Blood-Brain Barrier
Specialized Features Important for Function of BBB
(1) Greater number and volume of mitochondria as compared to peripheral endothelia (required for active transport from blood to brain) (2) Enzymatic barrier for metabolizing drugs and nutrients (3) Decrease in capillary wall thickness (allows for shortened transport time) (4) Polarity between luminal and abluminal surfaces
Receptor-mediated transport through the BBB
*occurs in minutes Examples: Growth Hormone, Transferrin (for Fe2+), Insulin, Lipoproteins, Leptin
Carrier-mediated transport through the BBB
*occurs in msecs 1) Facilitated diffusion (for CHO /AAcid metabolic substrates) - no ATP needed 2) Active transport (some vitamins, ions) - ATP needed
area postrema (chemoreceptor trigger zone)
- CVO in the 4th ventricle/medulla oblongata - has permeable capillaries and sensory neurons - involved in vomiting
Junctional adhesion molecules (JAM)
- Localized at tight junctions - Members of the immunoglobulin superfamily
Found in the on the abluminal membrane of the BBB (closest to brain)
- Na+-K+ ATPase - neutral amino acid transporter - glucose receptor GLUT-1
circumventricular organs (CVOs)
- Regions of 3rd and 4th ventricles that lack BBB - in contact with walls of ventricular system and lined with choroid plexus - functional interface between the nervous and endocrine system (important in distribution of hormones in blood) - Allow contact with and free exchange between peripheral blood and extracellular fluid of brain - Modified capillaries (endothelium exposed to blood is fenestrated; surface exposed to brain around the ventricles has tight junctions)
Brain Targetor Concept
- a drug is linked to a lipophilic targetor so that it is able to get through the BBB - Once there, it is converted to a hydrophilic form, causing it to be "locked in" to the brain - drug released enzymatically
Multiple sclerosis and flavonoids
- anti-oxidant for neuroinflammatory response - have high lipophilicity to cross the BBB
Examples of CVOs
- area postrema/chemoreceptor trigger zone - pituitary gland - pineal gland - parts of hypothalamus (incld median eminence) - subfornical organ - lamina terminalis - tumors (usually have leaky capillaries)
RMP-7
- bradykinin B2 receptor agonist (receptor-mediated permeabilizer) - helps in delivering carboplatin for brain tumors
Therapy of Parkinson's disease (L-dopa)
- crosses BBB - must use inhibitor of amino acid decarboxylase (which converts L-dopa to dopamine) to prevent systemic problems - Inhibitor does not cross BBB, but blocks this enzyme in peripheral vessels
zonula occludens (ZO 1, 2, 3)
- cytoplasmic proteins that interact with occludin to act as recognition proteins for tight junctional placement - have a number of sites for binding to cytoskeleton, kinases, and signal transduction proteins
Found on the luminal membrane of the BBB (closest to blood)
- g-GTP - alkaline phosphatase - P-glycoprotein drug efflux transporter
Enzymes found in the BBB include:
- g-glutamyl transpeptidase - alkaline phosphatase - aromatic acid decarboxylase
Function of the chorid plexus
-Formation/maintenance of CSF -Potential leakiness at base of choroid plexus -Both secretory and reabsorptive function (there are organic acid and base pumps that remove metabolites from CSF back to c. plexus for venous drainage)
Occludin
-Regulatory proteins that alter paracellular permeability -Brings opposing cell membranes into contact
Peri-endothelial structures of the BBB
-Thin basement membrane (basal lamina) supports abluminal surface - surrounds the endothelial cells and pericytes as well as astrocytes adjacent to endothelial cells
Claudin
-localized in tight junction strands -form dimers that bind to those on adjacent endothelial cells -FORM THE PRIMARY SEAL FOR TIGHT JUNCTIONS
Reese and Karnovsky (1967) and Brightman and Reese (1970)
-systemic injections of horseradish peroxidase (HRP) did not reach the brain extracellular fluid BUT -intraventricular injections into CSF stained extracellular fluid and extended all the way past the astrocytic endfeet and stopped at the tight junctions of the cerebral capillaries
Components of the Choroid Plexus
Fenestrated choroidal capillaries and tight junctions between choroidal epithelium
Junctional complexes
Include macula and zonula adherens as well as zonula occludens (tight junctions)
Passive diffusion through the BBB
Lipid mediation; restricted to small, lipid soluble molecules such as drugs
Structure of BBB capillary endothelium
Tight junctions (nonfenestrated) create a seal between adjacent cells in pial vessels and in vivo cerebral microvessels -Results in low paracellular permeability with high electrical resistance -Clefts between endothelial cells (next to tight junctions) allow for some movement of material
Tardive dyskinesia (TD)
a motor disorder that results from chronic use of certain antipsychotic drugs
Blood-CSF Barrier
barrier between blood & CSF; epithelium (tight junctions between ependymal cells)
Blood-Brain Barrier (BBB)
barrier between blood & extracellular fluid; endothelium; allows passage of lipophilic substances
Dura mater
blood vessels are fenestrated endothelium
Arachnoid and pia mater
blood vessels are nonfenestrated/tight junctions, component of BBB Specialized endothelial cells -Lack pinocytotic vesicles -Lack fenestrations -Tight junctions
Astrocytes
envelop ~99% of BBB endothelia Characteristics -Intercellular adhesion to endothelia by both gap junctions and adheren junctions -help determine BBB function, morphology, and protein expression -help guide vessel growth by interacting with both capillaries and neurons
Importance of CSF
essentially allows brain to float which limits forces acting upon it
Pericytes
regulate endothelial cell proliferation, survival, migration, differentiation, branching Characteristics -Lack a-actin, so not contractile -Gap junctions connect with endothelium -Send out projections -May be derived from microglial cells as they are phagocytic
Docosahexanoic Acid (DHA) with taxol
treatment of brain cancer
Docosahexanoic Acid (DHA) with dopamine (DOPREXIN)
treatment of tardive dyskinesia
BBB disruption via hyperosmotic mannitol
used to reduce intracranial pressure
Heroin\morphine
~68% uptake into brain in 30 sec
Restricted by the BBB
• Large molecules • Low lipid soluble molecules • High electrically-charged molecules • Toxins/Drugs
Functional significance of the BBB
•Protection / regulation CNS •Regulate neurotransmitters, ions, growth factors transfer from plasma to brain •Regulate dietary/salt/water movement •Barrier to passage of harmful substances in blood, eg. premature infants and newborns with kernicterus
