Lecture 26: Designing Neuroprotective Treatments For Perinatal Brain Injury

Question 1

4 phases in the evolution of injury

Answer 1

Primary, latency, secondary, tertiary

Question 2

Primary phase/ acute phase injury time course
BPIE

Answer 2

Brain cell swelling (No produce enough ATP, too much Na+ in cell, water attracted)

Primary cell loss

Increased glutamate release

EEG suppression -> brain adaptive response to remove less important processes (EEG rapidly shutdown)

Question 3

Latent phase injury time course
BEGO

Answer 3

Brain cell swelling settled

EEG power stays subdued

Glutamate conc -> return baseline

Oxidative metabolism restored towards normal

Question 4

Secondary phase injury time course
SOSGC

Answer 4

Secondary cell swelling

Oxidative metabolism collapse

Seizures

Glutamate release

Cell death

Question 5

Tertiary phase/ long term recovery injury time course
DRTS

Answer 5

Delayed cell death

Reduced EEG power & frequency

Tropic support loss

Sleep state cycling loss

Question 6

How can the evolution of injury be prevented

Answer 6

Therapeutic cooling

Question 7

Describe how therapeutic hypothermia can be utilised to treat a term neonate from hypoxia-ischaemia

Answer 7

1. Cool cap around head / cool blanket around body
2. Induce mild hypothermia (brain temperature : 32° - 34°)
3. During latent phase (~ 6hrs )
4. Lasts for 72 hours

Question 8

What has hypothermia shown?
LENS

Answer 8

Low neuronal loss

EEG improvement -> normal brain activity function

No 2° cell swelling

Seizure reduction

Question 9

What phase is important for the treatment of hypoxia-ischemia

Answer 9

Latent phase - therapeutic window of opportunity

Question 10

Describe the sequence of events that occurs during the latent phase
Right Over England Can Rachel Call Arrthy

Answer 10

Reperfusion injury -> Oxygen free radicals -> EEG activity suppression through microseizures -> cerebral hypoperfusion -> restored oxidative metabolism -> cell swelling restored -> apoptosis signals induced

Question 11

What can reperfusion injury lead to and what does that in turn result in

Answer 11

ROS overproduction

Lipid peroxidation, inflammation, calcium overload, mitochondrial dysfunction & pore transition

Question 12

How are ROS/free radicals triggered

Where do ROS originate from

What does ROS do

Answer 12

Ischemia overwhelms scavenging systems (endogenous mitochondrial & cytoplasmic) that usually inactivate ROS

Mitochondrial electron transport chain complex 1 & 3

Oxidative damage to mitochondria (cell damage)

Question 13

Describe latent phase hypoperfusion after insult

Answer 13

Common response (post-asphyxiai hypoperfusion)

Matches with suppressed EEG to protect brain which is then increased

CBF decreased -> active vasoconstriction

BP, oxygenation -> normal

Question 14

Latent phase : EEG suppression & microseizures

Answer 14

EEG activity suppressed

Asphyxia -> spikes : microseizures orchestrated by glutamate, trigger cell injury

EEG blocked by NMDA receptor inhibitors reduced brain injury

Question 15

Glutamate excitotoxicity in latent phase

Answer 15

During insult: energy deficit -> glutamate transporters failure -> extracellular glutamate accumulate & excessive glutamate receptor activation

After insult: normal glutamate levels from normal cerebral energy but glutamate receptors hypersensitive

Hyperactive NMDA receptors (microseizures) activity rather than extracellular glutamate that have returned to baseline -> stimulate high intracellular Ca2+ levels triggering cell death

Question 16

Latent phase: metabolism

Answer 16

ATP production and oxidative metabolism restored

ATP-dependent pumps control

Na+ & Ca2+ ions removed from cells

Question 17

Latent phase: cell swelling

Answer 17

Comes back to near baseline level

Question 18

Latent phase: Apoptosis pathways up regulation

Answer 18

Activated but apoptosis occurs in 2° phase

Lead to Caspase 3 activated in 2° phase

Question 19

What happens in the secondary phase

Answer 19

2° failure of oxidative metabolism even though engoue oxygen

Big seizures

Hyperaemia (Increased CBF & volume)

2° edema

Apoptosis

Question 20

What drives energy failure in secondary phase?

What drives energy failure during hypoxia-ischaemia?

Answer 20

Electron transport chain deficit despite normal oxygenation and blood flow

• mitochondrial failure (eg. external pore insertion)

Glucose & oxygen deficit -> oxidative metabolism failure

Question 21

Secondary phase EEG & seizures and treatments

Answer 21

Increase EEG power due to large brain seizures onset due to cell death

Question 22

Secondary phase edema with seizures

Answer 22

Recovers during latent phase

Increase during 2° phase (2° energy failure & cell membrane potential loss)

Question 23

What other injuries can be caused

Answer 23

Tertiary phase of injury

Long term inflammation

Trophic loss support

Ongoing cell death

Impaired connectivity -> affect signaling pathways -> affect brain function