Stroke Pathophysiology

Question 0

TPA side effects

Answer 0

• degrades blood brain barrier, inducing haemorrhage
• cleaves NMDA receptor, giving a knock on effect for glutamate excitotoxicity
• induce inflammation in the brain

Question 1

TPA

Answer 1

Only licensed drug for stroke. Clot busting
Protease which transforms plasminogen into plasmin.
4.5 hours therapeutic window

Question 2

Ischaemic core

Answer 2

DEAD TISSUE
Less than 20% blood flow to central region.
Cant do anything about it - dead in minutes

Question 3

Penumbra

Answer 3

Surrounding tissue around the ischaemic core
20-50% blood flow
Neurones still alive but at threshold of dying
Potential to rescue if quick

Question 4

Killers in the brain

Answer 4

• glutamate
• ions: calcium, sodium
• free radicals: abnorm oxygen molecules eg superoxide

Question 5

Reperfusion

Answer 5

Sudden burst of oxygen due to restoration of blood flow to previously ischaemic area
Caused by lysis or dislodgement of clot
Bad results - free radicals released into brain
- inflammation
- oxidative stress

Question 6

Oxidative stress

Answer 6

Formation of free radicals in brain - nitric oxide which combine to form supraoxynitrate. Hydroxyl radicals

Free radicals induce lipid peroxydation, preotein oxidation and DNA damage
LEADING TO CELL DEATH

Question 7

Apoptosis

Answer 7

Programmed cell death. After cell has undergone a lot of ischaemia
Disruption of mitochondria by Ca2+.
Causes it to release cytochrome C.
This cleaves caspase 9 and 3 to activate them
This leads to PARP cleavage, dna damage and then apoptosis

Question 8

Excitotoxicity

Answer 8

Hypoxia in brain causes Na+/K+ ATPase pump to become dysfunctional as it requires ATP to function
Na+ that enters cell during AP cant be pumped out, causing intracellular depolarisation.
Inward osmotic force causes water to move in - oedema and cell bursts
Swelling can also increase ICP

Question 9

Excitotoxicity - glutamate release

Answer 9

Reduced oxygen causes increased glutamate release.
This causes increased Ca2+ and Na+ influx
This leads to free radical production, proteolysis and eventually apoptosis
Ca2+ stimulates production of TNF and IL-1 and PAF (inflam)

Question 10

Inflammation

Answer 10

Very potent after ischaemia and reperfusion

Heat, redness swelling, pain, loss of function

Question 11

Inflammatory response

Answer 11

Glial cell activation
Oedema
Expression of adhesion molecules
Invasion of immune cells
Synthesis of inflammatory mediators

Question 12

Inflammatory mediators

Answer 12

Cytokines (TNF, IL-1)
Free radicals
Prostaglandins

Question 13

Timescale

Answer 13

First a large peak of excitotoxicity
Then a lesser wave of inflammation
Then much later apoptosis