Cerebral blood flow regulation and the BBB

Question 1

What is the oxygen supply to the brain in numbers?

Answer 1

55ml/100g tissue/min

15% CO

Question 2

What happens if the blood supply is reduced by 50+%?

Answer 2

Insufficient oxygen delivery and function is impaired

Question 3

What is the amount of time that stopping cerebral blood flow will cause unconsciousness?

Answer 3

4 seconds

Question 4

What are the causes of syncope/fainting?

Answer 4

Low bp
Vaso-vagal attack
Sudden changes in posture
Sudden pain
Emotional shock

Question 5

What is the glucose conc. level that is classified as hypoglycaemia in the brain?

Answer 5

Below 2mM (normal 4-6mM) can result in disorientation, slurred speech, impaired motor function
-> coma, unconsciousness, death
Cannot synthesise or store glucose, can use ketones temporarily in starvation

Question 6

What regulates cerebral blood flow?

Answer 6

Total cerebral blood flow

Activity related blood requirements (specific brain regions need altered localised blood flow)

Question 7

What is the range that arterial blood pressure is auto regulated between?

Answer 7

60-160mmHg

Question 8

What is autoregulation and what happens if it goes above or below the range?

Answer 8

Myogenic response (due to stretch-sensitive cerebral vascular muscle cells respond to changes in BP i.e. contract at high BP)
Arteries dilate or contract to maintain blood flow.

Below auto regulatory pressure range, blood supply is insufficient and above leads to swelling of the brain tissue and increase intracranial pressure

Question 9

Why is local auto regulation required?

Answer 9

Local brain activity determines the demand for 02 and glucose so local changes in blood supply are needed (neural or chemical control)

Question 10

What is neural control of local autoregulation?

Answer 10

Sympathetic nerve stimulation for vasoconstriction when arterial blood pressure is very high.
Parasympathetic (facial nerve) stimulation causing vasodilation
Production of vasoconstrictor molecules e.g. catecholamines by central cortical neurones
Dopaminergic neurones cause vasoconstriction due to localised increased brain activity

Question 11

How do dopaminergic neurones work to influence cerebral blood flow?

Answer 11

Dopaminergic neurones innervate the smooth muscle surrounding arterioles and the pericytes around capillaries. This may cause cerebral blood flow to be directed to areas of the brain with high activity.
Dopamine may cause contraction of pericytes via aminergic or serotoninergic receptors

Question 12

What is the arrangement of arteries, arterioles and capillaries in the brain?

Answer 12

Large vessels lie outside the CNS and penetrate the neural tissue.
The main arteries (superficial pal) receive sympathetic control.
Central arteries are surrounded by smooth muscle and lead down to capillaries surrounded by pericytes.
The capillaries drain into venues -> veins -> pial veins

Question 13

Give examples of the chemical control of cerebral blood flow

Answer 13

Localised effects causing vasodilation;
increased CO2 (indirect)
decreased pH
NO;  activates Guanylyl cyclase > GTP to cyclic GMP conversion > vasodilation
anoxia
K+
Adenosine
Histamine, kinins, prostaglandins

Question 14

What is the mechanism of indirect vasodilation from increased CO2 levels?

Answer 14

When there is increased metabolism/brain activity, pCO2 increases and there is increased local perfusion. CO2 diffuses across the BBB from endothelial cells to SM cells. The presence of carbonic anhydrase leads to H+ and carbonate production in neural tissue. H+ ions cause smooth muscle cells to relax and vasodilate.

Question 15

What does the CSF act as for the brain and its function?

Answer 15

It is a protective mechanism produced by choroid plexus in the cerebral ventricles (140ml circulates)- slight protection against trauma.
Function; nutrition of neurones, chemical and physical protection, transport of molecules

Question 16

How does the CSF flow around?

Answer 16

The ventricles, aqueducts and canals of the brain are lined with ependymal cells which are usually ciliated which helps move CSF around.

Question 17

Where are the choroid plexuses located in the ventricular system?

Answer 17

Posterior floor of the lateral ventricles, roof of the third ventricle and posterior aspect of the fourth ventricle.

Question 18

Describe the control of CSF circulation

Answer 18

Capillaries are leaky but the ependymal cells which produce CSF have tight junctions so can control the amount.

Question 19

Describe the movement of CSF in the ventricular system

Answer 19

CSF is secreted into the ventricles, circulates in the lateral ventricles and passes to the 3rd via the inter ventricular foramina. Travels down the cerebral aqueduct into the 4th ventricle and out through the medial and lateral apertures to circulate in the subarachnoid space.
It recirculates via the arachnoid granulations in the superior sagittal sinus back into the venous circulation.

Question 20

What is the volume of CSF that circulates?

Answer 20

80-150ml

Question 21

Where in the brain is there no BBB and what is the purpose of this?

Answer 21

Circumventricular organs, adjacent to ventricles and lack BBB properties (capillaries are fenestrated).
e.g. median eminence of hypothalamus, subfornical organ, neurohypophysis, Organum vasculosum of the lamina terminalis (OVLT)

Involved in secreting into the circulation
Sample the plasma for toxins/electrolyes

Question 22

What are the important differences between plasma and CSF?

Answer 22

Osmolarity is the similar
CSF is slightly more acidic and there is little protein (increased levels would indicate an infection)
Lower in CSF; K+, amino acids, calcium, bicarbonate
Higher in CSF; magnesium, chloride

Question 23

What are the two functions of the BBB?

Answer 23

Protects the brain from certain toxins and transmitters e.g. catecholamines
Protects the brain from wide variation in ion concentrations

Question 24

Give examples of where yo would find continuous, fenestrated and sinusoidal capillaries

Answer 24

Continuous; heart, skin
Fenestrated; endocrine organs
Sinusoidal; liver

Question 25

What plays a role in making the BBB impermeable to many molecules?

Answer 25

Ependymal cells with tight junctions
Capillaries are surrounded by pericytes which have ‘end feet’ running along the capillary wall and can contract (make it more permeable) or relax to influence solute and fluid leak across the capillary wall.

Question 26

Describe the filtering of molecules from the pial vessels to the BBB

Answer 26

Pial vessels; diapedesis occurs under normal conditions, reduced passage of proteins but permeable to most small molecules
Descending into the BBB: impermeable to hydrophilic molecules
At the BBB: Negligible permeability, polarised phenotype

Question 27

What is the difference between the brain capillaries and other capillaries of the body?

Answer 27

Little transcellular vesicular transport

Highly developed inter-endothelial junctions

Question 28

How do hydrophilic molecules e.g. water, glucose, amino acids, electrolytes cross the BBB?

Answer 28

Water; AQP1, AQP4
Glucose; GLUT1 proteins
Amino acids; 3 different transporters
Electrolytes; specific transporter systems

Question 29

What is the difference in the involvement of BBB between old antihistamines and second-generation?

Answer 29

Old histamines were hydrophobic so could cross the BBB and cause drowsiness.
Second generation are polar so cannot cross

Question 30

How does L-DOPA work in the treatment of PD?

Answer 30

L-DOPA can cross the BBB via amino acid transporter and is converted to dopamine via DOPA decarboxylase.
You must co-administer a DOPA decarboxylase inhibitor (e.g. Carbidopa) to stop the conversion of L-DOPA into dopamine outside the BBB so there is not reduced availability.