Lecture 25; Ischemic Brain injury 2 Flashcards
When thinking about ischemia and damage to the brain, what is it important to remember?
Lots of different cell types are affected in ischemia.
- Astrocytes, maintain homeostasis, clean up ions, neurotransmitter
- Microglia, post ischemia inflammation
- Oligiodendrocytes, myelin
How are pathways affected in ischemia?
Energy disruption!
- Mitochondria
- Intermitochondrial membrane
- TCA or Crebs
- ETC -> 32ATP
Ischemia -> Glycolysis (anaerobic ) -> Lactic acidosis = disrupts ions, RMP
Describe oxidative metabolism;
Requires oxygen and glucose to make ATP
Glycolysis in cytosol
Krebs cycle and electron transport chain in mitochondria
Glucose-> 38 ATP+ 6xCO2+ 6xH20
Describe anaerobic metabolism;
Glycolysis;
glucose-> 2ATP + lactate
During ischemia –no oxygen and glucose delivery
Usually oxygen runs out before glucose
Cells switch to anaerobic metabolism –generates small amount of ATP and increased lactate -lactic acidosis
Insufficient ATP for cellular function
What is an alternative to glycolysis for ATP generation?
Phosphocreatine
Once inside cell becomes phosphorylated
Anaerobically donate a phosphorus to ADP forming ATP
How can metabolism be measured?
MRS
NIS
What is MRS?
Magnetic Resonance Spectroscopy
•Phosphorus or hydrogen magnetic resonance spectroscopy
= range of metabolic products can be measured. (high energy vs low energy metabolites)
•Follow the evolution of cerebral energy metabolism
What did MRS show in terms of pCR?
Bilateral carotid artery occlusion in neonatal piglet
Initially ATP levels buffered by creatinekinase reaction leading to decreased PCr (ATP stablizes)
Once PCr is depleted ATP declines (secondary energy failure)
How long does it take following ischemia does it take for metabolism to return to normal?
After hypoxia ischemia metabolism is restored 1-6 hrs afterwards
But 23hr-> Secondary energy failure, loss of high energy metabolites
Dont forget there is secondary energy failure
What does NIS measure?
Near inferred light into the brain, measures output = can measure various protein states
i.e Cytochrome oxidase and electron acceptance and state
What is the function of cytochrome oxidase?
cytochrome oxidase: terminal electron acceptor of mitochondrial electron transport
Near-infrared light shows change in redox state of CytOxcopper A core
What did NIS show for preterm fetal sheep asphyxia in terms of Hb?
Marker of how well the brain is oxygenated
- Decreased oxygen Hb
- Can measure total Hb as indicator of total BV in brain
- Initially increase in BV to keep it oxygenated/alive at expense of other organs. Then as HI continues total Hb drops.
- Proportion of cytochrome oxidase increases. More oxidised. therefore no more E being passed along ETC (No O2)
- Reperfusion returns things back to normal (long term changes though)
What do the studies of fetal sheep tell us?
During ischemia:Failure of oxidative metabolism
No electrons on the electron transport chain
Depletion of phosphocreatine
Depletion of ATP
What does loss of ATP lead to?
Failure of ATP -dependent membrane pumps (for e.g. Na/K ATPase)
Sodium, Calcium, Chloride into cells
Potassium out of cells
Lose ability to extrude calcium
Loss of electrochemical gradient
Anoxic depolarisation = Neurotransmitter release, which can lead to neighbouring tissue to depolarise from excessive neurotransmitter (spreading depression)
lack of ATP means no protection
What is anoxic depolarisation?
Neurons depolarise due to hypoxia
Release glutamate at synaptic cleft
Followed by hyperpolarization
Trigger neighbouring neurons to depolarize
Waves of spreading depression
What is anoxic depolarisation accompanied by?
Anoxic depolarisation is accompanied by cell swelling (cytotoxic edema)
Ions move into the cell -uncontrolled movement of water from extracellular space into cytoplasm (allows measurement of IOS or increased impedance to the flow of current)
May be reversible or lead to necrosis
What does impedance measure?
It is an indicator of cell swelling.
Impedance: resistance to the f low of current through the extracellular space
What happens to impedance as cells swell?
As cells swell
- decreased extracellular space
- increased impedance to the flow of current
- Increases after approx 4 min
Resolves to near-baseline after end of occlusion
What is the idea of excitotoxicity?
Excessive glutamate is toxic to cells
Over-activation of glutamate receptors such as NMDA and AMPA receptor
Increase [Ca2+]I
Trigger cell death pathways
BUT
Do they think that excitotoxicity is really a problem?
Glutamate excitotoxicity is a symptom instead of propagatory problem
What did Microdialysis in near-term fetal sheep during bilateral carotid artery occlusion find?
- 2 fold increase in glutamate
- 2 fold increase in asparate
- 2.5 fold increase in glycine
- 40 fold increase in GABA
Fetus may be different from adult though
What happened to the excitotoxicity index during ischemia?
Excitotoxicityindex = (GLU x GLY)/GABA
3 –fold reduction!!!!!!
What happens in the adult brain in terms of excitotoxicty?
Adult brain shows bigger increase in glutamate (10-50-fold)
Postnatal rats show only a 3-fold increase in GABA
May be higher excitotoxicity index postnatally/in the adult brain
When does necrosis occur?
Cell swelling
Loss of cell membrane integrity
Release of products of cell death into extracellular space
Does not follow apoptotic signal transduction pathway
Released cellular contents - triggers influx as attracts microglia + Other inflam cells.
