Blood Brain Barrier Flashcards
Describe the blood flow to the brain
Blood flow to the brain: high at approx. 55ml/100g tissue/min
(~15% of cardiac output, while only ~2% of body weight and 20% O2 consumption)
Compare the oxygen consumption of the brain to that of other tissues
Brain- 3mlO2/min per 100g Kidney- 5 Skin- 0.2 Resting Muscle- 1 Contracting muscle- 50
Describe the consequences of reduced blood flow to the brain
Whenever blood flow to the brain reduced by more than 50% insufficient oxygen delivery function becomes significantly impaired
If total CBF is interrupted for as little as 4 seconds, unconsciousness will result
After a few minutes irreversible damage occurs to brain
Summarise syncope (fainting)
Syncope (= fainting) is a common manifestation of reduced blood supply to the brain.
Bleeding and loss of blood is a cause
Has many causes including low blood pressure, postural changes, vaso-vagal attack, sudden pain, emotional shock etc.
All result in a temporary interruption or reduction of blood flow to the brain.
Describe a vaso-vagal attack
Vasovagal syncope (vay-zoh-VAY-gul SING-kuh-pee) occurs when you faint because your body overreacts to certain triggers, such as the sight of blood or extreme emotional distress. It may also be called neurocardiogenic syncope. The vasovagal syncope trigger causes your heart rate and blood pressure to drop suddenly. Blood pools in the legs and extremities whilst going to the brain
Summarise the glucose supply to the brain
Normally, vast surplus provision of glucose (the principal energy source) to the brain via the blood.
Some estimates suggest that the brain uses 50-60% of the body’s glucose!
This supply of glucose vital because the brain cannot store, synthesize or utilise any other source of energy (although, in starvation, ketones can be metabolised to a limited extent – adaptation possible in chronic undernutrition?)
- Why is there a vast surplus of glucose delivery to the brain?
Because the brain can only metabolise glucose
Ketone bodies can be metabolized if there is a shortage of glucose but glucose is the main nutrient
Describe the consequences of hypoglycaemia on brain function
Many of us might have witnessed or experienced the effects of reduced glucose delivery to the brain in insulin-dependent diabetic individuals, where blood sugar levels drop- administering too much insulin- or not eating enough glucose
An individual appears disoriented, slurred speech, impaired motor function.
Doesn’t just happen to diabetics- anyone with hypoglycaemia will start to feel wobbly and lethargic
If the glucose concentration falls below 2mM it can result in unconsciousness, coma and ultimately death. (Normal fasting levels 4-6 mM)
What is the brain
One of the most metabolically demanding and vascularised tissues
Describe the importance of the maintenance of cerebral blood flow
Because of the constant need by the brain for oxygen and glucose
it is vital that the cerebral blood flow be maintained
which means that an efficient regulatory system must be operational.
The brain is vulnerable to interruptions in its blood supply because it can store neither oxygen nor glucose, and cannot normally undergo anaerobic metabolism.
Cranial blood vessels are controlled by autoregulation to maintain a constant blood supply.
Describe the metabolic adaptations of the CNS to starvation
Under conditions of starvation for several days, the central nervous system can adapt to use ketones (fat derivatives acetoacetate and hydroxybutyrate) as its main energy source. These compounds normally make up approximately 30% of the fuel for the brain in adults but, after fasting for 40 days, this can rise to 70%.
- On what levels do you get regulation of cerebral blood flow?
mechanisms affecting total cerebral blood flow- concerning the cerebral arteries supplying the brain tissue
mechanisms which relate activity to the requirement in specific brain regions by altered localised blood flow
- Between what range in mean arterial blood pressure can autoregulation maintain a constant cerebral blood flow?
Total cerebral blood flow IS AUTOREGULATED
between mean arterial blood pressures (MABP) of approximately 60 and 160 mm Hg
Explain how this auto regulation is achieved
Over a wide range of arterial pressures, the arteries and arterioles dilate or contract to maintain blood flow.
Stretch-sensitive cerebral vascular smooth muscle contracts at high BP and relaxes at lower BP.
Contracts to reduce blood flow
Relaxes to increase blood flow- to compensate for the reduced BP
Compare the consequences of reduced and increased MABP in the brain
Below this autoregulatory pressure range, insufficient supply leads to compromised brain function (as already discussed).- light-headed
Above this autoregulatory pressure range, increased flow can lead to swelling of brain tissue which is not accommodated by the “closed” cranium, therefore intracranial pressure increases – dangerous.
Can’t increase volume as the space is closed- therefore the pressure must increase- putting pressure on structures in the brain.
Summarise local auto regulation
The local brain activity determines the local O2 and glucose demands, therefore local changes in blood supply required:
Local autoregulation
- Name one important factor to do with the smooth muscle lining arterioles that allows regulation of blood flow.
Myogenic Mechanism – when the smooth muscle surrounding arterioles is stretched, it will contract to maintain a constant blood flow
This occurs when there is a change in blood pressure in the body
What are the two controls of the local regulation of cerebral blood flow
neural control- in response to various stimuli
chemical control- in response to physiology
Describe the pattern of vascularisation in CNS tissues
Arteries enter the CNS tissue from as branches of the surface pial vessels. These branches penetrate into the brain parenchyma branching to form capillaries which drain into venules and veins which drain into surface pial veins.
The veins coalesce and return to the surface
Describe how densely the CNS is vascularised
No neurone more than 100µm from a capillary.
Inject liquid resin into brain vessels- will form a plastic cast- digesting away the parenchyma- leaving behind only the vessels- which show how densely vascularised the CNS is on a scanning EM
What are the four types of neural control of blood flow
Sympathetic innervation of the main cerebral arteries – causes vasoconstriction when arterial blood pressure is high
Parasympathetic (facial nerve) stimulation – can cause a little bit of vasodilation
Central cortical neurons – neurons within the brain itself can release neurotransmitters such as catecholamines that cause vasoconstriction
Dopaminergic neurons – produce vasoconstriction (important in regulating differential blood flow to areas of the brain that are more active)- localised effect relating to brain activity.
What is important to remember about the neural control of global blood flow to the brain
The neural control on global brain blood flow is not well defined, and its importance is uncertain.
Chemical control- probably more important
Describe the local effect of dopaminergic neurones on CBF
Innervate penetrating arterioles and pericytes around capillaries
Pericytes are cells that wrap around capillaries; have diverse activities (e.g. immune function, transport properties, contractile)
may participate in the diversion of cerebral blood to areas of high activity - by contracting and reducing the blood flow to other areas
Dopamine may cause contraction of pericytes via aminergic and serotoninergic receptors
- Name some chemical factors that increase blood flow to particular tissues.
Carbon dioxide (indirect) NO pH (H+, lactic acid, etc, direct) Anoxia Adenosine K+ Other (e.g. kinins, prostaglandins, histamine, endothelins)- both natural and synthetic factors
All increase blood flow by causing vasodilation
What is the normal pCO2 and blood flow to the brain
40kPa
1.0
As the partial pressure of pCO2 increases in the brain- so does the blood flow- see graph
What may the contractile cells be
Smooth muscle
Pericytes (in smaller vessels and capillaries)
Are H+ and CO2 able to cross the BBB
H+ can’t- therefore can’t cross from plasma to the vascular smooth muscle
CO2 can- therefore can cross from plasma to the vascular smooth muscle
- Describe how carbon dioxide indirectly causes vasodilation in the cerebral vessels.
H+ ions can’t cross the blood-brain barrier but carbon dioxide can
Carbon dioxide moves from the blood through the blood-brain barrier into the smooth muscle cells
Within the smooth muscle cells, in the presence of carbonic anhydrase, the carbon dioxide reacts with water to form bicarbonate and H+ ions
This internally generated H+ ions within the smooth muscle cells cause smooth muscle relaxation (vasodilation)
Summarise the cerebral arterial vasodilation by CO2
CO2 from the blood or from local metabolic activity generates H+ using carbonic anhydrase in surrounding neural tissue and in the smooth muscle cells.
Elevated H+ means decreased pH. This causes relaxation of the contractile smooth muscle cells, dilation of vessels, resulting in increased blood flow.
Describe how the local changes to blood flow allow imaging of the brain
Local changes to cerebral blood flow allow imaging and mapping of brain activity using techniques such as PET scanning and functional MRI (fMRI).
In the CNS, increased blood flow equates to increased neuronal activity.
Can see this on the brain as a result of increased H+ ions
- Describe how nitric oxide (NO) causes vasodilation.
Nitric oxide stimulates guanylyl cyclase
Guanylyl cyclase converts GTP cGMP
cGMP causes vasodilation
Summarise the fluid compartments of the brain
The brain is essentially “floating” in cerebrospinal fluid produced by regions of choroid plexus in the cerebral ventricles.
This is an important protective mechanism.
brain also bathed in its own tissue fluid- with fluid moving in and out of the I.C fluid
Where is CSF found
In the ventricular system and within the spinal canal
Describe the arachnoid granulations
Where CSF can lead the ventricular system
Openings between ventricular system and plasma on the outer surface of the brain and vessels in the arachnoid mater
Arachnoid granulations (also arachnoid villi, and pacchionian granulations or bodies) are small protrusions of the arachnoid mater (the thin second layer covering the brain) into the outer membrane of the dura mater (the thick outer layer). They protrude into the dural venous sinuses of the brain, and allow cerebrospinal fluid (CSF) to exit the subarachnoid space and enter the blood stream.
The largest granulations lie along the superior sagittal sinus, a large venous space running from front to back along the center of the head (on the inside of the skull). They are, however, present along other dural sinuses as well.
How do the arachnoid granulations ensure the one-way flow of CSF
The arachnoid granulations act as one-way valves. Normally the pressure of the CSF is higher than that of the venous system, so CSF flows through the villi and granulations into the blood.
Summarise the ventricular system of the brain
The ventricles, aqueducts and canals of the brain are lined with ependymal cells (epithelial-like glial cells, often ciliated).
In some regions of the ventricles, this lining is modified to form branched villus structures: the choroid plexus.
- Describe the passage of CSF through the ventricular system.
CSF is produced by specialized ependymal cells of the choroid plexus (mainly in the lateral ventricles)
From the lateral ventricles it goes through the foramen of Monro (inter ventricular foramen) to the 3rd ventricle
From the 3rd ventricles, CSF flows down the cerebral aqueduct to the 4th ventricle
From the 4th ventricle it enters the subarachnoid space (via medial and lateral apertures) and eventually drains back into the venous system via arachnoid granulation
Describe the different parts of the lateral ventricle
Anterior horn
Inferior horn
Posterior horn
Describe the different parts of the forth ventricle
Median aperture and lateral aperture
The fourth ventricle is the most inferiorly located ventricle, draining directly into the central canal of the spinal cord.
- Where is CSF produced?
Choroid plexus – these are specific cells associated with the ventricles (in particular the lateral ventricles)
Summarise the formation of CSF by the choroid plexus
ependymal cells line ventricles and aqueducts, and lining modified in some regions to produce branched villi structures called the choroid plexus
Capillaries leaky, but local ependymal cells have extensive tight junctions.
Capillaries line the connective tissue of pia mater
Secrete CSF into ventricles (lateral ventricles, 3rd ventricle via interventricular foramina, down cerebral aqueduct into 4th ventricle and into subarachnoid space via medial and lateral apertures) – circulates.
What is the circulating volume of CSF in a normal person
Volume: 80-150ml.
What is the volume of CSF formed per day
450 mL/day
What are the functions of the CSF
Functions: protection (physical and chemical), nutrition of neurones, transport of molecules.
- State four components that have a lower concentration in the CSF than the plasma.
K+ Calcium Amino acids Bicarbonate Na+ (slightly lower)
- State two components that have a higher concentration in the CSF than the plasma.
Magnesium
Chloride
How does the osmolarity of the CSF and plasma differ
They are identical
- How is the pH different in the CSF compared to the plasma?
CSF is slightly more acidic
What is the clinical importance of the CSF having very little protein
if protein in CSF then could indicated infection or damage to choroid plexus
Describe the choroid plexus
Choroid plexus: capillaries in villi allow filtrate to pass into CSF and waste/unnecessary solutes to be removed
Experimentally, how did we discover the presence of a BBB
In the late 19th and early 20th centuries, it was noted that dyes, and other tracers, injected intravenously, accumulated in most tissues, but were excluded from most areas of the CNS (including the retina).
Organs removed from a mouse after intravenous injection with a blue dye.
The blue dye did not accumulate in the brain
This suggested the existence of a Blood-Brain Barrier.
Why does a BBB make sense
A Blood-Brain Barrier makes sense because the activity of neurones is highly sensitive to the composition of local environment, and the CNS must be protected from the fluctuations in the composition of the blood. Homeostasis is key for the brain.
It became apparent that the BBB was at the level of the CNS capillaries.
The blood–brain barrier exists to maintain the environment of the brain in a steady state, protected from extracellular ion changes, peripheral hormones (such as adrenaline (epinephrine)) and drugs. It also prevents neurotransmitters from the central nervous system entering the peripheral circulation.
Summarise capillaries
Most exchange between the blood and the tissues occurs across capillary walls.
They are generally thin-walled, and abundant (i.e. provide enormous surface area for exchange).
Estimated 400 miles of capillaries in the typical human brain.
Form 80% of the vasculature
Describe the different types of capillary
Continuous
Fenestrated- leaky- endocrine organs- to allow hormones to access the circulation and tissues
Sinusoid- very leaky- incomplete BM- liver and bone marrow
Describe how fluid is exchanged across capillaries
Pores or clefts between endothelial cells
Describe the circulation of plasma
Each day, 8L of plasma leaks out of blood vessels. Since the volume of blood plasma is ~3L, the entire plasma volume must pass into the interstitial space and back into the blood circulation every 9 hours!
Describe the capillaries of the BBB
the capillaries of the CNS parenchyma derived from surface pial vessels
Vessel BBB properties increased in deeper vessels.
BBB capillaries have extensive tight junctions at the endothelial cell-cell contacts, massively reducing solute and fluid leak across the capillary wall.
What is the Virchow-robin space
Perivascular spaces, also known as Virchow-Robin spaces, are pial-lined interstitial fluid-filled spaces in the brain that surround perforating vessels.
Lined by glia limitans membrane
ends at the fusion of the leptomeningeal layers
Compare cardiac muscle capillaries to that of the brain
Cardiac muscle capillary
(continuous type, with transcellular vesicular transport)
Brain capillary (continuous type, little transcellular vesicular transport)
Describe some other difference between peripheral and BBB capillaries
Pericytes are cells closely apposed to capillaries. They have important functions in maintaining capillary integrity and function. Peripheral vessels have sparse pericyte coverage, while BBB capillaries have dense pericyte coverage.
In addition, BBB capillaries are covered with “end-feet” from astrocytes. These associations are important for maintaining BBB properties.
Brain capillaries -more mitochondria- no intercellular clefts
Summarise BBB structure
capillaries have tight junctions and are the continuous type, with little transcellular vesicular transport.
Describe the inter endothelial junctions in the BBB
in peripheral capillaries, limited overlap, but with BBB capillaries, the boundary is tortuous and with more tight junctions.
Describe the importance of astrocytes for maintenance of the BBB
Astrocytes: produce growth factors to allow maintenance of BBB
Describe the key factors of the BBB that allow the control of the balance between the CSF and the plasma
The endothelial cells of the cerebral capillaries have very high resistance tight junctions between them. As a result, even small ions will not permeate between endothelial cells in brain capillaries. Brain capillary endothelial cells also lack the methods of transcellular transport which are present in peripheral capillaries (fluid-phase and carrier-mediated endocytosis).
•
Astrocytes have foot processes which adhere to the capillary endothelial cells such that they are entirely enclosed. Astrocytic foot processes also secrete factors that help to maintain the tight junctions between endothelial cells.
- Describe the structure of the blood-brain barrier. Which cells are involved?
The capillaries in the brain have endothelial cells with very tight junctions so there is tight control of what can pass through the wall of the capillary
The capillaries are also surrounded by pericytes with end-feet running along the capillary wall
When the pericytes contract they make it more likely for the molecules to leave the capillary
Which type of molecules can cross the BBB easily
Lipophilic molecules, such as diamorphine (an opioid analgesic)
Describe exchange across the BBB
Because of the “tightness” of the BBB capillaries, solutes that can exchange across peripheral capillaries cannot cross the BBB.
This applies mainly to hydrophilic solutes such as glucose, amino acids, many antibiotics, some toxins and many others.
This allows the BBB to control the exchange of these substances using specific membrane transporters to transport into and out of the CNS. (influx and efflux transporters)
Where are CNS infections more likely to occur and why
Blood-borne infectious agents may have reduced entry into CNS tissue. (CNS infections more commonly affect the meninges, whose vessels are not BBB).
(Some evidence that loss of BBB can help with clearing some infections by allowing immune cells access.)- astrocytes contact the BBB
Describe the exchange of lipophilic molecules across the BBB
Lipophilic molecules (e.g. O2, CO2, alcohol, anaesthetics?) cross the BBB so access to, or removal from, CNS directly via diffusion down concentration gradients.
How do hydrophilic substances cross the BBB
Many hydrophilic substances to enter the CSF and brain ECF by means of specific transport mechanisms, examples being:
a) water, via aquaporin (AQP1, AQP4) channels b) glucose, via GLUT1 transporter proteins c) amino acids, via 3 different transporters d) electrolytes, via specific transporter systems
Describe how glucose crosses the BBB
D-glucose, for example, has a stereospecific membrane transporter that facilitates diffusion from the circulation to the CSF at high rates because the brain relies heavily on glucose for energy. However, in situations where there is a dramatic fall in plasma glucose levels (e.g. in diabetic hypoglycaemic states), glucose may diffuse back out of the CSF into the plasma. This is a medical emergency as the neurons needs glucose to survive.
Describe how amino acids cross the BBB
Other transport systems include those for amino acids – one each for basic (e.g. arginine), neutral (e.g. phenylalanine) and acidic (e.g. glutamate) amino acids. Clinically, the neutral transporter is important as it will transport L-dopa (used to replace dopamine lost from the substantia nigra in Parkinson’s disease). However, dopamine cannot be given as a treatment because it does not have a transporter.
What is meant by the circumventricular organs
In some areas of the brain, it is necessary that the capillaries lack BBB properties. These areas are found close to the ventricles, and are known collectively as the circumventricular organs (CVOs).
Describe the features of the circumventricular organs
Their capillaries are fenestrated (therefore leaky). The ventricular ependymal lining close to these areas can be much tighter than in other areas, limiting the exchange between them and the CSF.
What are the roles of the circumventricular organs
These regions of the brain (marked as red spots in the diagram on the left) are generally involved in secreting into the circulation, or need to sample the plasma.
List some of the circumventricular organs and their roles
For example:
the posterior pituitary and median eminence secrete hormones
the area postrema (brainstem) samples the plasma for toxins and will induce vomiting
others are involved in sensing electrolytes and regulate water intake.
subcommisural and subfornical organs, organum vasculosm lamina terminalis (OVLT)
Pineal body
CVOs need leaky, fenestrated vessels to carry out these functions.
Summarise the circumventricular organs
In certain regions of the brain (including the posterior pituitary and choroid plexus) the capillaries are fenestrated and so there is no blood–brain barrier. Specialized ependymal cells (tanycytes) isolate these areas from the rest of the brain. The absence of the blood–brain barrier at the posterior pituitary allows oxytocin and vasopressin to be secreted directly into the systemic circulation. At other sites, it enables the brain to analyse the concentrations of water and ions for homeostatic functions.
When can the BBB break down
The BBB breaks down in many pathological states: inflammation, infection, trauma, stroke, which obviously can have profound effects on CNS function.
Trauma to the CNS will result in loss of BBB.
Localised trauma, and the resulting local loss of BBB is illustrated the image on the left. The intravenous dye leaks into the brain tissue at the site of damage and surrounding areas.
Describe the importance of the BBB in pharmacology
A major issue is in relation to pharmacology:
Do you want a particular drug to get into the brain, or not?
Many therapeutic drugs cannot access the brain.
Others may access the brain too readily causing adverse effects.
Describe anti-histamines and the BBB
In the treatment of allergy, the “old-fashioned” H1 blockers are hydrophobic and can cross the BBB by diffusion.
Since histamine is important in wakefulness and alertness, these antihistamines made people drowsy. Today, used as sleep aids (often over-the-counter, e.g. Nytol (Diphenhydramine Hydrochloride)).
Second-generation antihistamines are polar (i.e. have hydrophilic attachment), therefore do not readily cross the BBB, so do not cause drowsiness.
Describe how BBB affects the treatment of Parkinson’s
A key therapy in Parkinson’s disease is pharmacologically raising the levels of dopamine in the brain.
Peripheral administration of dopamine not the answer, as dopamine cannot cross the BBB.
L-DOPA can cross the BBB via an amino acid transporter, and is converted to dopamine in the brain.
What is the key issue with L-dopa as a treatment and how can we circumnavigate this
Most of the circulating L-DOPA is converted to Dopamine peripherally (outside of the CNS), so less is available to access the brain. So, need to inhibit this conversion outside of the brain, without affecting it inside.
Co-administration with the DOPA decarboxylase inhibitor, Carbidopa, does the job. Carbidopa cannot cross the BBB, so does not affect conversion of L-DOPA in the brain.
Describe the consequences of abrupt changes in ionic changes on neurones
Abrupt changes in the ionic concentration can be damaging to neurons. The blood–brain barrier not only helps to protect the brain from such changes in plasma levels, but also helps to remove excess ions from the CSF. For example, intense neuronal activity can increase the CSF potassium concentration. A high concentration of K+ channels on endothelial cells clears the excess.
Describe some infections that can disrupt the BBB
Brain ischaemia, brain tumours, haemorrhage, systemic acidosis or infections such as bacterial meningitis can break down the blood–brain barrier.
what happens in cerebral ischaemia
In cerebral ischaemia the blood–brain barrier opens, resulting in cytotoxic cerebral oedema: paucity of oxygen causes a decline in endothelial cell ATP which secondarily disrupts the function of the NA+/K+ATPase pump. As a result Na+ accumulates in the cell, water follows osmotically and the cell swells. This swelling compromises the integrity of the tight functions, allowing an influx of ions and water into the brain extracellular space.
What happens in diabetic ketoacidosis
In diabetic ketoacidosis (where plasma glucose concentration becomes excessively high), pH of the plasma may fall below 7, at which point the blood–brain barrier is compromised and neuronal death occurs.
How is CSF calculates
Cerebral blood flow (CBF) is determined by the difference in systemic blood pressure (SBP) and intracranial pressure (ICP): CBF = SBP – ICP. Therefore, patients with raised intracranial pressure will be hypertensive.
