Stroke and Excitotoxity

Question 1

What is a stroke?

Answer 1

A stroke is a transient or permanent interruption in the cerebral blood supply.
This has a cardiovascular cause and leads to ischaemia, which is a lack of O2 and glucose.

Question 2

Types of stroke

Answer 2

Ischaemic (or thrombotic)
Haemorrhagic

Question 3

What causes ischaemic strokes?

Answer 3

Blocked vessels
Thrombotic (internal) causes are the most common type and can occur in large or small vessels
Embolic (external) causes are things like air and fat

Question 4

Ischaemic stroke

Answer 4

Everything downstream of the blockage becomes ischaemic.
Incidence is 85%
Lower mortality than haemorrhagic

Question 5

What causes haemorrhagic strokes?

Answer 5

Ruptured blood vessels

Question 6

Haemorrhagic stroke

Answer 6

Incidence is 15%
Higher mortality
Intracerebral or Subarachnoid

Question 7

Intracerebral haemorrhagic stroke

Answer 7

The blood vessel involved is inside the brain or provides blood to the centre of the brain

Question 8

Subarachnoid haemorrhagic stroke

Answer 8

Blood vessel is below the arachnoid membrane which surrounds the brain

Question 9

Symptoms of a stroke

Answer 9

Face - drooping on the side
Arms - loss of feeling or increased weakness on one side
Speech - Difficulty talking or understanding words
Severe headache
Sudden decreased or blurred vision
dizziness or loss of balance

Question 10

FAST: what does T stand for?

Answer 10

Time
The first 3 hours are critical.
If you get treatment now you have a good prognosis

Question 11

What can be seen around the epicentre of a stroke?

Answer 11

Deficits of tissue (necrosis)
When a neuron dies it doesn’t regenerate

Question 12

How does the damage of a stroke spread?

Answer 12

Starts with structural damage in the epicentre and reduced function in the surrounding areas.
Over time the whole area becomes more structurally damaged

Question 13

What is the goal of stroke treatment?

Answer 13

To prevent the spread of damage

Question 14

What is the primary cause of cell death in stroke?

Answer 14

Ecotoxicity
Apoptosis due to high levels of Ca2+

Question 15

Peri-infarct depolarisation

Answer 15

Neurons in the core never depolarise and die by necrosis
Neurons in the penumbra repolarise which uses ATP and depletes stores, causing further depolarisation.
This is a cycle lasting 6-8 hours and resulting in more excitotoxic death

Question 16

What is the only licenced treatment for a stroke?

Answer 16

Tissue plasminogen activator (tPA)

Question 17

Tissue plasminogen activator (tPA)

Answer 17

Restores blood flow (disperses thrombus)
Good prognosis with in 3 hours
Only for ischaemic stroke

Question 18

Neuroprotective agents as stroke treatments

Answer 18

• AMPA/NMDA receptor blockers
• Glutamate release blockers
• Na+/Ca2+ blockers

Question 19

Drugs to reduce risks of stroke

Answer 19

• Antihypertensives (eg. ACE inhibitors) – ischaemic and haemorrhagic
• Statins - cholesterol reduction – ischaemic
• Antiplatelet drugs (eg. aspirin, clopidogrel) – ischaemic only
• Anticoagulants (eg. warfarin) – ischaemic only

Question 20

How to reduce risk of stroke

Answer 20

Address lifestyle issues such as obesity, lack of exercise, smoking and alcohol

Question 21

Transient ischaemic attacks (TIAs)

Answer 21

Short lived neurological signs (ministroke).
The initial symptoms are identical to stroke and are often precursors to a real one

Question 22

Long term symptoms and recovery of stroke depend on _

Answer 22

Area

Question 23

Stroke in motor cortex

Answer 23

Responsible for movement
If the right is compromised then there are issues with movement on the left side.
Vice versa

Question 24

Stroke in Broca’s area

Answer 24

Essential for language production
Broca’s aphasia is the inability to produce language

Question 25

Stroke in Wernicke’s area

Answer 25

Involved in understanding language
Wernicke’s aphasia can result in speaking absolute nonsense

Question 26

Recovery from a stroke

Answer 26

Other neurons can learn to take over the functions of damaged areas

Question 27

Excitotoxicity

Answer 27

• Excessive release of glutamate
• The neurones are “excited to death”
• Ca2+ overload within neurons.

Question 28

Excitotoxic mechanism stage 1

Answer 28

During ischaemia there is a resting potential of roughly + 40 mV
No supply of oxygen and glucose means no ATP
This means that the ATPase pump stops working and depolarises
Depolarising will cause release of glutamate.
Can’t repolarise until pump works again

Question 29

Excitotoxic mechanism stage 2

Answer 29

Glutamate activates Na+ channel which causes depolarisation
The depolarization triggers NMDA receptors and VGCC which also contribute to the depolarization.
NMDA and VGCC will add Ca++ in and some Na+.
If there is too much Na+ in the cell then sodium calcium exchanger will replace some with Ca++

Question 30

What does high Ca2+ activate?

Answer 30

Proteases, lipases and caspases which break down cytoskeletal and intracellular compartments
Here caspases cause apoptosis when it’s not wanted
Free radicals – extremely reactive and destructive

Question 31

High levels of Ca2+ =

Answer 31

Apoptosis

Question 32

Amnesiac shellfish poisoning

Answer 32

Caused by domoic acid - glutamate receptor agonist
Causes excitotoxicity

Question 33

Neurolathyrism

Answer 33

Glutamate receptor agonist
Causes excitotoxity

Question 34

Guam disease

Answer 34

Glutamate receptor agonist
Causes excitotoxicity
Symptoms of Motor neurone disease, Alzheimer’s and Parkinson’s