Spreading depolarizations trigger caveolin-1-dependent endothelial transcytosis

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Abstract

<div class="section"> <a class="named-anchor" id="S1">  </a> <h5 class="section-title" id="d4834165e237">Objective:</h5> <p id="P3">Cortical spreading depolarizations (CSDs) are intense and ubiquitous depolarization waves relevant for the pathophysiology of migraine and brain injury. CSDs disrupt the blood-brain barrier (BBB), but the mechanisms are unknown. </p> </div><div class="section"> <a class="named-anchor" id="S2">  </a> <h5 class="section-title" id="d4834165e242">Methods:</h5> <p id="P4">A total of six cortical SDs (CSDs) were evoked over 1h by topical application of 300 mM KCl or optogenetically with 470 nm (blue) LED over the right hemisphere in anesthetized mice (C57BL/6J wild type, Thy1-ChR2-YFP line 18 and cav-1 <sup>-/-</sup>). BBB disruption was assessed by Evans Blue (2% EB, 3ml/kg, intra-arterial) or Dextran (200 mg/kg, Fluorescein, 70,000 MW, intra-arterial) extravasation in parietotemporal cortex at 6–24h after CSD. Endothelial cell ultrastructure was examined using transmission electron microscopy 0–24h after the same CSD protocol in order to assess vesicular trafficking, endothelial tight junctions and pericyte integrity. Mice were treated with vehicle, isoform non-selective ROCK inhibitor fasudil (10 mg/kg, IP 30 min before CSD), or ROCK-2 selective inhibitor KD025 (200 mg/kg, PO bid for 5 doses before CSD). </p> </div><div class="section"> <a class="named-anchor" id="S3">  </a> <h5 class="section-title" id="d4834165e250">Results:</h5> <p id="P5">We show that CSD-induced BBB opening to water and large molecules is mediated by increased endothelial transcytosis starting between 3 and 6 hours and lasting approximately 24 hours. Endothelial tight junctions, pericytes and basement membrane remain preserved after CSDs. Moreover, we show that CSD-induced BBB disruption is exclusively caveolin-1-dependent, and requires rho-kinase 2 activity. Importantly, CSD-induced BBB disruption is independent of tissue hypoxia, as hyperoxia failed to prevent CSD-induced BBB breakdown. </p> </div><div class="section"> <a class="named-anchor" id="S4">  </a> <h5 class="section-title" id="d4834165e255">Interpretation:</h5> <p id="P6">Our data elucidate the mechanisms by which CSDs lead to transient BBB disruption, with diagnostic and therapeutic implications for migraine and brain injury. </p> </div>

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The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease.

Jens P. Dreier (2011)

The term spreading depolarization describes a wave in the gray matter of the central nervous system characterized by swelling of neurons, distortion of dendritic spines, a large change of the slow electrical potential and silencing of brain electrical activity (spreading depression). In the clinic, unequivocal electrophysiological evidence now exists that spreading depolarizations occur abundantly in individuals with aneurismal subarachnoid hemorrhage, delayed ischemic stroke after subarachnoid hemorrhage, malignant hemispheric stroke, spontaneous intracerebral hemorrhage or traumatic brain injury. Spreading depolarization is induced experimentally by various noxious conditions including chemicals such as potassium, glutamate, inhibitors of the sodium pump, status epilepticus, hypoxia, hypoglycemia and ischemia, but it can can also invade healthy, naive tissue. Resistance vessels respond to it with tone alterations, causing either transient hyperperfusion (physiological hemodynamic response) in healthy tissue or severe hypoperfusion (inverse hemodynamic response, or spreading ischemia) in tissue at risk for progressive damage, which contributes to lesion progression. Therapies that target spreading depolarization or the inverse hemodynamic response may potentially treat these neurological conditions.

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Stepwise recruitment of transcellular and paracellular pathways underlies blood-brain barrier breakdown in stroke.

Daniel Knowland, Ahmet Arac, Kohei Sekiguchi … (2014)

Brain endothelial cells form a paracellular and transcellular barrier to many blood-borne solutes via tight junctions (TJs) and scarce endocytotic vesicles. The blood-brain barrier (BBB) plays a pivotal role in the healthy and diseased CNS. BBB damage after ischemic stroke contributes to increased mortality, yet the contributions of paracellular and transcellular mechanisms to this process in vivo are unknown. We have created a transgenic mouse strain whose endothelial TJs are labeled with eGFP and have imaged dynamic TJ changes and fluorescent tracer leakage across the BBB in vivo, using two-photon microscopy in the t-MCAO stroke model. Although barrier function is impaired as early as 6 hr after stroke, TJs display profound structural defects only after 2 days. Conversely, the number of endothelial caveolae and transcytosis rate increase as early as 6 hr after stroke. Therefore, stepwise impairment of transcellular followed by paracellular barrier mechanisms accounts for the BBB deficits in stroke. Copyright © 2014 Elsevier Inc. All rights reserved.

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Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury.

Martin Lauritzen, Jens Peter Dreier, Martin Fabricius … (2011)

Cortical spreading depression (CSD) and depolarization waves are associated with dramatic failure of brain ion homeostasis, efflux of excitatory amino acids from nerve cells, increased energy metabolism and changes in cerebral blood flow (CBF). There is strong clinical and experimental evidence to suggest that CSD is involved in the mechanism of migraine, stroke, subarachnoid hemorrhage and traumatic brain injury. The implications of these findings are widespread and suggest that intrinsic brain mechanisms have the potential to worsen the outcome of cerebrovascular episodes or brain trauma. The consequences of these intrinsic mechanisms are intimately linked to the composition of the brain extracellular microenvironment and to the level of brain perfusion and in consequence brain energy supply. This paper summarizes the evidence provided by novel invasive techniques, which implicates CSD as a pathophysiological mechanism for this group of acute neurological disorders. The findings have implications for monitoring and treatment of patients with acute brain disorders in the intensive care unit. Drawing on the large body of experimental findings from animal studies of CSD obtained during decades we suggest treatment strategies, which may be used to prevent or attenuate secondary neuronal damage in acutely injured human brain cortex caused by depolarization waves.