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Medsci 317 > Lecture 25; Ischemic Brain injury 2 > Flashcards

Lecture 25; Ischemic Brain injury 2 Flashcards

1
Q

When thinking about ischemia and damage to the brain, what is it important to remember?

A

Lots of different cell types are affected in ischemia.

  • Astrocytes, maintain homeostasis, clean up ions, neurotransmitter
  • Microglia, post ischemia inflammation
  • Oligiodendrocytes, myelin
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2
Q

How are pathways affected in ischemia?

A

Energy disruption!

  • Mitochondria
  • Intermitochondrial membrane
  • TCA or Crebs
  • ETC -> 32ATP

Ischemia -> Glycolysis (anaerobic ) -> Lactic acidosis = disrupts ions, RMP

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3
Q

Describe oxidative metabolism;

A

Requires oxygen and glucose to make ATP

Glycolysis in cytosol

Krebs cycle and electron transport chain in mitochondria

Glucose-> 38 ATP+ 6xCO2+ 6xH20

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4
Q

Describe anaerobic metabolism;

A

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

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5
Q

What is an alternative to glycolysis for ATP generation?

A

Phosphocreatine

Once inside cell becomes phosphorylated

Anaerobically donate a phosphorus to ADP forming ATP

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6
Q

How can metabolism be measured?

A

MRS

NIS

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7
Q

What is MRS?

A

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

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8
Q

What did MRS show in terms of pCR?

A

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)

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9
Q

How long does it take following ischemia does it take for metabolism to return to normal?

A

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

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10
Q

What does NIS measure?

A

Near inferred light into the brain, measures output = can measure various protein states

i.e Cytochrome oxidase and electron acceptance and state

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11
Q

What is the function of cytochrome oxidase?

A

cytochrome oxidase: terminal electron acceptor of mitochondrial electron transport 

Near-infrared light shows change in redox state of CytOxcopper A core

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12
Q

What did NIS show for preterm fetal sheep asphyxia in terms of Hb?

A

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)
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13
Q

What do the studies of fetal sheep tell us?

A

During ischemia:Failure of oxidative metabolism

No electrons on the electron transport chain

Depletion of phosphocreatine

Depletion of ATP

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14
Q

What does loss of ATP lead to?

A

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

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15
Q

What is anoxic depolarisation?

A

Neurons depolarise due to hypoxia

Release glutamate at synaptic cleft

Followed by hyperpolarization

Trigger neighbouring neurons to depolarize

Waves of spreading depression

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16
Q

What is anoxic depolarisation accompanied by?

A

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

17
Q

What does impedance measure?

A

It is an indicator of cell swelling.

Impedance: resistance to the f low of current through the extracellular space

18
Q

What happens to impedance as cells swell?

A

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

19
Q

What is the idea of excitotoxicity?

A

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

20
Q

Do they think that excitotoxicity is really a problem?

A

Glutamate excitotoxicity is a symptom instead of propagatory problem

21
Q

What did Microdialysis in near-term fetal sheep during bilateral carotid artery occlusion find?

A
  • 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

22
Q

What happened to the excitotoxicity index during ischemia?

A

Excitotoxicityindex = (GLU x GLY)/GABA

3 –fold reduction!!!!!!

23
Q

What happens in the adult brain in terms of excitotoxicty?

A

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

24
Q

When does necrosis occur?

A

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.

25
Q

What happens after ischemia?

A

Ischemia (primary phase)

Latent Phase (before secondary energy failure)

Secondary Phase

26
Q

What can happens in the latent phase?

A

Reperfusion: restoration of cerebral blood flow

Can result in overproduction of reactive oxygen species (ROS)

Inflammation

Lipid peroxidation (degredation due to oxidation)

Calcium overload

Mitochondrial dysfunction and mitochondrial pore transition

27
Q

What are the cellular sources of free radicles?

A 
Cellular sources of free radicals:
Xanthine oxidase
Cyclooxygenase
Lipoxygenase
Cytochrome P450
Endothelial nitric oxide synthase
NADPH oxidase
28
Q

What are mROS?

A

Superoxide anion (O2-)

H2O2

Hydroxyl radical (OH-)

29
Q

What is normally the function of free radicals?

A

ROS are normally inactivated by endogenous mitochondrial and cytoplasmic scavenging systems

Scavenging systems become overwhelmed after ischemia

30
Q

What happens during ischemia to the free radicals?

A

ROS originating from mitochondrial complex 1 and 3 of the electron transport chain causes oxidative damage to mitochondria –cell damage

31
Q

What does imaging show about latent phase metabolism?

A

Restoration of oxidative metabolism

Return of NTP/eppand PCr/eppseen using 31P MRS

(although time till restoration depends on duration of insult)

32
Q

What does NIRS show about latent phase metabolism?

A

Normalisation of ΔHb, THband Cytoxseen using NIRS in preterm fetal sheep after asphyxia

33
Q

What happens to impedance in the latent phase?

A

Cell swelling (impedance) resolves to near baseline levels in near-term fetal sheep after global cerebral ischaemia

34
Q

What happens to glutamate in the latent phase?

A

Extracellular glutamate returns to baseline levels

35
Q

What happens in the latent phase?

A

Metabolism, cell swelling and excitotoxicityare resolving -things appear to be improving!

However, key pathways are being triggered which lead to large-scale cell death in the secondary phase

36
Q

Summerise the lecture;

A

Summary

Acute mechanisms of injury

  • mitochondrial failure leading to ATP depletion
  • loss of control of membrane pumps
  • influx of sodium and calcium into cells
  • Cell swelling necrosis
  • Reperfusion can trigger in lammation and oxidative stress

Only a small proportion of cells die in acute period

How do these acute mechanisms lead to delayed cell death?

Medsci 317 (32 decks)

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