Calcitonin gene-related peptide prevents blood-brain barrier injury and brain edema induced by focal cerebral ischemia reperfusion

Cerebral ischemia is one of the diseases that most compromise the human species. Therapeutic recovery of blood-brain barrier (BBB) disruption represents a novel promising approach to reduce brain injury after stroke. To determine the effects of calcitonin gene-related peptide (CGRP) on the BBB participate in stroke progression, rat cerebral ischemia reperfusion injury was induced by a 2-hour left transient middle cerebral artery occlusion (MCAO) using an intraluminal filament, followed by 46h of reperfusion. CGRP (1μg/ml) at the dose of 3μg/kg (i.p.) was administered at the beginning of reperfusion. Subsequently, 48h after MCAO, arterial blood pressure, infarct volume, water content, BBB permeability, BBB ultrastructure, levels of aquaporin-4 (AQP4) and its mRNA were evaluated. CGRP could reduce arterial blood pressure (P<0.001), infarct volume (P<0.05), cerebral edema (P<0.01), BBB permeability (P<0.05), AQP4 mRNA expression (P<0.05) and AQP4 protein expression (P<0.01). Furthermore, CGRP treatment improved ultrastructural damage of capillary endothelium cells and decreased the loss of the tight junction observed by transmission electronic microscopy (TEM) after 46h of reperfusion. Our findings show that CGRP significantly reduced postischemic increase of brain edema with a 2-hour therapeutic window in the transient model of focal cerebral ischemia. Moreover, it seems that at least part of the anti-edematous effects of CGRP is due to decrease of BBB disruption by improving ultrastructural damage of capillary endothelium cells, enhancing basal membrane, and inhibiting AQP4 and its mRNA over-expression. The data of the present study provide a new possible approach for acute stroke therapy by administration of CGRP.     

Functional expression of the serotonin transporter in immortalized rat brain microvessel endothelial cells

There is evidence from recent studies that the brain endothelium (of capillaries and/or larger vessels) may serve as a specific target for serotonin [5-hydroxytryptamine (5-HT)]. This neurotransmitter is expected to be involved in the regulation of the blood-brain barrier (BBB) permeability and/or of the cerebral blood flow via receptor-mediated mechanisms. Effective control of these processes depends on a speedy uptake and metabolism of released 5-HT molecules. To realize this, a similar mechanism of 5-HT uptake as in brain may exist at the BBB. In this study, we have demonstrated using RT-PCR that 5-HT transporter mRNA is present in the brain endothelium and that a saturable transport system for 5-HT is functionally expressed in immortalized rat brain endothelial cells (RBE4 cells). These cells take up [3H]5-HT by an active saturable process with a Km value of 397 +/- 64 nmol/L and a transport capacity of 51.7 +/- 3.5 pmol x g(-1) x min(-1). The 5-HT uptake depends on Na+, as indicated by the replacement of NaCl by LiCl. The 5-HT uptake was sensitive to specific 5-HT transport inhibitors such as paroxetine, clomipramine, fluoxetine, and citalopram but not to inhibitors of the vesicular amine transporter such as reserpine or tetrabenazine. Our results demonstrate that cerebral endothelial cells are able to participate actively in the removal and metabolism of the released 5-HT, which supports the concept of direct serotoninergic regulation of the BBB function.     

血脑屏障与脑血管疾病的相关研究

血脑屏障（blood brain barrier,BBB）的主要结构包括：脑毛细血管内皮细胞及其间的紧密连接（tight junction,TJ）、基底膜、基 底膜下星型胶质细胞终足。血脑屏障是存在于血液和脑组织之间的一层屏障系统,在许多大脑疾患的病理过程中,BBB 的破坏导 致通透性增高都是不可避免的一个环节。BBB是保证中枢神经系统的正常生理功能的重要屏障系统。目前已有大量关于血脑屏 障通透性在脑血管疾病中的变化研究。本文分别从血脑屏障的结构和功能,药物通过血脑屏障的方法和功能,脑缺血损伤、阿尔 茨海默病、帕金森病和多发性硬化症等不同的脑病变与血脑屏障通透性的变化及中医药应用等方面做一综述。有针对性地对 BBB和大脑疾病进行进一步的研究与探索,将会为临床治疗相关疾病带来新的视角与机遇。     

Blood to Brain and Brain to Blood Passage of Native Horseradish Peroxidase, Wheat Germ Agglutinin, and Albumin: Pharmacokinetic and Morphological Assessments

Abstract: Native horseradish peroxidase (HRP) and the lectin wheat germ agglutinin (WGA) conjugated to HRP are protein probes represented in the blood-brain barrier (BBB) literature for elucidating morphological routes of passage between blood and brain. We report the application of established pharmacokinetic methods, e.g., multiple-time regression analysis and capillary depletion technique, to measure and compare bidirectional rates of passage between blood and brain for radioactive iodine-labeled HRP (I-HRP), WGA-HRP (I-WGA-HRP), and the serum protein albumin (I-ALB) following administration of the probes intravenously (i.v.) or by intracerebroventricular (i.c.v.) injection in mice. The pharmacokinetic data are supplemented with light and electron microscopic analyses of HRP and WGA-HRP delivered i.v. or by i.c.v. injection. The rates of bidirectional movement between blood and brain are the same for coinjected I-HRP and I-ALB. Blood-borne HRP, unlike WGA-HRP, has unimpeded access to the CNS extracellularly through sites deficient in a BBB, such as the circumventricular organs and subarachnoid space/pial surface. Nevertheless, blood-borne I-WGA-HRP enters the brain ?10 times more rapidly than I-HRP and I-ALB. Separation of blood vessels from the neocortical parenchyma confirms the entry of blood-borne I-WGA-HRP to the brain and sequestration of I-WGA-HRP by cerebral endothelial cells. Nearly half the I-WGA-HRP radioactivity associated with cortical vessels is judged to be subcellular. Light microscopic results suggest the extracellular pathways into the brain available to blood-borne native HRP do not represent predominant routes of entry for blood-borne WGA-HRP. Ultrastructural analysis further suggests WGA-HRP is likely to undergo adsorptive transcytosis through cerebral endothelia from blood to brain via specific subcellular compartments within the endothelium. Entry of blood-borne I-WGA-HRP, but not of I-ALB, is stimulated with coinjected unlabeled WGA-HRP, suggesting the latter may enhance the adsorptive endocytosis of blood-borne I-WGA-HRP. With i.c.v. coinjection of I-WGA-HRP and I-ALB, I-WGA-HRP exits the brain more slowly than I-ALB. The brain to blood passage of I-WGA-HRP is nil with inclusion of unlabeled WGA-HRP, which does not alter the exit of I-ALB. Adsorptive endocytosis of i.c.v. injected WGA-HRP appears restricted largely to cells lining the ventricular cavities, e.g., ependymal and choroid plexus epithelia. In summary, the data suggest that the bidirectional rates of passage between brain and blood for native HRP are comparable to those for albumin. Blood-borne WGA-HRP is assessed to enter the brain more rapidly than native HRP and albumin, perhaps by the process of adsorptive transcytosis through BBB endothelia, but has difficulty leaving the CNS; the latter result may be due to avid binding and adsorptive endocytosis of WGA-HRP by exposed CNS cells. Neither native HRP nor WGA-HRP alters the integrity of the BBB to albumin. For this reason, both native HRP and WGA-HRP are suitable probes for investigating the permeability of the BBB to macromolecules in vivo.     

Influence of the corticotropin releasing hormone (CRH) on the brain-blood barrier permeability in cerebral ischemia in rats.

The increase in the blood-brain barrier (BBB) permeability and a developing cerebral oedema due to the ischemic infarction appear a few hours, and intensify during a few days, after closing the carotid arteries. It fails to be clear, however, what causes the increase in the microvessels damage, and whether the damage is a secondary result of the vasoactive substances released by the neurones and glia cells damaged by the ischemia. CRH, which plays an essential role in integrative the nervous, endocrine, and immunological systems, has a positive effect on the decrease in the permeability of the BBB damaged by various physical and chemical factors. Therefore, the examination of the CRH role in the cerebral ischemia may prove useful for explaining the processes taking place in the foci of the cerebral infarction and their environment. The experiment was carried out on rats which, 20 minutes before closing of both internal carotid arteries, was administered 10 microg CRH to cerebrospinal fluid via cisterna magna of the brain. The BBB permeability was measured 30 minutes, 3 hours, 3 days, and 7 days after closing the arteries. The experiment has shown the CRH protective effect on the BBB and its consequent effect on the decrease in the BBB permeability which appears in the 3 hours after closing the arteries (p<0.05), and is high significant during the chronic phase of the cerebral ischemia (p<0.03). It can be thus concluded that CRH, by affecting directly the endothelium of the cerebral vessels, decreases the endothelial damage in the acute phase of the ischemia. The decrease is noted to be more significant in the chronic phase of the ischemia; such an effect can be attributed to CRH stimulating the hypothalamic-adrenal axis, and to the secondary activation of the mechanisms decreasing the BBB permeability.     

Blood-brain barrier permeability during dopamine-induced hypertension in fetal sheep.

Dopamine is often used as a pressor agent in sick newborn infants, but an increase in arterial blood pressure could disrupt the blood-brain barrier (BBB), especially in the preterm newborn. Using time-dated pregnant sheep, we tested the hypothesis that dopamine-induced hypertension increases fetal BBB permeability and cerebral water content. Barrier permeability was assessed in nine brain regions, including cerebral cortex, caudate, thalamus, brain stem, cerebellum, and spinal cord, by intravenous injection of the small tracer molecule [(14)C]aminoisobutyric acid at 10 min after the start of dopamine or saline infusion. We studied 23 chronically catheterized fetal sheep at 0.6 (93 days, n = 10) and 0.9 (132 days, n = 13) gestation. Intravenous infusion of dopamine increased mean arterial pressure from 38 +/- 3 to 53 +/- 5 mmHg in 93-day fetuses and from 55 +/- 5 to 77 +/- 8 mmHg in 132-day fetuses without a decrease in arterial O(2) content. These 40% increases in arterial pressure are close to the maximum hypertension reported for physiological stresses at these ages in fetal sheep. No significant increases in the brain transfer coefficient of aminoisobutyric acid were detected in any brain region in dopamine-treated fetuses compared with saline controls at 0.6 or 0.9 gestation. There was also no significant increase in cortical water content with dopamine infusion at either age. We conclude that a 40% increase in mean arterial pressure during dopamine infusion in normoxic fetal sheep does not produce substantial BBB disruption or cerebral edema even as early as 0.6 gestation.     

Mental health benefits of omega-3 fatty acids may be mediated by improvements in cerebral vascular function

Since the pivotal role of long chain omega-3 (n-3) polyunsaturated fatty acids (PUFA) in brain structure and development became apparent in the 1970s, these lipids have been investigated in relation to a range of psychiatric disorders, with some positive and some conflicting evidence to support their use as a supplementary treatment for various symptoms. A number of mechanisms of action have been proposed to account for their potential benefits, largely based on their structural role in brain development and purported influences on central neurotransmission.Theories on the pathogenesis of mental health and psychiatric illness have traditionally focused on the role of neurotransmitters, although there is also ample evidence that psychiatric disorders are associated with impaired cerebral blood flow (CBF) or impairments in blood-brain barrier (BBB) function. Associations between cardiovascular and psychiatric pathologies are further indicative of a possible underlying vascular component to psychiatric illness. We hypothesise that treatment with vasoactive nutrients that can improve cerebral perfusion may help to improve a variety of mental disorders.In presenting our hypothesis, we provide an overview of cerebral vascular function, focusing specifically on the role of the endothelium in CBF and BBB integrity, and review evidence for associations between impaired CBF/endothelial function and psychiatric illness. Then, as an example of a potential treatment, we review the influence of n-3 PUFA on endothelial function, drawing on evidence of anti-inflammatory, anti-aggregatory and vasodilatory roles in blood flow and vascular permeability. We hypothesise that n-3 PUFA may act on the blood side of the BBB as well as on central neural pathways to influence cerebral functions. In the former case, they may act on endothelial cells to influence both vasodilation and selective permeability, thereby assisting in CBF and delivery of oxygen and glucose to brain tissue in response to requirements.     

The effect of high energy electron irradiation on blood-brain barrier permeability to haloperidol and stobadin in rats

Summary The heads of rats were irradiated by 4 MeV electrons in doses 90, 180, and 360 Gy. The observed times of deaths ranged 120–600, 60–420, and 150–370 min after 90, 180, and 360 Gy, respectively. A dose dependent decrease of the brain uptake index of haloperidol was observed 1 and 3 h post radiation. On the other hand an increased brain uptake index was found for stobadin after head irradiation with doses of 180 and 360 Gy. Regional cerebral blood flow, blood pressure, and heart rate were not significantly altered in the period following irradiation with 180 Gy. The observed changes in blood-brain barrier (BBB) permeability seem to be the result of the damaged function of morphological structures forming the BBB rather than altered regional blood flow.     

Refining in vitro neurotoxicity testing--the development of blood-brain barrier models

The purpose of this paper is to review the current state of development of advanced in vitro blood-brain barrier (BBB) models. The BBB is a special capillary bed that separates the blood from the central nervous system (CNS) parenchyma. Astrocytes maintain the integrity of the BBB, and, without astrocytic contacts, isolated brain capillary endothelial cells in culture lose their barrier characteristics. Therefore, when developing in vitro BBB models, it is important to add astrocytic factors into the culture system. Recently, novel filter techniques and co-culture methods have made it possible to develop models which resemble the in vivo functions of the BBB in an effective way. With a BBB model, kinetic factors can be added into the in vitro batteries used for evaluating the neurotoxic potential of chemicals. The in vitro BBB model also represents a useful tool for the in vitro prediction of the BBB permeability of drugs, and offers the possibility to scan a large number of drugs for their potential to enter the CNS. Cultured monolayers of brain endothelial cell lines or selected epithelial cell lines, combined with astrocyte and neuron cultures, form a novel three-dimensional technique for the screening of neurotoxic compounds.     

Expression of the neonatal Fc receptor (FcRn) at the blood-brain barrier

The blood-brain barrier (BBB) restricts transport of immunoglobulin G (IgG) in the blood to brain direction. However, IgG undergoes rapid efflux in the brain to blood direction via reverse transcytosis across the BBB after direct intracerebral injection. This BBB IgG transport system has the characteristics of an Fc receptor (FcR), but there is no molecular information on the putative BBB FcR. The present study uses confocal microscopy and an antibody to the rat neonatal FcR (FcRn), and demonstrates the expression of the FcRn at the brain microvasculature and choroid plexus epithelium. Co-localization with the Glut1 glucose transporter indicates the brain microvascular FcRn is expressed in the capillary endothelium. The capillary endothelial FcRn may mediate the 'reverse transcytosis' of IgG in the brain to blood direction.     

Adrenomedullin and the blood-brain barrier.

Adrenomedullin (ADM) is present both in the periphery and brain. In addition to its peripheral effects, this peptide can exert central effects such as decreasing food ingestion. We used multiple-time regression analysis to determine that labeled ADM can cross from blood to brain with an apparent influx constant (K(I)) of 5.83 +/- 1.44 x 10(-4) ml/g-min, much faster than that of albumin, the vascular control. HPLC showed that almost all of the injected 125I-ADM in the brain was intact, and capillary depletion showed that it could reach the parenchyma of the brain. However, more 125I-ADM was reversibly associated with the brain vasculature than we have seen with any other peptide tested by these methods. After intracerebroventricular injection, 125I-ADM exited the brain with the bulk reabsorption of cerebrospinal fluid at an efflux rate comparable to that of albumin. Although there was no blood-to-brain saturation, in situ brain perfusion of 125I-ADM in blood-free physiological buffer showed self-inhibition by excess unlabeled ADM. This, along with evidence of the lack of protein binding shown by capillary zone electrophoresis, indicated competition for the binding site of ADM at the BBB. The low lipophilicity of ADM determined by the octanol/buffer partition coefficient was also consistent with the prominent reversible association of ADM with the vasculature of the BBB. This suggests a function for ADM at the cerebral blood vessels, such as altering cerebral blood flow and perfusion, without disruption of the BBB.     

Effects of losartan on the blood-brain barrier permeability in long-term nitric oxide blockade-induced hypertensive rats

Hypertension is closely associated with vascular endothelial dysfunction. The aim of this study was to investigate the effects of Angiotensin II (ANG II) receptor antagonist losartan on the blood-brain barrier (BBB) permeability in L-NAME-induced hypertension and/or in ANG II-induced acute hypertension in normotensive and hypertensive rats. Systolic blood pressure was measured by tail cuff method before, during and following L-NAME treatment (1 g/L). Losartan (3 mg/kg) was given to the animal for five days. Acute hypertension was induced by ANG II (60 microg/kg). Arterial blood pressure was directly measured on the day of the experiment. BBB disruption was quantified according to the extravasation of the albumin-bound Evans blue dye. Losartan significantly reduced the mean arterial blood pressure from 169 +/- 3.9 mmHg to 82 +/- 2.9 mmHg in L-NAME and from 171 +/- 2.9 mmHg to 84 +/- 2.9 in L-NAME plus losartan plus ANG II groups (p < 0.05). The content of Evans blue dye in the cerebral cortex significantly increased in L-NAME (p < 0.01). Moreover, the content of Evans blue dye markedly increased in the cerebellum (p < 0.001) and slightly increased in diencephalon region (p < 0.05) in L-NAME plus ANG II. Losartan reduced the increased BBB permeability to Evans blue dye in L-NAME (p < 0.01) and L-NAME plus ANG II (p < 0.001). These results indicate that L-NAME and L-NAME plus ANG II both lead to an increase in microvascular Evans blue dye efflux to brain, and losartan treatment attenuates this protein-bound dye transport into brain tissue presumably due to its protective effect on endothelial cells of brain vessels.     

Differing effects of vasopressin on regional cerebral blood flow of dogs following intracisternal vs. intra-arterial administration

We investigated the differential effect of the intracisternal and intraarterial administration of vasopressin on the regional cerebral blood flow (rCBF) in the parietal cortex of dogs. Regional CBF, velocity and blood volume were assayed by laser flowmetry. The intracisternal injection of 1 nmol vasopressin significantly increased the rCBF and velocity, without affecting blood volume. However, the intravertebral arterial injection of 1 nmol vasopressin significantly decreased the rCBF and velocity. This discrepancy can be explained by a difference in the affected vasculature; large blood vessels in the subarachnoid space vs. whole cerebral vascular system. The intracisternal and intraarterial injection of the nitric oxide inhibitor N^G-monomethyl-L-arginine reduced the rCBF from the base line, and significantly suppressed the rCBF elevation induced by vasopressin. The effect of vasopressin may be considered as the summation of the increased flow from the dilated large vessels via the release of nitric oxide from the endothelium, and of the decreased flow from the contracted small vessels.     

Advances in cell biology of blood-brain barrier transport.

The blood-brain barrier (BBB) is present in the brain of all vertebrates, and arises from epithelial-like high resistance tight junctions that join virtually all capillary endothelium in brain. Recent advances in understanding the cell biology of BBB transport are extending prior physiologic models. For example, glucose transport through the BBB is mediated by a protein that is expressed by the GLUT-1 glucose transporter gene and is asymmetrically localized on lumenal and ablumenal membranes of brain endothelium. Other examples of polarized function at the BBB include asymmetric distribution of endothelial surface charge and ectoenzymes. The tissue-specific gene expression within the brain capillary endothelium is believed to be orchestrated by neighboring cells such as astrocytes, the foot process of which cover more than 95% of the brain microvascular endothelium.     

Protection of the blood-brain barrier during acute and chronic hypertension

A new concept about sympathetic nerves has emerged recently: not only is sympathetic tone important in short-term regulation of vascular resistance, but chronic effects of nerves on vessels have important effects. This concept is supported by studies of mechanisms by which sympathetic nerves protect the blood-brain barrier (BBB). The BBB is susceptible to disruption during acute and chronic hypertension. Acute, severe hypertension produces passive dilatation of cerebral vessels with disruption of the BBB. Sympathetic stimulation attenuates the increase in cerebral blood flow during acute hypertension and thereby protects the BBB. During chronic hypertension, we have observed disruption of the barrier, which may contribute to hypertensive encephalopathy. Sympathetic nerves protect against disruption of the BBB during chronic hypertension. This protective effect is apparently related to a trophic effect of nerves in promotion of cerebral vascular hypertrophy during chronic hypertension. Thus, this is the first evidence that, in the same vascular bed, sympathetic nerves have two different protective effects. Protection of the BBB is accomplished acutely by sympathetic neural effects on vascular resistance and chronically by promotion of vascular hypertrophy.     

Saturable Retention of Vasopressin by Hippocampus Vessels In Vivo, Associated with Inhibition of Blood-Brain Transfer of Large Neutral Amino Acids

Vasopressin receptors have been reported in the endothelium of brain capillaries. The function of these receptors is not known. To test the prediction that vasopressin receptors in brain capillary endothelium affect amino acid transport across the blood-brain barrier and to assess the role of vasopressin transport across the cerebral vascular endothelium, we measured (a) the endothelial permeability to the large neutral amino acid leucine in the absence and presence of arginine vasopressin (AVP) and (b) the permeability of the blood-brain barrier to AVP relative to manitol. In brain regions protected by the blood-brain barrier, after circulation for 20 s, coinjection of leucine and AVP intravenously led to a decrease of leucine transport unrelated to changes of blood flow. The decrease was most pronounced in hippocampus (42%) and least pronounced in olfactory bulb and colliculi (17 and 19%, respectively). In the latter regions, the endothelial permeability to AVP did not significantly exceed that of mannitol. In hippocampus and in regions with no blood-brain barrier (pituitary and pineal glands), AVP retention in excess of mannitol retention was blocked by unlabeled AVP. The findings do not contradict the hypothesis of a role for AVP in the regulation of large neutral amino acid transfer into brain tissue.     

A model for the blood–brain barrier permeability to water and small solutes

The blood–brain barrier (BBB) has unique structures in order to protect the central nervous system. In addition to the tight junction of the microvessel endothelium, there is a uniform and narrow matrix-like basement membrane (BM) sandwiched between the vessel wall and the astrocyte foot processes ensheathing the cerebral microvessel. To understand the mechanism by which these structural components modulate permeability of the BBB, we developed a mathematical model for water and solute transport across the BBB. The fluid flow in the cleft regions of the BBB were approximated by the Poiseuille flow while those in the endothelial surface glycocalyx layer (SGL) and BM were approximated by the Darcy and Brinkman flows, respectively. Diffusion equations in each region were solved for the solute transport. The anatomical parameters were obtained from electron microscopy studies in the literature. Our model predicts that compared to the peripheral microvessels with endothelium only, the BM and the wrapping astrocytes can reduce hydraulic conductivity (L_p) of the BBB and the permeability to sodium fluorescein (P^NaF) by up to 6-fold when the fiber density in the BM is the same as that in the SGL. Even when the SGL and the tight junctions of the endothelium are compromised, the BM and astrocyte foot processes can still maintain the low L_p and P^NaF of the BBB. Our model predictions indicate that the BM and astrocytes of the BBB provide a great protection to the CNS under both physiological and pathological conditions.     

Endocardial endothelium in the rat: junctional organization and permeability

Selective permeability of endocardial endothelium has been suggested as a mechanism underlying the modulation of the performance of subjacent myocardium. In this study, we characterized the organization and permeability of junctional complexes in ventricular endocardial endothelium in rat heart. The length of intercellular clefts viewed en face per unit endothelial cell surface area was lower, and intercellular clefts were deeper in endocardial endothelium than in myocardial vascular endothelium, whereas tight junctions had a similar structure in both endothelia. On this basis, endocardia endothelium. might be less permeable than capillary endothelium. However, confocal scanning laser microscopy showed that intravenously injected dextran 10000 coupled to Lucifer Yellow penetrated first the endocardial endothelium and later the myocardial capillary endothelium. Penetration of dextran 10000 in myocardium occurred earlier through subepicardial capillary endothelium than through subendocardial capillary endothelium. Penetration of tracer might thus be influenced by hydrostatic pressure. Dextran of MW 40000 did not diffuse through either endocardial endothelium or capilary endothelium. The ultrastructure of endocardial endothelium may constitute an adaptation to limit diffusion driven by high hydrostatic pressure in the heart. Differences in paracellular diffusion of dextran 10000 between endocardial endothelium and myocardial vessels, may result from differing permeability properties of the endocardium and underlying myocardium.     

Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders

The neurovascular unit (NVU) comprises brain endothelial cells, pericytes or vascular smooth muscle cells, glia and neurons. The NVU controls blood-brain barrier (BBB) permeability and cerebral blood flow, and maintains the chemical composition of the neuronal 'milieu', which is required for proper functioning of neuronal circuits. Recent evidence indicates that BBB dysfunction is associated with the accumulation of several vasculotoxic and neurotoxic molecules within brain parenchyma, a reduction in cerebral blood flow, and hypoxia. Together, these vascular-derived insults might initiate and/or contribute to neuronal degeneration. This article examines mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer's disease, and highlights therapeutic opportunities relating to these neurovascular deficits.     

The breakup of intravascular microbubbles and its impact on the endothelium

Encapsulated microbubbles (MBs) serve as endovascular agents in a wide range of medical ultrasound applications. The oscillatory response of these agents to ultrasonic excitation is determined by MB size, gas content, viscoelastic shell properties and geometrical constraints. The viscoelastic parameters of the MB capsule vary during an oscillation cycle and change irreversibly upon shell rupture. The latter results in marked stress changes on the endothelium of capillary blood vessels due to altered MB dynamics. Mechanical effects on microvessels are crucial for safety and efficacy in applications such as focused ultrasound-mediated blood–brain barrier (BBB) opening. Since direct in vivo quantification of vascular stresses is currently not achievable, computational modelling has established itself as an alternative. We have developed a novel computational framework combining fluid–structure coupling and interface tracking to model the nonlinear dynamics of an encapsulated MB in constrained environments. This framework is used to investigate the mechanical stresses at the endothelium resulting from MB shell rupture in three microvessel setups of increasing levels of geometric detail. All configurations predict substantial elevation of up to 150 % for peak wall shear stress upon MB breakup, whereas global peak transmural pressure levels remain unaltered. The presence of red blood cells causes confinement of pressure and shear gradients to the proximity of the MB, and the introduction of endothelial texture creates local modulations of shear stress levels. With regard to safety assessments, the mechanical impact of MB breakup is shown to be more important than taking into account individual red blood cells and endothelial texture. The latter two may prove to be relevant to the actual, complex process of BBB opening induced by MB oscillations.