Cerebral blood flow regulation and the blood brain barrier

Question 1

What is the level of blood flow to the brain?

Answer 1

High: 55ml/100g tissue/min.

Question 2

What are the consequences of reduction of blood flow to the brain by more than 50%?

Answer 2

Insufficient oxygen delivery.

Function becomes significantly impaired.

Question 3

What is the result of total cerebral blood flow interruption for as little as 4 seconds?

Answer 3

Unconsciousness.

Question 4

What is the consequence of total cerebral blood flow interruption after a few minutes?

Answer 4

Unconsciousness.

Irreversible damage occurs to the brain.

Question 5

What is syncope?

Answer 5

Fainting- a common manifestation of reduced blood supply to the brain.
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.

Question 6

What is the importance of glucose supply to the brain?

Answer 6

Normally, vast surplus provision of glucose (the principal energy source) to the brain via the blood.
This supply of glucose is vital because the brain cannot store, synthesise or utilise any other source of energy (although, in starvation, ketones can be metabolised to a limited extent).

Question 7

How does hypoglycaemia affect brain function?

Answer 7

An individual appears disoriented, slurred speech, impaired motor function.
If the glucose concentration falls below 2mM it can result in unconsciousness, coma and ultimately death.

Question 8

What are the normal fasting levels of glucose in the blood?

Answer 8

4-6mM

Question 9

Why does cerebral blood flow need to be maintained and regulated?

Answer 9

Because of the constant need by the brain for oxygen and glucose.

Question 10

What is cerebral blood flow regulated by?

Answer 10

Mechanisms affecting total cerebral blood flow.

Mechanisms which relate activity to the requirement in specific brain regions by altered localised blood flow.

Question 11

What is the range of MABP within which cerebral blood flow can be maintained by auto regulation?

Answer 11

60-160mmHg

Question 12

How is cerebral blood flow autoregulated?

Answer 12

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.

Question 13

What is the result of MABP falling below the autoregulatory pressure range?

Answer 13

Insufficient supply leads to compromised brain function.

Question 14

What is the result of MABP rising above the autoregulatory pressure range?

Answer 14

Increased flow can lead to swelling of brain tissue which is not accommodated by the ‘closed’ cranium, therefore intracranial pressure increases- dangerous.

Question 15

How is the local cerebral blood flow regulated?

Answer 15

The local brain activity determines the local oxygen and glucose demands, therefore local changes in blood supply are required- local autoregulation.

Question 16

What are the types of control of local cerebral blood flow?

Answer 16

Neural

Chemical

Question 17

What is the role of dopaminergic neurones in local regulation of cerebral blood flow?

Answer 17

Innervate penetrating arterioles and pericytes around capillaries.
Pericytes wrap around capillaries and have diverse activities: immune function, transport properties, contractile.
May participate in the diversion of cerebral blood to areas of high activity.
Dopamine may cause contraction of pericytes via aminergic and serotoninergic receptors.

Question 18

What is the pattern of vascularisation in the CNS tissues?

Answer 18

Arteries from pia penetrate into the brain parenchyma branching to form capillaries which drain into venules and veins which drain into pial veins.
Dense network of capillaries- no neurone is more than 100µm from a capillary.

Question 19

Give examples of chemical factors involved in localised regulation of cerebral blood flow.

Answer 19

Mostly vasodilators:

• carbon dioxide (indirect).
• pH (i.e. H+, lactic acid, etc.).
• nitric oxide
• K+
• adenosine
• anoxia
• kinins, prostaglandins, histamine, endothelins

Question 20

How does carbon dioxide cause cerebral artery vasodilatation?

Answer 20

Carbon dioxide from the blood or from local metabolic activity gets converted to H+ by 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 and increased blood flow.

Question 21

What is cerebrospinal fluid produced by?

Answer 21

Regions of choroid plexus in the cerebral ventricles- important protective mechanism.

Question 22

What is the choroid plexus?

Answer 22

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.
Capillaries leaky, but adjacent ependymal cells have extensive tight junctions.

Question 23

What happens to CSF once it leaves the choroid plexus?

Answer 23

Choroid plexus secretes CSF into ventricles (lateral ventricles, third ventricle via interventricular foramina, down cerebral aqueduct into fourth ventricle and into subarachnoid space via medial and lateral apertures)- circulates.

Question 24

What is the volume of CSF?

Answer 24

80-150ml

Question 25

What are the functions of CSF?

Answer 25

Protection (physical and chemical).
Nutrition of neurones.
Transport of molecules.

Question 26

CSF has very little protein- why is this clinically important?

Answer 26

Indicates tissue damage and/or infection if protein is high in CSF.

Question 27

What are the features of capillaries of the blood brain barrier?

Answer 27

Extensive tight junctions at the endothelial cell-cell contacts, massively reducing solute and fluid leak across the capillary wall.
Derived from surface pial vessels.

Question 28

What are the differences between peripheral and blood brain barrier capillaries?

Answer 28

Dense pericyte coverage in BBB capillaries.
‘End feet’ from astrocytes cover BBB capillaries.
Tighter interendothelial junctions.
Little transcellular vesicular transport across BBB capillaries.

Question 29

What is the significance of the ‘tightness’ of the BBB capillaries?

Answer 29

Solutes that can exchange across peripheral capillaries cannot across the BBB.
This applies mainly to hydrophilic solutes such as glucose, amino acids, many antibiotics, some toxins, etc.
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).
Blood-borne infectious agents have reduced entry into CNS tissue. CNS infections more commonly affect the meninges, whose vessels are not BBB.

Question 30

What molecules can cross the BBB?

Answer 30

Lipophilic molecules (e.g. oxygen, carbon dioxide, alcohol, anaesthetics?)) directly via diffusion down concentration gradients.
Many hydrophilic substances by means of specific transport mechanisms, e.g:
-water, via AQP1 and AQP4 channels
-glucose, via GLUT1 transporter proteins
-amino acids, via 3 different transporters
-electrolytes, via specific transporter systems

Question 31

What are circumventricular organs?

Answer 31

In some areas of the brain, capillaries lack BBB properties.
These areas are found close to the ventricles.
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.
Generally involved in secreting into the circulation, or need to sample the plasma.

Question 32

Give examples of circumventricular organs.

Answer 32

Posterior pituitary and median eminence secrete hormones.
Area postrema samples the plasma for toxins and will induce vomiting.
Others sense electrolytes and regulate water intake.

Question 33

What is the clinical importance of the BBB?

Answer 33

Breaks down in many pathological states: inflammation, infection, trauma, stroke.
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.

Question 34

How does the BBB affect treatment of Parkinson’s disease?

Answer 34

A key therapy in Parkinson’s disease is pharmacologically raising the dopamine levels in the brain.
Peripheral administration of dopamine doesn’t work- dopamine can’t cross the BBB.
L-DOPA can cross the BBB via an amino acid transporter, and is converted to dopamine in the brain by DOPA decarboxylase. Also converted to dopamine outside of the brain when given peripherally.
Need to inhibit this conversion outside of the brain without affecting it inside.
Coadministration with the DOPA decarboxylase inhibitor, Carbidopa, works- cannot cross the BBB, so does not affect conversion of L-DOPA in the brain.