The Cerebral Microvasculature: Investigation of the Blood—Brain Barrier

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Investigation of the Blood-Brain Barrier

Protein extravasation secondary to BBB compromise and damage to extracellular proteins increases the osmotic gradient and abnormal fluid accumulation. This is overwhelmed in TBI, and the extravasated proteins retard the clearance of fluid from the brain. Secondary brain injury is essentially ischaemic in nature and induces a cellular component to the oedema formation—cytotoxic oedema. This occurs because of disruption of the BBB secondary to disorganization of TJ proteins, release of inflammatory mediators, such as inter-cellular adhesion molecule ICAM-1 and vascular endothelial growth factor VEGF , and mitochondrial dysfunction.

Activation of matrix metalloproteinases MMP causes proteolysis of the basal lamina and contributes to the progression of tissue damage. In addition to these mechanisms, trans-membrane water transport also plays a role in the brain-swelling process. In normal brain, the water channel protein, aquaporin-4 AQP4 , is expressed in perimicrovessel astrocyte foot processes.

The development of therapeutic strategies to abate the different stages of oedema formation is focused on the manipulation of barrier dynamics after injury. Recent studies have demonstrated that early neurosurgical intervention, such as decompressive craniectomy and contusiectomy, correlates with a decrease in MMP levels and limitation of the pathological processes of BBB breakdown. Ischaemic stroke-related cerebral ischaemia sets in motion a series of events that leads to increased BBB permeability.

The main factors include cytokines, VEGF, and nitric oxide. This leads to cerebral oedema formation with the risk of ongoing ischaemia and the potential for further infarction of the penumbra. VEGF antagonism limits TJ protein disruption and paracellular permeability, and reduces post-ischaemic oedema thereby halting the progression of ischaemic brain injury.

Septic encephalopathy is the commonest form of encephalopathy in general intensive care units and is associated with increased morbidity and mortality. It results in a symmetrical, diffuse brain dysfunction associated with breakdown of the BBB and cerebral oedema. These are the consequences of the effects of circulating inflammatory mediators on the cerebral endothelium, the neurotransmitter composition of the reticular activating system, astrocyte dysfunction, and direct neuronal injury. The microvasculature of brain tumours is poorly developed, lacks a BBB, and leaks fluid that leads to cerebral oedema and additional mass effect that often exceeds that related to the tumour itself.

Blood–brain barrier | BJA Education | Oxford Academic

Investigations of the ultrastructure of human gliomas and metastatic adenocarcinoma have confirmed opening of interendothelial TJs, which is associated with an increase in paracellular permeability and peri-microvessel oedema. Neoplastic astrocytes fail to produce the necessary factors to maintain BBB integrity in peri-tumoral areas and may also secrete permeability factors that counteract normal barrier function.

The mainstay of therapy of brain tumour-related oedema is corticosteroids and, although the exact mechanism of action is unclear, they appear to reduce endothelial permeability. The BBB is a major impediment to the entry of many therapeutic substances acting on the CNS and the delivery of drugs to the brain after systemic administration requires transport through the BBB. In determining whether a given drug may undergo significant transport across the BBB, the two most important factors are its lipophilicity and molecular weight.

Lipophilic drugs enter the brain compartment by either passive diffusion or by becoming solubilized into the lipid bilayer of the endothelial cell membrane. The lipophilicity of a drug as an index of BBB transport is only valid when the molecular weight is less than or approximately equal to — Da.

Even if a drug is highly lipid soluble, it will not be transported across the BBB in pharmacologically significant amounts if its molecular weight exceeds Da. An additional stumbling block for drug delivery to the CNS is the presence of an active drug efflux system within the BBB. P-glycoprotein P-gp is an ATP-dependent kDa phosphorylated glycoprotein membrane transporter that is involved in the active cellular extrusion of drugs and potentially toxic metabolites from the brain. P-gp is located on the apical surface of the endothelial cells of the brain capillaries and contributes to the poor BBB penetration of many highly lipophilic drugs by blocking their entry at the level of the capillary endothelium.

The presence of P-gp in the BBB is a potential target for drug design. P-gp inhibitors with low toxicity are in trial for the treatment of multi-drug resistance in tumours. In order to overcome the difficulties in CNS penetration, various drug delivery strategies have been developed.

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These generally fall into one or more of the following three categories: drug manipulation, disruption of the BBB, and alternative routes of drug delivery. CNS penetration is favoured by low molecular weight, lack of ionization at physiological pH, and lipophilicity. For example, diamorphine, a diacyl derivative of morphine, crosses the BBB times more easily than its parent drug just because it is more lipophilic. A drug's lipophilicity correlates strongly with cerebrovascular permeability so, in theory, lipophilic analogues of small hydrophilic drugs should penetrate the BBB more readily.

This strategy has been frequently used, but the results have been disappointing. Drugs can be administered as prodrugs which, by virtue of their improved characteristics, are brought closer to the receptor site and maintained there for longer periods of time. At the receptor site, the prodrug gets converted to the active form. Unfortunately, simple prodrugs suffer from several important limitations. Whilst increased lipophilicity may improve movement across the BBB, it also tends to increase uptake into other tissues causing an increased systemic tissue burden.

This is especially detrimental in the case of potent drugs such as steroids or cytotoxic agents when toxicity is exacerbated at non-target sites. Carrier- and receptor-mediated transport pathways are available for certain circulating nutrients and peptides and can be utilized as portals of entry to the brain for many drugs. Utilization of differences in the affinity and maximal transport activity among these transport systems is an attractive strategy for controlling the delivery and retention of drugs in the brain.

Receptor-mediated drug delivery uses chimeric peptide technology wherein a non-transportable drug is conjugated to a transport vector, usually a modified protein- or receptor-specific monoclonal antibody, which undergoes receptor-mediated transcytosis through the BBB. Various therapeutic agents have been delivered to the brain using this technology, including peptide-based pharmaceuticals such as a vasoactive peptide analogue, neurotrophins, and small molecules incorporated within liposomes.

However, the effective utilization of this technique is still under investigation. This is an invasive strategy for enhanced CNS drug delivery which involves transient BBB disruption in association with systemic drug administration. This results in enhanced extravasation rates in the cerebral endothelium leading to increased brain parenchymal drug concentrations. Various techniques have been used to disrupt the BBB, but many are unacceptably toxic and hence not clinically applicable. These include the infusion of solvents such as dimethyl sulphoxide or ethanol and metals such as aluminium.

Irradiation and the induction of pathological conditions, including hypertension, hypercapnia, hypoxia, or ischaemia, have similar effects. Osmotic opening of the BBB involves intracarotid injection of an inert hypertonic solution such as mannitol or arabinose to initiate endothelial cell shrinkage and opening of TJ for a period of a few hours. This has been used to permit delivery of anti-neoplastic agents to the brain.

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Although this treatment is still investigational, there are anecdotal data to suggest that it may be beneficial in some patients who fail to respond to systemic chemotherapy. A third class of strategies aimed at enhancing CNS penetration of drug molecules is composed of delivery methodologies that do not rely on the cardiovascular system.

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Blood Supply to Brain - Neuroanatomy - Part 1/11

Key points. Structure of the BBB. Transport at the BBB.

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Opening of the BBB in physiology. Opening of the BBB in pathophysiology. Transport of drugs across the BBB. Drug delivery and the BBB. Conflict of interest. Blood—brain barrier Bradley K. Specialist Registrar. Oxford Academic.

Google Scholar. Meanwhile, optimizing the cerebral capillary perfusion by the strategies such as fluid administration may cause brain edema due to the BBB opening post trauma. View on Nature. Open Access.

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The Cerebral Microvasculature: Investigation of the Blood—Brain Barrier The Cerebral Microvasculature: Investigation of the Blood—Brain Barrier
The Cerebral Microvasculature: Investigation of the Blood—Brain Barrier The Cerebral Microvasculature: Investigation of the Blood—Brain Barrier
The Cerebral Microvasculature: Investigation of the Blood—Brain Barrier The Cerebral Microvasculature: Investigation of the Blood—Brain Barrier
The Cerebral Microvasculature: Investigation of the Blood—Brain Barrier The Cerebral Microvasculature: Investigation of the Blood—Brain Barrier
The Cerebral Microvasculature: Investigation of the Blood—Brain Barrier The Cerebral Microvasculature: Investigation of the Blood—Brain Barrier

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