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Medsci 317 > Lecture 26; Ischemic Brain injury 3 > Flashcards

Lecture 26; Ischemic Brain injury 3 Flashcards

1
Q

Describe the stages of ischemic injury;

*** Revisit slide 1

A

Hypoxia-ischemia

- Primary Injury
(Reperfusion)
- Latent Phase (~6hrs)
Secondary Phase 6-72hrs
Tertiary Phase (days-months)

= Brain Injury

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2
Q

Whats the reality of the primary phase injury?

A

Only very few cells actually die

Bulk cell death in secondary phase due to incapacity to generate ATP

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3
Q

What happens in the secondary phase of injury?

A

12-72 h after ischemia

Bulk cell death 

Seizures

Secondary cell swelling

Secondary energy failure (in the presence of normal oxygen and glucose supply)

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4
Q

Describe what happens to cytochrome oxidase over time;

*** look at the graphs for her three lectures to understand

A
  • Primary phase = Increase in Cyt C becomes oxidised
  • Secondary phase (delayed loss) = Drop off of cytox b/c loss of mitochondrial function due to damage and cyt.c is pushed out of the mitochondria (partially responsible for secondary energy failure) as part of apoptotic signalling.
  • Sham control demonstrates mitochondrial circadian rhythm with increased activity at night.

Note*** Delayed mitochondrial failure after asphyxia in fetal sheep

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5
Q

What else happens after ischemia?

A

Delayed seizures and secondary cell swelling after ischemia

During this time there is also secondary cytotoxic edema.

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6
Q

Describe the EEG for ischemia evolving injury;

A

Ischemia ; Rapid depression of EEG activity as brain shuts down to save energy

Latent phase; remains depressed

Secondary phase; Increased activity, reflecting seizures (high amp, evolving nature) (also secondary cytotoxic edema as measured by impedence)

Fetus age and injury length dependant

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7
Q

What are the signals of ischemic brain injury?

A 
Apoptotic signals
Connexin hemichannel opening
ATP
Glutamate
Inflammation
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8
Q

What is ATP release from cells a signal of death/disruption/ a problem?

A

ATP released from cells is highly toxic and can potentiate inflammation and neighboring cell death

Glutamate- reflects cells undergoing anoxic depolarisaiton

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9
Q

Describe apoptosis in relation to ischemia;

A

Balance between pro and anti-apoptotic signals

  • Increased apoptotic molecules through latent and secondary phase contributing to bulk cell death
  • Cyt C released post mitochondrial injury, signals apoptosis and it is elevated for 24hrs
  • Caspase 8 (present early) - progressive increase
  • Caspase 3 (final executive signal) only triggered (activated) during secondary phase there pro-apoptotic signals triggered early and build up over time to this

= cells probably dont die via apoptosis early on and this means theres a window (latent phase) for intervention

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10
Q

Describe apoptotic morphology;

A
  • Blebbing of the cell membrane
  • Cell shrinkage
  • Nuclear fragmentation
  • Chromatin condensation
  • Chromosomal DNA fragmentation
  • mRNA decay
  • Mitochondrial function preserved during apoptosis
  • Energy Dependant process (therefore mitochondria are preserved)
  • Programmed cell death
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11
Q

Is it true that primary phase = necrosis, secondary phase = apoptosis?

A

Its a continuum!!!!!

  • Clear apoptosis
  • Continuum
  • Clear necrosis

A lot of it is mixed morphology.

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12
Q

What is the apoptosis necrosis continuum?

A

6 things for continuum;

  • Partial activation of the caspase cascade
  • Intermediate forms of cell degradation
  • Incomplete packaging of nuclear and cytoplasmic contents
  • Impaired trafficking of mitochondria to axons
  • Loss of mitochondrial structural integrity and function
  • Loss of cytochrome C activity
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13
Q

Describe the cellular appearance of a necrotic cell;

A
  • Translucent cytoplasm
  • disbursed and minimal chromatin condensation
  • intact nuclear membrane
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14
Q

Describe the cellular appearance of a continuum cell;

A
  • Incomplete packaging of nuclear and cytoplasmic contents
  • Partially condense cytoplasm within intact cell membrane
  • Variably swollen and disrupted mitochondria and vacuolated cytoplasm
  • Irregularly condensed chromatin
  • At least partial segregation of nuclear and cytoplasmic contents
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15
Q

Describe the cellular appearance of a apoptosis cell;

A
  • Intact cell membrane
  • Dense cytoplasm
  • Highly organised chromatin condensation
  • Complete loss of nuclear membrane
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16
Q

What controls the mode of cell death?

A

Severity of the insult

The maturity of the cell type injured

The glutamate receptor subtypes stimulated
The degree of cellular calcium overload

Mitochondrial dysfunction
Depletion of cellular energy supply

17
Q

What leads to mitochondrial dysfunction?

A

Injured by reactive oxygen species

High intracellular Ca2+

Loss of membrane potential

Leads to loss of species through Mitochondrial permeability transition pore (MPTP)

  • outer membrane rupture
  • H loss (intermembrane space)
  • Cyt c exits and activated procaspase 9
18
Q

What happens in the MPTP in secondary energy failure?

A

Protons and other molecules move across the outer mitochondrial membrane

Disrupt the electrochemical gradient

Disrupts the electron transport chain

Stops ATP production

Mitochondrial become permeable to molecules <1.5kDaCa2+ release damage neighbouring mitochondria

Mitochondrial swelling

Rupture of the outer mitochondrial membrane

Release of cytochrome C

Triggers apoptosis

19
Q

What happens during brian injury that allows inflammation?

A

Breakdown of the blood-brain barrier

Macrophage infiltration

Microglial activation

Cytokine release

20
Q

During injuryu what happens when microglia become activated?

A

Normally microglia are inhibited by neurons as surveillance cells.

But during they can become activated and form M1, M1/M2 and M2 phenotypes

21
Q

Describe the different microglia phenotypes;

A 
M1 = Profinflam
M2 = Anti-inflam

Phenotypic continuum of course

M1-M2 classificationM1 (classical): pro-inf lammatory microglia

M2a (alternative)

M2b (type II)

M2C (deactivated)

M2 microglia: involvement in Type II responses, immunoregulation and tissue remodelling

22
Q

What is astrocyte function?

A

Maintain homeostasis

Glutamate uptake and recycling

H+ uptakeK+ uptake and redistribution

Tripartite synapse

Astrocytic syncytium coupled by gap junctions

Important role in healthy tissue and after injury

23
Q

What is the astrocyte response to injury?

A

Activation

Proliferation

Hypertrophy

May form glial scars after stroke and spinal cord injury

Exacerbate inflammatory response

24
Q

What are connexin hemichannels?

A

1/2 gap junctions

  • These can open under normal conditions allowing molecules to move freely from the cyotplasm i.e water, ca, glutamate
25
Q

What happens to the connexin hemichannels in stroke?

A
  • Open up esp. in stroke ischemic inflammation
  • Cytokines open these
  • Abnormal cell function
26
Q

What did they find in studies that blocked the hemi channels?

A

Blocking hemichannelsfrom 90 min after ischemia improved recovery of brain activity, reduced seizures, reduced cell death

•Continuing blockade for 25 hour was better than one hour

27
Q

What did the follow up study of the hemichannels show?

A

In a follow-up study, I showed Connexin hemichannelscontribute to spread of injury in first three hours after ischemia

Release glutamate

Release ATP

Cell swelling

Seizure activity

28
Q

What is the role of ATP in signalling?

A

Acts as a signalling molecule

P2X ionotropicand P2Y metabatropicreceptors

Stimulate microglial activation and inflammation

29
Q

Summerise the latent phase;

A

Restoration of oxidative metabolism 
Resolution of cell swelling 
Resolution of extracellular glutamate concentration
Activation of cell death pathways (Bax, Caspase-9)
Connexin hemichannel opening
ATP releaseInf lammation -cytokines
Blood brain barrier breakdown

30
Q

Summerise the secondary phase;

A

Seizures
Cell swelling
Cell death via apoptosis, necrosis and the apoptotic necrotic continuum
Secondary energy failure 
Mitochondrial permeability transition pore
Mitochondrial collapse Inflammation -microglia and astrocytes

31
Q

Does injury end after the secondary phase?

A

Long-term inf lammation
Ongoing cell death
Loss of trophic support
Impaired connectivity

32
Q

What to study?

A

What is focal/global brain ischemia?
What is the pattern of injury evolution after focal brain ischemia?
How does the injury spread in the penumbra?
Describe the phases of injury in global brain ischemia
Mechanisms of injury during the primary, latent and secondary phase/ what happens

learn esp about hemi channels as her area

Medsci 317 (32 decks)

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