Cerebral Ischaemia

Question 1

How did the incidence of stroke change between 1990 and 2010?

Answer 1

It decreased 25%

Question 2

Define cerebral ischaemia

Answer 2

A transient or permanent reduction in cerebral blood flow

Question 3

Give at least 3 ways of improving blood flow in acute ischaemic stroke

Answer 3

Tissue plasminogen activator, mechanical thrombectomy, aspirin, anti-platelet drugs

Question 4

Describe how occlusion causes cell death

Answer 4

Occlusion leads to the activation of adhesion molecules in the vascular endothelium, enhancing the penetration of inflammatory cells into the brain. This is enhanced by release of proteases and cytokines

Question 5

Describe one way in which the vascular endothelium promotes recovery

Answer 5

It releases nitric oxide, which causes vessel relaxation and increases blood flow

Question 6

What is the normal rate of blood flow in the brain?

Answer 6

Above 50ml/100g/min

Question 7

At what perfusion level does olighaemia occur from hypoperfusion?

Answer 7

22-50ml/100g/min

Question 8

What is the perfusion level in the ischaemic penumbra?

Answer 8

10-22ml/100g/min

Question 9

Define the ischaemic penumbra

Answer 9

Tissue at risk of infarction where perfusion is adequate to maintain cell viability but inadequate for normal neuronal function

Question 10

Describe the effects of focal ischaemia on brain metabolism

Answer 10

Decreased ATP, decreased glucose utilisation, decreased protein synthesis, increased cell water content, increased sodium and potassium ion concentration

Question 11

Describe what happens to the affected area within minutes of cerebral ischaemia

Answer 11

Energy failure and excitotoxicity

Question 12

Describe what happens to the affected area within hours of cerebral ischaemia

Answer 12

Induction of immediate early genes

Question 13

Describe the cause and consequences of energy failure

Answer 13

The reduction in blood flow reduces the amount of ATP, causing the sodium-potassium pump to fail and the membrane potential to not be maintained. Energy-dependent glutamate transporters are inactivated, so extracellular glutamate increases, and sodium and chloride ions enter the cell. Water diffuses after the ions, causing oedema

Question 14

How long does it take for glutamate changes to be detected in the blood plasma after a stroke?

Answer 14

6 hours

Question 15

Name 3 neurotransmitters affected by ischaemia

Answer 15

Glutamate, GABA, adenosine

Question 16

Describe the process of excitotoxicity after cerebral ischaemia?

Answer 16

High levels of glutamate interact with AMPA and NMDA receptors on the neuronal surface, leading to sodium and calcium entry and activation of calcium-dependent enzymes like xanthine dehydrogenase and PLA2. This leads to free radical production, loss of cell membrane integrity, and cytochrome c release leading to apoptosis

Question 17

Summarise the consequences of excitotoxicity and calcium overload

Answer 17

1) Actin degradation due to activation of proteolytic enzymes
2) Free radical generation due to activation of COX
3) Nitric oxide generation
4) Mitochondrial dysfunction causing cytochrome c release and triggering apoptosis

Question 18

Name the three substances produced by nitric oxide synthase

Answer 18

1) nNOS - retrograde messenger, leading to toxic levels of NO free radicals
2) eNOS - vasodilator, improves cerebral blood flow
3) iNOS - immune mediator

Question 19

Name at least 3 endogenous antioxidants and free radical scavengers

Answer 19

Superoxide dismutase (SOD), catalase, glutathione peroxidase, alpha-toxopherol, ascorbic acid

Question 20

Describe the effect of iNOS and nNOS knockout on mice

Answer 20

Neuroprotective against stroke

Question 21

Describe the effect of giving exogenous superoxide dismutase to mice

Answer 21

Neuroprotective against stroke

Question 22

How does NMDA receptor mediated toxicity vary with the severity of the insult?

Answer 22

In a mild insult, transient depolarisation occurs with reduced ATP, calcium-ion loaded mitochondria, and cytochrome c release leading to apoptosis. In a severe insult, calcium ions enter and are taken up by the mitochondria, with free radical generation, severe ATP depletion, and mitochondrial swelling leading to necrosis