Week 3- Blood brain Barrier Flashcards
what is the blood brain barrier?
network of vessels that form
a structural and chemical barrier
between the brain and systemic
circulation
what is required for the brain to work in a stable environment? function
-requires precise communication between nerve cells in the the brain
-Protects the brain against xenobiotics(foreign chemicals/material) but
also a barrier to neuroactive pharmaceuticals
what are the two main cells of the BBB?
- astrocytes, which attach to outside capillary endothelium cells
- brain capillaries
what is the big mian different between a brain capillary and other capillaries?
-they dont have foot processes which is a type of glial cell found in the brain
what is the astroctyte foot processes important for. and its function?
-Essential for formation and maintenance of the BBB
-Secreted factors maintain brain pH, uptake and metabolism of
neurotransmitters, antioxidant production
what are all the differences between brain and general capillaries?
- Systemic/general capillary Fenestrated or continuous small solutes can diffuse through intercellular clefts pinocytosis independent of molecular size (pass large molecules)
what are all the differences between brain and general capillaries?
-Brain capillary Continuous tight junctions reduced pinocytosis Efflux transporters no fenestrations Astrocyte foot processes for support and allowing secretion
what are some regions of the brain that are not enclosed by BBB?
known as the circumventricular organ (CVO) • Pineal gland • Subfornical organ • Organum vasculosum of the lamina terminalis (OVLT) • Area Postrema • Median eminence • Neurohypophysis (Posterior pituitary)
What is the transport mechanism for capillaries in the brain?
- liquid soluble substances can pass
- theres tight junctions as theres no pores
- theres carrier-mediated transport
what type of cells is the CVO surrounded by? function?
CVO’s surrounded by tanycytic membrane (specialisedependymal cells) possessing tight junctions (TJ) and limiting diffusion of proteins from CVO to deeper brain tissues
what are the 4 different types of ventricles in the brain?
theres 4 (two lateral, third and fourth)
• Membrane bound cavities lined with
ependymal cells.
• Filled with CSF (10 mm Hg pressure)
• CSF (cerebralspinal fluid) production: walls of lateral ventricle and
third ventricle, by choroid plexus
what is cerebrospinal fluid?
is a clear fluid present in the ventricles of the brain, the central canal of the spinal
cord, and the subarachnoid space. Normal: almost no blood cells, little protein
what is the function of Cerebrospinal fluid?
• Gives protection (mechanical and chemical). By circulating it exchanges nutrients and wastes. • Maintenance of a constant external environment for neurons and glia • Mechanical cushion to protect the brain, provides buoyancy • Serves as a conduit for neuropeptides • pH of CSF regulates pulmonary ventilation and CBF
where is the CSF secreted from?
-the chorid plexus
-made from epithelial cells stitched together by tight junctions
• Secretes CSF (lateral and 3rd), secretes proteins (e.g. prealbumin), removes waste products,
serves as a barrier blood-CSF, active transport
• Display tight junctions limiting passive protein transport from blood to intraventricular
space containing CSF
how does the CSF flow? then reabsorbed
• CSF flows from the lateral ventricle to the third ventricle• The third ventricle and fourth ventricle are connected to each other by the cerebral aqueduct. • CSF then flows through the central spinal cord canal into the subarachnoid space • Resorbed by arachnoid villi and granulations, either by classical lymphatics in sinonasal tissues or recently described meningeal–dural sinus lymphatics back into the systemic circulation or to regional and cervical lymph nodes
what way is a drug injected straight into the cerebrospibal fluid?
Intrathecal drug administration involves the direct injection
of the drug into the CSF within the intrathecal space of the spinal column
-done at the bottom of the back
what indications would allow intra-thecal drug administration?
Chronic spasticity due to injury, multiple sclerosis and cerebral
palsy (eg, baclofen)
Management of cancer, chronic non-malignant or
neuropathic pain (eg, morphine)
Chemotherapy lymphomatous meningitis
(eg, methotrexate, cytarabine)
Antibiotic treatment adjuvant to systemic
therapy in bacterial meningitis and other
infections of the central nervous system
(eg, gentamicin)
what are the different routes across the blood brain barrier?
1-cell migration 2- passive diffusion 3- Carrier Mediated Efflux 4- Carrier Mediated Influx 5- Receptor Mediated Transcytosis 6- Adsorptive Mediated Transcytosis 7-TJ Modulation
how exactly does passive diffusion work to allow crossing of the blood brain barrier?
where a drug with appropriate properties can partition down the conc gradient and into the brain
how exactly does carrier mediated efflux work to allow crossing of the blood brain barrier?
- reduced the amount of drug that gets into the brain
- as if it is recognised by efflux transporter is pulled out of the cell and effluxed back into the brain
how exactly does carrier mediated influx work to allow crossing of the blood brain barrier?
-to increase influx into brain like metabolic materials like amino acids and glucose
how exactly does receptor mediated transcytosis work to allow crossing of the blood brain barrier?
-whereby macro molecules antibodies. due to size and polarity they cant do passive movement so they rely on this whereby a receptor picks a molecule up and shuttles it across the cell
-molecules like Transferrin
Insulin
Leptin
Cytokines
Viruses
how exactly does Adsorptive Mediated Transcytosis work to allow crossing of the blood brain barrier?
how exactly does tight junction modulation work to allow crossing of the blood brain barrier?
- these are between epithelial cells
- if the tight junction permeability is increased it can increase the temporary influx of polar molecules
what are the molecular properties needed for passing through the membrane passively?
Molecule Properties
- Steric; Molecular size, volume, shape
- Hydrophobicity; lipid / water due to partioning if its to polar wont partition properly
- Ionic properties; Hydrogen bonding potential, pKa
whats the process and how does passive movement entail?
Processes
- Partitioning into cell membrane form extracellular fluid (inc. ECF - Membrane, Membrane cytosol, organelle interactions etc.)
- Diffusion (inc. organelle and macromolecule interactions etc)
what is polar surface area?
Processes Partitioning (inc. ECF - Membrane, Membrane cytosol, organelle interactions etc.) Diffusion (inc. organelle and macromolecule interactions etc) -if its high they'll have a lower penetration into the brain
what is the name of the family of drug transporters in the brain?
ABC (ATP-binding cassette) transporters
how many ATP binding cassettes are there and how are they grouped?
-48 human ABC transporters described
-Grouped by homology into 7 families ABC- A to G
most common are:
-ABC B - Peptides, phosphatidylcholine, bile salts, iron, drugs (Pgp)
Hydrophobic planar molecules neutral or cationic
-ABC C - Organic anions, anionic conjugates, nucleotides, nucleosides, bile salts,
peptides (MRP) include glutathione, glucuronate and sulphate conjugates
-ABC G - Sterols, lipids, drugs (BCRP) include mitoxantrone, topotecan
-most popular is Pgp
-other important ones are MRP and BRCP
what is P-glycoprotein?
- also known as MDR1
- ABC B1 in humans
- very large
- has 6 transmembrane domains
- molecules that are Hydrophobic planar molecules neutral or cationic can pass through
- BBB has Pgp and is expressed in the brain a lot to limit what drugs enter the blood and is on the blood side of the BBB
what are the general features of Pgp substartes?
- Lipid solubility with some amphiphilic properties, need to be able to partition into cell membrane
- Large planar molecules
- if charged - mildly cationic
how have antihistamines developed from 1st Generation to 2nd?
- 2nd Gen aren’t drowsy
- aren’t drowsy due to them having a lower amount that is able to pass the BBB as they are Pgp substrates so less drug can bind to receptors in the brain
what is the structure of multidrug resistance associate protein ?
has 17 transmembrane domains
what is the structure of breast cancer resistant proteins ABC G2?
has 6 transmembrane domains
what is LAT1?
-LAT1 is a heterodimeric membrane transport
protein that preferentially transports neutral
branched (valine, leucine, isoleucine) and
aromatic (tryptophan, phenylalanine, tyrosine)
amino acids
-LAT is highly expressed in brain capillaries
relative to other tissues.
-A functional LAT1 transporter is composed of
two proteins encoded by two distinct genes:
* 4F2hc heavy subunit protein
* CD98 light subunit protein
-CD98 is a glycoprotein that comprises the
light subunit of the Large neutral amino acid
Transporter (LAT1).
what is Parkinsons disease?
- neurodegenerative disorder
- medication relies on LAT1
- due to deneneration of dopaminergic neurons projecting from the substantia nigra to striatum.
- drug used to treat is levodopa is an immediate precursor of dopamine
why isnt dopamine able to cross over the BBB?
due to lack of carboxyl group on its structure as this group is important for substrate binding into LAT1
what is needed to happen with L-DOPA to treat Parkinsons?
need to not be metabolised to dopamine before it gets into the brain
what drugs have been developed to treat parkinsons?
• Carbipoda/benserazide
• L-aromatic amino acid decarboxylase (LAAD) coverts L-DOPA to
dopamine
• LAAD converts 95% of L-DOPA dose to dopamine before CNS
penetration
• Carbidopa inhibits peripheral LAAD allowing a greater fraction of L-DOPA to pass through the BBB
• Carbidopa does not penetrate BBB and is always co-formulated
with L-DOPA
how much levodopa is lost if given alone?
70% of dose lost to gut metabolism
27-29% of dose lost in peripheral tissue (toxicity)
1-3 % available for brain penetration
how much levodopa is lost when given with carbidopa/benserazide?
40% of dose lost to gut metabolism
50% of dose peripheral tissue (toxicity)
10% available for brain penetration
