Metabolic Blood-Brain Relationships Flashcards
What proportion of the brain’s oxygen is used in the grey vs. white matter?
75% in grey matter
How does the brain cope with increased metabolic demand?
No storage of oxygen or fuels so increases blood flow
What happens in the brain when ATP is lost?
Na/K-ATPase pump is inhibited and ion gradients are destroyed, causing energy failure
What is phosphocreatine?
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
How are astrocytes involved in synaptic transmission?
Their processes ensheath the synapse
What are the 5 ways things can pass through the BBB?
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
Where in the brain is glucose stored?
Usually not! Some glycogen is stored in astrocytes.
How does glucose enter the brain?
GLUT1 transporter on BBB and astrocytes
GLUT3 into neurons
What else can the brain use for fuel apart from glucose?
Lactate and ketone bodies
When does the brain use ketones as fuel?
During starvation and development
When is lactate produced?
Not in oxidative phosphorylation
In anaerobic glycolysis (limited O2)
In aerobic glycolysis (glucose -> lactate in presence of O2) AKA Warburg effect
How is lactate used?
Converted to pyruvate then enters TCA to make ATP
Where does the brain source lactate from?
- From blood via lactate transporters
- Local aerobic glycolysis
- Astrocyte-neuron shuttle hypothesis (astrocytes break down glycogen)
What occurs in the early stages of a hypoglycaemic coma?
O2 consumption continues and ATP/phosphocreatine levels stay constant
What occurs in later stages of a hypoglycaemic coma?
ATP decreases to 25-30% of control levels
Neuronal damage from oxidative stress, but death takes several hours
Neuronal release of glutamate often increased
What is oxidative stress and what damage results?
Imbalance between ROS and antioxidants
Oxideses proteins, lipids and DNA :. mitochondrial damage, DNA damage, energy failure and cell death
What is hypoxia and how do we tolerate it?
Lack of oxygen: poorly tolerated as the brain needs O2 for energy ++
Cellular oxygen-sensing systems activate short-term and long-term adaptions
What adaptions are activated in response to hypoxia?
Increase in local blood supply
Non-essential energy consuming mechanisms are shut down
RBC production and angiogenesis stimulated by gene transcription
What is total energy failure?
Lack of O2, PCR used, ATP exhausted through blockage of Na/K-ATPase and ion gradients collapse, causing rapid and large depolarisation
What events occur within 1 minute of brain ischaemia?
ATP failure
Collapse of ion gradients and depolarisation
Glutamate release and NMDA receptor activation
Ca influx
Excessive acidification
How does the brain get energy during ischaemia?
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!
What are the 3 secondary mechanisms of ischaemic cell death?
- Intracellular Ca overload (increased glutamate release) causes metabolic stress and death
- Inflammatory reaction via microglia
- Eventually we get blood vessel leakage, oedema and BBB breakdown
What are the steps of hypoxic ischaemia brain injury?
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
Which neuronal populations are most vulnerable to ischaemic damage?
Hippocampal CA1 and all of the middle laminae of the cortex
