneficial effects on stroke outcome but can impair vascular function and exacerbate ischemic injury after longer durations of I/R. This review focuses on current knowledge on the effects of I/R on the structure and function of different vascular segments in the brain and highlight some of the more promising targets for vascular protection.

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Section: Microcirculation During I/rmentioning

confidence: 99%

Section: Microcirculation During I/rmentioning

confidence: 99%

Vascular Protection Following Cerebral Ischemia and Reperfusion

Palomares

Cipolla²

2011

J Neurol Neurophysiol

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“…6,8,9 Increased blood-brain barrier (BBB) permeability occurs during hyperglycemic stroke and is essential for development of cerebral edema. 8–10 The BBB is therefore an important therapeutic target to limit edema formation that can be fatal during hyperglycemic stroke.…”

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confidence: 99%

“…8–10 The BBB is therefore an important therapeutic target to limit edema formation that can be fatal during hyperglycemic stroke. 6,9 While several mechanism are thought to contribute to enhanced edema during hyperglycemic stroke, activation of protein kinase C (PKC) in the cerebral endothelium is likely a central mediator of the BBB changes that occur. PKC activity is rapidly increased in endothelium in response to hyperglycemia due to de novo synthesis of diacylglycerol, the primary activator of PKC.…”

mentioning

confidence: 99%

“…11,12 PKC activation can directly affect BBB permeability through its ability to phosphorylate zona occluden-1(ZO-1) and disrupt tight junctions 13,14 as well as promote calcium/calmodulin-dependent endothelial cell contraction. 15 Further, other agents that induce BBB permeability including bradykinin, histamine and thrombin produce these effects through PKC-dependent mechanisms (for review see [9]).…”

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confidence: 99%

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Inhibition of Protein Kinase Cβ Reverses Increased Blood–Brain Barrier Permeability During Hyperglycemic Stroke and Prevents Edema Formation In Vivo

Cipolla

Huang

Sweet

2011

Stroke

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Purpose We investigated the effect of circulating factors and protein kinase Cβ (PKCβ) on blood-brain barrier permeability and edema during hyperglycemic stroke. Methods Male Wistar rats that were hyperglycemic by streptozotocin (50 mg/kg) for 5–6 days underwent middle cerebral artery occlusion (MCAO) for 2 hours with 2 hours of reperfusion. Blood-brain barrier permeability was measured in MCAs that were ischemic (MCAO) or nonischemic (CTL) and perfused with plasma (20% in buffer) from MCAO or CTL animals. A separate set of MCAO vessels was perfused with the PKCβ inhibitor CGP53353 (0.5 μmol/L) and permeability measured. Lastly, hyperglycemic rats were treated i.v. with CGP53353 (10 or 100 μg/kg or vehicle 15 minutes prior to reperfusion and edema formation measured by wet:dry weights (n=6/group). Results MCAO vessels had increased permeability compared to controls, regardless of the plasma perfusate. Permeability (water flux, μm3 × 108) of CTL vessel/CTL plasma (n=8), CTL vessel/MCAO plasma (n=7), MCAO vessel/CTL plasma (n=6) and MCAO vessel/MCAO plasma (n=6) was 0.98±0.11, 1.13±0.07, 1.36±0.02, and 1.34±0.06; p<0.01). Inhibition of PKCβ in MCAO vessels (n=6) reversed the increase in permeability (0.92±0.1; p<0.01). In vivo, hyperglycemia increased edema vs. normoglycemia after MCAO (water content = 78.84±0.11% vs. 81.38±0.21%; p<0.01). Inhibition of PKCβ with 10 or 100 μg/kg CGP53353 during reperfusion prevented the increased edema in hyperglycemic animals (water content = 79.54±0.56% and 79.99±0.43%; p<0.01 vs. vehicle). Conclusions These results suggest that the pronounced vasogenic edema that occurs during hyperglycemic stroke is mediated in large part by activation of PKCβ.

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