Blood Brain Barrier and CSF (Dr A Brown) Flashcards
What is brain ECF?
Brain extracellular fluid
Lots of association and interaction with the CSF
Concentrations of solutes in the ECF fluctuate with neuronal activity and on the other hand, changes to the ECF composition effects neuronal behaviour.
How is the ECF regulated?
CSF synthesised by the choroid plexus influences the composition of the ECF BBB protects the ECF from fluctuations in blood composition and limits entry of compounds into the ECF Glial cells (astrocytes) condition the ECF, and if needed, buffer K+ and NTs.
What is the function of cerebrospinal fluid?
15-20% of CSF is filing ventricles (30mls). 120mls remaining forms a thin layer around the brain and spinal cord in the subarachnoid space.
The volume of CSF turns over 3x per day, 500ml is produced each day, pushing the fluid around and through ventricle system.
Acts as a shock absorber, maintains the buoyancy of the brain.
Provides appropriate conditions for neurones and glia
Medium exchange between brain ECF and systemic blood.
Removal of waste products, metabolism, drugs, NT, metabolites.
Interface between brain and peripheral endocrine function i.e. releasing hormones from hypothalamus
How does CSF move around the brain?
Cortex lateral ventricles Foramina of Monroe Third ventricle (Thalamus) Cerebral aqueduct of Sylvius Fourth ventricle (Brain stem) Two foraminae of Luschka and foramina of Magendie Subarachnoid space
How does CSF circulate?
Structures of the ventricle system come from embyological cells from the centre of the neural tube during development.
Which sites are vulnerable to physical blockages to CSF?
Foramina and cerebral aqueduct –> Hydrophcephalus
How does CSF secretion happen?
Two stage process; ultra filtration of plasma across fenestrated capillary wall into ECF beneath the basolateral membrane of the choroid epithelial cell. The choroid epithelial cell then secretes fluid into the ventricles.
How is CSF used in diagnostics?
Spinal tap or lumbar puncture allows sampling of CSF for detection of pathogens e.g. MS, meningitis. Is used to measure CSF pressure for detection of hydrocephalus, sub-arachnoid haemorhage. Routine clinical procedure at L3-5.
How can CSF be used clinically?
Diagnostics
Anaesthetic spinal block, anaethetises below the application (distal), intrathecal drug application.
Routine procedure
Injection into the third ventricle = unlimited access to the ECF and thus neurones and glia. (Not a routine procedure)
Blood Brain Barrier
The CNS requires an ultrastable internal environment and therefore tight control and regulation of transport between blood and brain.
What is different to capillary endothelium in brain capillaries compared to normal capillaries?
Capillary endothelium have tight junctions, NOT fenestrations as other capillaries to avoid leakage and unwarranted fluid movement. This limits acces to molecules with molecular weight greater than 2000.
What factors regulate the passage across the BBB?
Lipid solubility - high lipid solubility -> greater access
Degree of ionisation - drugs ionised at physiological pH pKa 7.4 have less access
PKa value = pH at which 50% of the drug molecules are ionised.
Degree of plasma binding - in the bound state molecules are too large to cross the BBB
How is glucose transported across the BBB?
Facilitated transport of monosacharides
Specific to D glucose
Competitive
Which amino acids are readily transported across the BBB?
Tyrosine and tryptophans Leucine Phenylalanine Isoleucine Methionine Valine Threonine Histidine
Transmitter amino acids are not transported across
Essential amino acids are
L-DOPA can cross the BBB (dopamine cannot)
What are the metabolic barriers to Tx in the BBB? How does this relate to Parkinson’s Tx?
Endothelial cells, rich in certain metabolic enzymes, e.g. monoamine oxidase MAO
Dopamine is charged ( ionised at pH7.4 ) and cannot cross the BBB and is metabolised by MAO
Using L-DOPA and a peripheral DOPA decarboxylase inhibitor allows L-DOPA to cross the BBB unionised at pH 7.4 (the inhibitor is ionised and doesn’t enter the brain but just makes sure L-DOPA isnt converted to Dopamine before it can cross the BBB.
