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Learning Objectives: Blood Brain Barrier 1.

Outline the cellular and molecular basis of the barrier ● Cerebral endothelial cells form tight junctions, are surrounded by basement membrane, astrocyte foot processes, and pericytes. Sometimes neurons connect too. Astrocytes tell the endothelial cells to make the tight junctions (apparently). ● Posterior Pituitary does not have a BBB because it must secrete into blood. ● Tight Junctions form around the 4th fetal month. ● Permeability to small water-soluble molecules is greater in fetal (developing) brain (susceptible to alcohol and other drugs) ● Specific transport mechanisms for ions, amino acids, etc develop as brain grows. ● When BBB begins working, CSF protein concentration drops. ● Selective Uptake at BBB of molecules in high demand in brain ● Enzyme Barrier: Lumenal side of endothelial cells has peptidases, esterases, decarboxylases 2.Discuss the key molecular parameters involved in the penetration of the barrier ● Before 6th fetal month, alpha-fetoprotein etc freely access CNS; not after. ● Other chemicals and neurotoxins and hormones can access brain in this period—implications for feminization or masculinization if imbalances are present. ● Brain Uptake Index (BUI) = relative uptake of a molecule compared to the uptake of deuterium water (DOD) which is arbitrarily 100%. BUI Nicotine= 131% BUI Alcohol= 104% BUI Caffeine= 90% BUI Heroin= 68% BUI Vitamin C= 3% BUI Morphine= 2.6% BUI Aspirin= 1.8% BUI Most Anti-Cancer Drugs= <2.5% ● Partition Coefficient (PI) = partition between ocanol and saline, which predicts accumulation between blood brain barrier (higher number = greater brain uptake) ● Gases enter CNS rapidly (nitrous oxide, anesthetics) ● Lipids (insecticides etc) and heroin accumulate and get trapped in CNS compartments ● Glucose enters by facilitated diffusion (no energy needed) 8 GLUT transporters exist. Galactosemia inhibits facilitated glucose uptake Isotope labeled 2-deoxyglucose (metabolic inhibitor) used to ID brain regions of high metabolic activity ● Mannitol poorly permeable; dehydrates brain by osmosis and used to reduce swelling of cerebral edema. Can shrink brain by 10% volume in 12-24 minutes. 3.Summarize the clinical relevance of the blood brain barrier and its manipulation

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Glucose enters by facilitated diffusion (no energy needed) 8 GLUT transporters exist. Galactosemia inhibits facilitated glucose uptake Isotope labeled 2-deoxyglucose (metabolic inhibitor) used to ID brain regions of high metabolic activity Mannitol poorly permeable; dehydrates brain by osmosis and used to reduce swelling of cerebral edema. Can shrink brain by 10% volume in 12-24 minutes. Toxins: Bordetella pertussis destroys tight junctions Intra cerebral bacterial endotoxins—lipopolysaccharides, cause inflammation in brain—high MMPs (gelatinases). Also in AIDS, meningitis, hemorrhage, MS, reperfusion injury s/p stroke. If we can inhibit the MMPs it will be great for treatment. Drug Abuse: can cause permanent BBB damage & branching of capillaries. Also damage to BBB in aging, diabetes, Alzheimer’s Disease, hypertension, cardiovascular disease. Purposeful BBB Penetration: Antibodies to transferrin receptors to help transport items in. Like Nerve Growth Factor attached to TR. Bilirubin Encephalopathy (kernicterus): free bilirubin (unconjugated) enters CNS in newborns, toxic to brain. Caused by Rh incompatibility mom vs. baby. Bilirubin binds to gangliosides—interferes with glycolysis—can cause hearing loss and intellectual defects. Infection: lymphocytes, macrophages, stem cells can enter CNS at tissue damage sites because of Cell Adhesion Molecules (CAMs) at those areas. Can we exploit it by coupling medicines to CAM ligands to allow BBB passage? Also, autimmune attack on CNS might be caused by lymphocytes attaching to these CAMS inappropriately.