BBB 2 Flashcards
How do things get into the brain?
through uptake transporters for all molecules
5 types of transport:
1) paracellular
2) transcellular
3) carrier mediated transport
4) receptor mediated transcytosis (RMT)
5) adsorptive mediated transcytosis (AMT)
paracellular - through tight junctions b/w endothelial cells - very small water soluble molecules
transcellular - directly through endothelial cell - diffusion of lipid soluble molecules
brain needs constant supply of glucose, aa, nucleotides, peptides
- these essential water soluble compounds are transported via specific carrier mediated transporters
- GLUT1 - glucose
- MCT1 - lactate (monocarboxylate)
- LAT1 - leucine - aa
recognition site on transporters for specific compounds - pore opens up in membrane of endothelial cell so molecule can pass through
RMT - specific transport of larger molecules e.g. transferrin, insulin, lipoproteins, viruses
AMT - non-specific transport of large charged proteins e.g. histones, albumin
these involve endocytosis to get the larger compounds in vesicles, transport it across and exocytosis to release it into the brain - process is TRANSCYTOSIS
what is the clinical significance for transporters?
amino acid transporters used to deliver L-dopa to treat Parkinson’s disease
transcytosis used to deliver antibodies to treat Alzheimer’s disease
Describe the neurovascular unit and how blood flow can be increased?
Neurovascular unit - neurones linked to astrocytes linked to capillaries
neurones astrocytes and pericytes can increase blood flow to supply nutrients
- neurones communicate with BBB capillaries through astrocytes + pericytes
active neurones release NTs which stimulate astrocytes
- astrocytes detects NT, increases calcium which is picked up by pericyte and releases vasoactive substances e.g. potassium, prostaglandin E2, arachidonic acid which relax the pericytes
- pericytes act as smooth muscle and cause capillary dilation - increases blood flow
what is the clinical significance of neurovascular unit and blood flow?
clinical significance - more blood flow - more drug can get to the brain
- in neurodegenerative disorders - neurones and astrocytes are damaged - slows blood flow - less drug to brain
- small changes in blood flow can be measured by functional MRI which idenitifies neuronal activity
describe CSF, blood-CSF barrier and compare to BBB?
CSF made in 4 ventricles of brain
choroid plexuses makes CSF and forms blood-CSF barrier
- CP has a dense blood capillary network - these are leaky just like peripheral capillary unlike BBB capillaries
- they also have a separate layer of epithelial cells - secretory epithelia which can move water and salts
BBB - formed by tight junctions b/w capillary endothelial cells
Blood-CSF barrier - tight junctions b/w secretory epithelial cells
similarities b/w both barriers:
- physical barrier - but more TJ in bbb
- transport barrier - efflux transporters
- maintain ion conc. for optimal neural signalling K+, Ca2+ Mg2+
primary function - production of CSF
describe how CSF is made and its composition?
secretory epithelial cells use an active Na/K ATPase pump
- Na actively pumped out
- Cl follows it
- H20 follows both - goes through a specialised aquaporin 1 water channel
- get a salt solution of Na, Cl and H20
- similar composition to plasma but - low protein (0.5%), glucose + AA low, some electrolytes low e.g. K+, Ca2+
also transports folic acid, vitamin C, riboflavin and vitamin B
composition of CSF:
- protein
- glucose
- ions - Na+, Cl-, K+
- cells - very few lymphocytes + macrophage
ALL of these are very few
Describe CSF flow around brain?
made in ventricles
CSF goes out ventricles round the surface of the brain
space under surface of brain = sub-arachnoid space
- one on side of it is the brain
- other side is the arachnoid membrane - which keeps the fluid close to the brain
CSF moves through a series of valves b/w CSF, sub-arachnoid space and venous blood - pressure system
- goes round and over surface of brain into venous sinus - then into venous blood
- bulk drainage of fluid
- this is the major way metabolites + toxins removed from brain
what are the diff mechanisms of blockage of CSF flow and what is the result?
blocked drainage to venous blood from sub-arachnoid space
- usually caused by calcification of valves
blocked drainage from ventricles to sub-arachnoid space
- usually due to brain tumours
if fluid can’t get through valve system in sub-arachnoid space and drain into venous blood
- will build up and cause hydrocephalus and cognitive impairment
How does CSF get into the brain
via the perivascular route
- CSF flows over surface of brain
- can also flow along outer surface of blood vessels - perivascular route
- then permeates through tissue
CSF can move into brain via perivascular route
brain interstitial fluid can move out of brain via this route
direction of flow of CSF + interstitial fluid depends on pressure - how much there is
drug metabolite clearance depends on drug conc. gradients
what are the main functions of CSF?
excretion and clearance via drainage of toxic metabolites, large compounds and drugs
- acts as lymphatic system for brain clearing
provides buoyancy to brain - reduces crushing spinal nerves (brain weight reduced from 1400g to 50g)
distributes nutrients to brain - vit C, folate, riboflavin
distributes hormonal secretion through CNS - leptin, IGF
how is the heart associated with CSF clearance
CSF drainage aided by pulsatile flow
CSF flow matches heart beat
CSF velocity varies with cardiac cycle
during cardiac cycle
- when heart contracts - CSF moving from where its made in centre of brain - generally back - toward posterior brain
when heart relaxes - CSF goes back from posterior to anterior brain
CSF flow mirrors cardiac cycle - pulses back and fourth through ventricles, SAS and perivascular space
- see SAS getting bigger and smaller due to pumping
why does CSF production change throughout the day and what is the clinical significance
CSF flow has a circadian rhythm
- lowest production at midday
- increases throughout the day with peak secretion at midnight
sleeping increases CSF production - will increase drug clearance
- e.g. anaesthesia will increase drug clearance
clinically - to keep drugs in brain for longest administer in the morning not at night due to increased clearance
what does clearance of drug depend on?
size - larger molecules take longer to clear
whether its taken up by cells or binds to neurons
what are the major obstacles for getting drugs into brain and why is it a problem esp for drugs targeting neurodegeneration and brain tumours
BBB physical barrier - only small (<400 Da) + lipid soluble molecules can penetrate
BBB transport barrier - active efflux transporters remove large lipid soluble drugs
BBB metabolic barrier - CYP450 enzymes in capillary endothelial cells metabolise small permeant drugs
CSF - clears drugs from brain fluids via drainage, quicker rate at NIGHT
problem for drugs treating Alzheimer’s and Parkinson’s and brain tumours
- new biologic drugs - large peptide or antibody drug therapy - hydrophilic
- chemotherapeutic drugs - highly lipid soluble but substrates for efflux transporters
why can’t we breakdown the barrier?
this would allow all blood components into the brain
which can cause:
1) increased risk of seizures
- more potassium can depolarise neurones, increasing excitability
- delays repolarisation
2) risk of oedema
– swelling of brain crushing neurones due to protein flowing in
3) risk of excitotoxicity and neurodegeneration due to excess calcium and glutumate flooding into brain from blood
