Stroke and Excitotoxity Flashcards
What is a stroke?
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.
Types of stroke
Ischaemic (or thrombotic)
Haemorrhagic
What causes ischaemic strokes?
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
Ischaemic stroke
Everything downstream of the blockage becomes ischaemic.
Incidence is 85%
Lower mortality than haemorrhagic
What causes haemorrhagic strokes?
Ruptured blood vessels
Haemorrhagic stroke
Incidence is 15%
Higher mortality
Intracerebral or Subarachnoid
Intracerebral haemorrhagic stroke
The blood vessel involved is inside the brain or provides blood to the centre of the brain
Subarachnoid haemorrhagic stroke
Blood vessel is below the arachnoid membrane which surrounds the brain
Symptoms of a stroke
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
FAST: what does T stand for?
Time
The first 3 hours are critical.
If you get treatment now you have a good prognosis
What can be seen around the epicentre of a stroke?
Deficits of tissue (necrosis)
When a neuron dies it doesn’t regenerate
How does the damage of a stroke spread?
Starts with structural damage in the epicentre and reduced function in the surrounding areas.
Over time the whole area becomes more structurally damaged
What is the goal of stroke treatment?
To prevent the spread of damage
What is the primary cause of cell death in stroke?
Excitotoxicity
Apoptosis due to high levels of Ca2+
Peri-infarct depolarisation
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
What is the only licenced treatment for a stroke?
Tissue plasminogen activator (tPA)
Tissue plasminogen activator (tPA)
Restores blood flow (disperses thrombus)
Good prognosis with in 3 hours
Only for ischaemic stroke
Neuroprotective agents as stroke treatments
- AMPA/NMDA receptor blockers
- Glutamate release blockers
- Na+/Ca2+ blockers
Drugs to reduce risks of stroke
- Antihypertensives (eg. ACE inhibitors) – ischaemic and haemorrhagic
- Statins - cholesterol reduction – ischaemic
- Antiplatelet drugs (eg. aspirin, clopidogrel) – ischaemic only
- Anticoagulants (eg. warfarin) – ischaemic only
How to reduce risk of stroke
Address lifestyle issues such as obesity, lack of exercise, smoking and alcohol
Transient ischaemic attacks (TIAs)
Short lived neurological signs (ministroke).
The initial symptoms are identical to stroke and are often precursors to a real one
Long term symptoms and recovery of stroke depend on _
Area
Stroke in motor cortex
Responsible for movement
If the right is compromised then there are issues with movement on the left side.
Vice versa
Stroke in Broca’s area
Essential for language production
Broca’s aphasia is the inability to produce language
Stroke in Wernicke’s area
Involved in understanding language
Wernicke’s aphasia can result in speaking absolute nonsense
Recovery from a stroke
Other neurons can learn to take over the functions of damaged areas
Excitotoxicity
- Excessive release of glutamate
- The neurones are “excited to death”
- Ca2+ overload within neurons.
Excitotoxic mechanism stage 1
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
Excitotoxic mechanism stage 2
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++
What does high Ca2+ activate?
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
High levels of Ca2+ =
Apoptosis
Amnesiac shellfish poisoning
Caused by domoic acid - glutamate receptor agonist
Causes excitotoxicity
Neurolathyrism
Glutamate receptor agonist
Causes excitotoxity
Guam disease
Glutamate receptor agonist
Causes excitotoxicity
Symptoms of Motor neurone disease, Alzheimer’s and Parkinson’s
