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Blood-Brain Barrier (BBB) Types of barriers
-Blood + Interstitial fluid : Blood brain barrier
-Blood -ventricular CSF: Choroid plexus
-Blood- Subdural CSF - arachnoid epithelium Core: BBB - role of endothelial cells; astrocyte induction. This barrier was first identified by experiments by Paul Ehrlich in 1882, in which living animals were given intravenous injections of trypan blue dye. The stain spread easily throughout the body, except to the central nervous system.When stain was injected directly into the brain, the tissue was stained but there was no stain in the peripheral tissue. Showing that there is a barrier It was later shown with electron-dense markers such as horseradish peroxidase that the strong tight junctions between cells of the vascular endothelium are responsible for this barrier action.
-These tight junctions are much stronger than those found in capillaries elsewhere in the body, due to the presence of a number of specific proteins: claudins, occludins these also bind to cytoplasmic zona occludins
-Capillaries in the brain are also surrounded by the processes of astrocytes, which are thought to provide signals to the endothelial cells, causing the strong tight junctions to be maintained.
-In transplant experiments, placing a 'normal' capillary in the brain can induce it to become a specialised BBB capillary.
-Astrocytes also play an important role in ensuring basal expression of transport proteins through secreting basic fibroblast growth factor. Astrocytes also control cerebral microcirculation through controlling pericytes- smooth muscle like cells
-Pericyte stimulated with current- capillaries constrict-decrease in diamter Functions of Blood brain barrier
-Ion regulation: Control of ISF/CSF (2.9mM) Stabalising resting membrane potential in neurons
-Excluding amino acids used as neurotransmitters
-Excluding macromolecules- albumin/prothrombin/ plasminogen
-Excluding macromolecules - albumin, prothrmobin and plasminogen
-Excluding exogenous or xenobiotic neurotoxins
-Provide nutrient and remove waste products Transport through the blood brain barrier Core: selective transport through barrier; significance for drugs, infection, immune system.
Extension: chemical and physical interruption of receptor-mediated transport across blood-brain barrier; areas lacking blood-brain barrier in CNS.
-The paracellular pathway between cells is largely unavailable because of the very tight junctions.
-Small or lipid-soluble molecules, including oxygen and water, can freely cross the BBB because they can pass through the endothelial cells. Glucose and electrolytes pass through slowly, and it is almost completely impermeable to proteins and macromolecules.
-There is a relatively close correlation between lipophilicity and the transport of a molecule across the BBB. Lipophilicity is therefore an important property of drugs that need to access the brain, such as many general anaesthetics.
-There are, however, some specialised transport mechanism, such as protein transporters, receptor-mediated endocytosis and adsorptive endocytosis, in which some proteins attach to negative charges on the luminal surface and are endocytosed.
-Glucose is one example of a substance that is selectively transported; its uptake of glucose is much higher than would be predicted from its lipophilicity. It is transferred from the lumen to the extracellular space of the brain via facilitated diffusion on Glut1 which is present on both the luminal and abluminal membranes of the endothelial cell. Glucose enters via Glut 3.
-Understanding these mechanisms is very important in pharmacology, for example in the choice of L-DOPA over dopamine. L-Dopa can enter via facilitated diffusion- specific transporters - L system?
-Some molecules- although they have a high oil water partition have a low relative extraction/ concentration found in the brain interstitial fluid is low. This is because they are pumped out used ABC-ATP binding cassette transporter Efflux
-P glycoprotein = multi drug resistance 1 = ABCC1 = PUMP OUT TOXIC DRUGS. These are found on the luminal side of endothelial cells.
-Alzeihmers decreased level of ABC proteins- to remove B amyloid proteins
-Antibodies are largely excluded by the BBB but leukocytes are still able to cross the endothelium, provided that the necessary adhesion proteins are expressed.
-This can be problematic, however, as the leukocytes may carry viruses to the brain, which is ordinarily very well protected against pathogens.
-Certain parts of the brain, known as the circumventricular organs, are outside the BBB.
-This is important in allowing these regions to sense the composition of the blood and for the release of hormones (pineal gland and neurohypophysis) into the blood.
-Neurohypophysis-oxytoxocin and vasopressin secretion, area postrema-vomitting centre, organum vasculosum lamina terminalis-osmoreceptors, subfornical organosmoreceptors, pineal-light sensing, melanin secretion. Factors affecting the integrity of the BBB The BBB is immature at birth so its selectivity and protective ability is lower.
-Integrity can also be reduced during inflammation, by bradykinin and histamine in particular. Increased permeability of the blood brain barrier- IL6,
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