Metabolic Blood-Brain Relationships

Question 1

What proportion of the brain’s oxygen is used in the grey vs. white matter?

Answer 1

75% in grey matter

Question 2

How does the brain cope with increased metabolic demand?

Answer 2

No storage of oxygen or fuels so increases blood flow

Question 3

What happens in the brain when ATP is lost?

Answer 3

Na/K-ATPase pump is inhibited and ion gradients are destroyed, causing energy failure

Question 4

What is phosphocreatine?

Answer 4

Precursor to creatine, can be used transiently to regenerate ATP under anaerobic conditions (ie. intense muscular effort or neuronal demand)
This occurs before ATP is used

Question 5

How are astrocytes involved in synaptic transmission?

Answer 5

Their processes ensheath the synapse

Question 6

What are the 5 ways things can pass through the BBB?

Answer 6

A. Paracellular aqueous through occluding tight junction
B. Transcellular lipophilic pathway (most drugs)
C. Transport proteins eg. glucose and AAs
D. Receptor-mediated transcytosis eg. insulin
E. Absorptive transcytosis

Question 7

Where in the brain is glucose stored?

Answer 7

Usually not! Some glycogen is stored in astrocytes.

Question 8

How does glucose enter the brain?

Answer 8

GLUT1 transporter on BBB and astrocytes

GLUT3 into neurons

Question 9

What else can the brain use for fuel apart from glucose?

Answer 9

Lactate and ketone bodies

Question 10

When does the brain use ketones as fuel?

Answer 10

During starvation and development

Question 11

When is lactate produced?

Answer 11

Not in oxidative phosphorylation
In anaerobic glycolysis (limited O2)
In aerobic glycolysis (glucose -> lactate in presence of O2) AKA Warburg effect

Question 12

How is lactate used?

Answer 12

Converted to pyruvate then enters TCA to make ATP

Question 13

Where does the brain source lactate from?

Answer 13

1. From blood via lactate transporters
2. Local aerobic glycolysis
3. Astrocyte-neuron shuttle hypothesis (astrocytes break down glycogen)

Question 14

What occurs in the early stages of a hypoglycaemic coma?

Answer 14

O2 consumption continues and ATP/phosphocreatine levels stay constant

Question 15

What occurs in later stages of a hypoglycaemic coma?

Answer 15

ATP decreases to 25-30% of control levels
Neuronal damage from oxidative stress, but death takes several hours
Neuronal release of glutamate often increased

Question 16

What is oxidative stress and what damage results?

Answer 16

Imbalance between ROS and antioxidants

Oxideses proteins, lipids and DNA :. mitochondrial damage, DNA damage, energy failure and cell death

Question 17

What is hypoxia and how do we tolerate it?

Answer 17

Lack of oxygen: poorly tolerated as the brain needs O2 for energy ++
Cellular oxygen-sensing systems activate short-term and long-term adaptions

Question 18

What adaptions are activated in response to hypoxia?

Answer 18

Increase in local blood supply
Non-essential energy consuming mechanisms are shut down
RBC production and angiogenesis stimulated by gene transcription

Question 19

What is total energy failure?

Answer 19

Lack of O2, PCR used, ATP exhausted through blockage of Na/K-ATPase and ion gradients collapse, causing rapid and large depolarisation

Question 20

What events occur within 1 minute of brain ischaemia?

Answer 20

ATP failure
Collapse of ion gradients and depolarisation
Glutamate release and NMDA receptor activation
Ca influx
Excessive acidification

Question 21

How does the brain get energy during ischaemia?

Answer 21

Anaerobic glycolysis produces lactate (accumulation of this causes acidosis and aggravates brain damage)
- no lactic acidosis in hypoglycaemia as glucose precursor needed to make lactate!

Question 22

What are the 3 secondary mechanisms of ischaemic cell death?

Answer 22

1. Intracellular Ca overload (increased glutamate release) causes metabolic stress and death
2. Inflammatory reaction via microglia
3. Eventually we get blood vessel leakage, oedema and BBB breakdown

Question 23

What are the steps of hypoxic ischaemia brain injury?

Answer 23

Insult
Primary energy failure within 2-10mins
Na overload/increased glutamate has transient reperfusion
Ca overload and oxidative stress causes secondary phase (6-72hrs after)
Mitochondrial dysfunction, inflammation, BBB failure and permanent injury

Question 24

Which neuronal populations are most vulnerable to ischaemic damage?

Answer 24

Hippocampal CA1 and all of the middle laminae of the cortex

Question 25

What happens to brain metabolism in the ictal phase of a seizure?

Answer 25

Hypermetabolic state, increased blood flow, increased lactate production

Question 26

During interictal periods?

Answer 26

Lower glucose uptake and blood flow as energy requirements decrease

Question 27

What is the acute (mins to hours) response to a seizure?

Answer 27

Cell death after 1-3 hrs
Hippocampal sclerosis which results in glutamate excitotoxicity
Inflammation and BBB failure
Moderate lactic acidosis

Question 28

Hrs-months response?

Answer 28

Chronic Ca increase and synaptic remodelling

Acquired channel and BBB dysfunction