Cerebral Blood Flow Regulation And The Blood Brain Barrier

Question 1

Blood flow to the brain

Answer 1

High at approximately 55ml/100g tissue/min

Question 2

Whenever blood flow tot he brain is reduced by more than 50%…

Answer 2

Insufficient oxygen delivery

Function becomes significantlt impaired

Question 3

If total CBF is interrupted for as little as 4 seconds…

Answer 3

Unconscioness will result

After a few minutes, irreversible damage occurs to brain

Question 4

Syncope

Answer 4

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 5

Glucose supply to the brain

Answer 5

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 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 6

If glucose concentration falls below 2mM…

Answer 6

It can result in unconsciousness, coma and ultimately death (normal fasting levels = 4-6mM)

Question 7

Cerebral blood flow is regulated by…?

Answer 7

Mechanisms affecting total cerebral blood flow

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

Question 8

TRUE OR FALSE:

Total cerebral blood flow is autoregulated

Answer 8

TRUE
Between mean arterial blood pressures (MABP) of approximately 60-160mmHg

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Question 9

Autoregulation of CBF

Answer 9

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
Below this autoregulatory pressure range, insufficient supply leads to compromised brain function
Above this range = increased flow can lead to swelling of brain tissue which is not accommodated by the “closed” cranium = intracranial pressure increases = dangerous

Question 10

Local cerebral blood flow

Answer 10

The local brain activity determines the local O2 and glucose demands, therefore local changes in blood supply required:
Local autoregulation
Controlled on the neural level and the chemical level

Question 11

Pattern of vascularisation in the CNS tissues

Answer 11

Arteries enter the CNS tissue from 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

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The CNS is densely vascularised
No neurone more than 100um from a capillary

Question 12

Neural factors that regulate cerebral blood flow

Answer 12

Sympathetic nerve stimulation to main cerebral arteries = vasoconstriction (probably only operates when arterial blood pressure is high)
Parasympathetic (facial nerve) stimulation producing slight vasodilation
Central cortical neurones releasing a variety of vasoconstrictor neurotransmitters, such as catecholamines (e.g. adrenaline, noradrenaline)
Dopaminergic neurones producing vasoconstriction (localised effect related to increased brain activity)

NOTE: the neural control on global brain blood flow is not well defined, and its importance is uncertain

Question 13

Dopaminergic neurones (local effect)

Answer 13

Innervate penetrating arterioles and pericytes around capillaries
- pericytes = cells that wrap around capillaries and have diverse activities (e.g. iimmune system, transport properties, contractile)
May participatein the diversion of cerebral blood to areas of high activity
Dopamine may cause contraction of pericytes via aminergic and sertoninergic receptors

Question 14

Chemical factors regulating cerebral blood flow

Answer 14

Vasodilators:
     - CO2 (indirect)
     - pH (i.e. H+, lactic acid, etc.)
     - NO
     - K+
     - adenosine
     - anoxia
Other (e.g. kinins, prostaglandins, histamine, endothelins

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Question 15

Cerebral arterial vasodilation by CO2

Answer 15

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

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Question 16

Local changes to cerebral blood flow

Answer 16

Local changs to cerebral blood flow allow imaging and mapping of brainactivity using techniques such as PET scanning and functional MRI (fMRI)
In the CNS, increased blood flow equates to increased neuronal activity

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Question 17

Fluid compartments of the brain

Answer 17

The brain is essentially “floating” in cerebrospinal fluid produced by regions of choroid plexus in the cerebral ventricles
This is ann important protective mechanism

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Question 18

Cerebrospinal fluid production

Answer 18

The ventricles, aqueducts and canals fo 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

FORMATION:
- capillaries leaky, but locall ependymal cells have extensive tight junctions
- secrete cSF into ventircles (lateral ventricles, 3rd ventricle vai interventircular formaina, down cerebral aqueduct into 4th ventricel and into subarachnoid space via medial and lateral apertures) = circulates
- volume = 80-150ml
- functions: protection (physical and chemical), nutrition of neurones, transport of molecules
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Question 19

CSF has little protein. This is clinicallly important. Why?

Answer 19

Could indicate infection

Indicates a breach/damage

Question 20

The blood-brain barrier

Answer 20

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

Question 21

Different capillary types

Answer 21

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Question 22

Exchang3e across the capillary wall

Answer 22

Slide 29 [pic]

Question 23

BBB capillaries

Answer 23

The capillaries of the CNS parenchyma derived from surface pial vessels
Have extensive tight junctions at the endothelial cell-cell contacts, massively reducing solute and fluid leak across capillary walls
Vessel BBB properties increased in deeper vessels

Question 24

More differences between peripheral and BBB capillaries

Answer 24

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

Question 25

TRUE OR FALSE:

CNS infections affect the meninges moreso than the brain

Answer 25

TRUE

Blood-borne infectious agents may have reduced entry into oCNS tissue (due to the “tightness” of the BBB capillaries)

Question 26

How do hydrophilic substances enter the CSF and brain ECF?

Answer 26

Specific transport mechanisms:

 - water via aquaporin (AQP1, AQP4) channels
 - glucose via GLUT1 transporter proteins
 - amino acids via 3 different transporters
 - electrolytes via specific transporter systems

Question 27

TRUE OR FALSE:

Lipophilic molecules can cross the BBB

Answer 27

TRUE
They diffuse down concentration gradients
E.g. O2, CO2, alcohol, anaesthetics

Question 28

In some areas of the brain, it is necessary that the capillaries lack BBB properties…

Answer 28

Areas are found close to ventricles
Known collectively as circumventricular organs (CVOs)
These capillaries are fenestrated (therefore leaky)
Ventricular ependymal lining close to these areas can be much together than in other areas, limiting the exchange between them and the CSF
Regions are generally involved in secreting into the circulation, or need to sample the plasma

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E.g.
- posterior pituitary and median eminence secrete hormones
- the area postrema samples the plasma for toxins and will induce vomiting
- others are involved in sensing electorlytes and regulate water intake

Question 29

Clinical importance of the BBB

Answer 29

BBB breaks down in many pathological states: inflammation, infection, trauma, stroke etc.
Also 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

Question 30

Antihistamines and the BBB

Answer 30

“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
Second-generation antihistamines are polar (i.e. have hydrophilic attachment) = do not readily cross the BBB = do not cause drowsiness

Question 31

BBB affects treatment of Parkinson’s

Answer 31

Key therapy = raising levels of dopamine in brain
Peripheral administration of dopamine cannot cross BBB
L-DOPA can cross the BBB via an amino acid transporter and is converted to dopamine in the brain

HOWEVER!
Most of the circulating L-DOPA is converted to dopamine peripherally, 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 works. Carbidopa cannot cross the BBB, so does not affect conversion of L-DOPA in the brain
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