5. Cerebral Blood Flow Regulation and the Blood Brain Barrier

Question 1

Describe the oxygen supply to the brain. What happens if the blood supply is reduced?

Answer 1

• HIGH - 55 ml/100 g tissue /min
• 15% of cardiac output
• Whenever blood flow to the brain is reduced by more than 50%:
  
  • Insufficient oxygen delivery
  • Function becomes impaired
• If the total cerebral blood flow is interrupted for as little as 4 seconds, you will become unconscious
• After a few minutes, irreversible damage will occur to the brain

Question 2

Define Syncope and its causes

Answer 2

Syncope = fainting is 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 3

Explain the glucose supply to the brain.

Answer 3

• Normally a VAST SURPLUS of glucose to the brain via the blood
• A supply of glucose is really important because the brain can’t synthesise or utilise any other source of energy
• Ketones can be metabolised if there is a shortage of glucose but glucose is the main nutrient
• Hypoglycaemia can lead to a loss of brain function
• If the blood glucose concentration falls below 2 mM it can result in unconsciousness,coma and DEATH

Question 4

What happens to brain function in hypoglycaemia?

Answer 4

• 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. (Normal fasting levels 4-6 mM)

Question 5

What mechanisms regulate Cerebral Blood Flow?

Answer 5

• Mechanism affecting total cerebral blood flow
• Mechanisms that relate activity to requirement in specific brain regions by altered localised blood flow - you need a system that can divert blood to the parts of the brain that really need it at the time

Question 6

How is total cerebral blood flow autoregulated?

Answer 6

• Autoregulation occurs within a relatively wide breadth of the arterial blood pressure from 60 - 160 mm Hg
• One Factor: MYOGENIC(response to stretch)
• The smooth muscle lining the arteries can stretch in response to blood flow
• An increase in pressure on the vessel wall will result in a myogenic response that leads to contraction of the smooth muscle - this decreases cerebral blood flow
• This myogenic response occurs when there is a change in blood pressure in the body
• Also, the local delivery of oxygen to brain tissue is related to the needs of that tissue by local autoregulation
• Stretch-sensitive cerebral vascular smooth muscle contracts at high BP and relaxes at lower BP.
• Below this autoregulatory pressure range, insufficient supply leads to compromised brain function (as discussed).
• 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.

Question 7

Explain the local cerebral blood flow.

Answer 7

• The local brain activity determines the local O₂ and glucose demands, therefore local changes in blood supply required: Local autoregulation
• This consists of Neural and Chemical control

Question 8

Describe the function of Dopaminergic Neurones.

Answer 8

• NOTE: Capillaries in the brain have PERICYTES around them, which are contractile
  
  • Pericytes are a type of brain macrophage
  • They have a variety of functions e.g. immune function, transport properties, contractile
• Dopaminergic neurones innervate the smooth muscle surrounding arterioles and the pericytes around the capillaries
• When the dopaminergic neurones are active, they can cause the contraction of pericytes to decrease the blood flow to a particular area thus diverting blood to other, more active areas of the brain
• Dopamine may cause contraction of pericytes via aminergic and serotoninergic receptors
• Arteries from pia penetrate into the brain paremchyma branching to form capillaries which drain into venules and veins which drain into pial veins.

Question 9

Describe the arrangement of arteries, arterioles and capillaries in the brain.

Answer 9

• The main arteries will be innervated by the sympathetic fibres
• Deeper down you get arterioles with smooth muscle around them and the capillaries surrounded by pericytes
• Innervation of the pericytes and arteriolar smooth muscle is how the dopaminergic neurones can regulate blood flow at a capillary level

Question 10

Describe the neural control of local cerebral blood flow.

Answer 10

• Neural Control:
  
  • Sympathetic Nerve Stimulation
    
    • ​Sympathetic innervation of the main cerebral arteries can cause vasoconstriction-this only happens when the arterial blood pressure is HIGH
  • Parasympathetic (facial nerve) Stimulation
    
    • ​We don’t normally associate the PSNS with vasculature
    • However, facial nerve fibres are innervated by parasympathetic fibres - this causes a slight vasodilation
  • Central Cortical Neurones
    
    • ​The neurones within the brain itself can release neurotransmitters such as catecholamines that cause vasoconstriction
  • Dopaminergic Neurones
    
    • ​Produce vasoconstriction
    • They are important in regulating differential blood flow to areas of the brain that are more active

Question 11

Explain the chemical control of local cerebral blood flow.

Answer 11

• These chemical are likely to be localised
• They increase blood flow to particular tissues
• when cells are active they will produce lactic acid - the H+ ions in the lactic acid will cause a drop in pH and cause vasodilation in that area
• K+ is released at one stage of the action potential and acts as a vasodilator

Question 12

How does CO₂ cause vasodilation of cerebral arteries.

Answer 12

• CO₂ 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.
• H⁺ ions DO NOT cross the BBB

Question 13

Describe the formation of CSF.

Answer 13

• Formed by the choroid plexus (region of the ventricle which is modified to form branches villus structure)
• Capillaries leaky, but adjacent ependymal cells have extensive tight junctions
• Ependymal cells secrete molecules into the ventricles to make the CSF (this is why the CSF is different to the blood)
• Path of CSF:
  
  1. Lateral Ventricles
  2. 3rd ventricle (via inteventricular foramina)
  3. Cerebral Aqueduct
  4. 4th Ventricle
  5. Subarachnoid Space (via medial and lateral apertures)
• Volume of CSF = 80-150ml
• Volume of CSF formed per day = 450 ml/say

Question 14

What is the function of CSF?

Answer 14

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

Question 15

Compare the composition of plasma and CSF.

Answer 15

• LOWER in the CSF
  
  • K⁺
  • Ca²⁺
  • Amino Acids
  • HCO₃^-
• HIGHER in the CSF
  
  • Mg²⁺
  • Cl^-
• Osmolarity is the same
• The pH of CSF is slightly more ACIDIC

Question 16

What is the function of the BBB.

Answer 16

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 capillaries CNS.

• Protects the brain tissue from certain toxins and circulating transmitters like catecholamines
• It also protects the brain from wide variations in ion concentrations

Question 17

Describe the structure of the BBB

Answer 17

• The endothelial cells that line the capillaries in the brain, unlike the rest of the body, have VERY TIGHT JUNCTION - the capillaries are non-fenestrated
• These tight junctions mean that a lot of molecules can’t pass readily through the BBB
• In addition, these capillaries are surrounded by pericytes that have end-feet that run along the capillary wall
• When the pericytes contract, they make it more likely for molecules to escape the capillary
• So it is mainly the tight junctions between endothelial cells that form the BBB but the pericytes are also involved

Question 18

What can and can’t pass through the BBB?

Answer 18

• The “tightness” of the BBB capillaries means that 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)
• Blood-borne infectious agents have reduced entry into CNS tissue. (CNS infections more commonly affect the meninges, whose vessels are not BBB).
• Some molecules - lipophilic molecules- cross the BBB relatively easily (e.g. alcohol and anaesthetics) – so access to, or removal from, CNS directly via diffusion down concentration gradients.

Only certain hydrophilic substances are allowed through the BBB by means of specific transport mechanisms including:

• Water via aquaporin channels
• Glucose via GLUT1 proteins
• Amino acids via 3 different transporters
• Electrolytes via specific transporter systems

Question 19

Explain what circumventricular organs are and why we need them.

Answer 19

• 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).
• Circumventricular organs have fenestrated capillaries (so leaky) and therefore they lie outside the BBB
• These regions of the brain are generally involved in secreting into the circulation, or need to sample the plasma.
  
  • e.g. the posterior pituitary and median eminence secrete hormones, and the area postrema samples the plasma for toxins and will induce vomiting. Others are involved in sensing electrolytes and regulate water intake.
• Circumventricular organs include:
  
  • Median eminence region of the hypothalamus
  • Subfornical organ (SFO)
  • Organum vasculosum of the lamina terminalis (OVLT)

Question 20

Explain the importance of antihistamines and the BBB.

Answer 20

• In the treatment of allergy, the “old-fashioned” H1 blockers are hydrophobic and could cross the BBB. Since histamine is important in wakefulness and alertness, these antihistamines made people drowsy. Used as sedatives (often over-the-counter).
• Second-generation antihistamines are polar (i.e. have hydrophilic attachment), therefore do not readily cross the BBB, so do not cause drowsiness.

Question 21

Explain the importance of the BBB in the treatment of Parkinson’s Disease.

Answer 21

• 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 by DOPA decarboxylase.
• A lot of the L-DOPA will converted into Dopamine outside the brain therefore no much can go through the BBB.
• Solution: 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.