Stroke and excitotoxicity Flashcards
1
Q
What is ischaemia
A
- Ischaemia is a restriction in blood supply to tissues, causing a shortage of oxygen that is needed for cellular metabolism
2
Q
What happens in an ischaemic (or thrombotic) stroke
A
- Blocked vessels
- incidence 85%
- Lower mortality
- thrombotic -internal- large or small vessels
- embolic - external - air, fat introduced into blood vessels
3
Q
What happens in a Haemorrhagic stroke
A
- Ruptured vessels
- Incidence 15%
- Higher mortality
- Intracerebral- blood vessels in brain
- Subarachnoid- around outside
4
Q
What happens to damage after stroke
A
- Spread of damage after stroke
2. Damage spreads outwards from core
5
Q
What is the primary cause of cell death in stroke
A
- excitotoxicity
- Excessive release of glutamate
- Neurones “excited to death”
- Ca2+ overload
- Also, Alzheimer’s, Parkinson’s, Huntington’s, amyotrophic lateral sclerosis (aka motor neurone disease/ Lou Gehrig disease)
6
Q
Describe Excitotoxic mechanisms - stage 1
A
- Glutamatergic synapse
- During ischaemia there is lack of O2 and glucose
- Not enough ATP - cell can’t respire
- Na/K ATPase pump stops working
- Lose imbalance of ionic concentrations- become balanced
- Causes resting membrane to change
- Activation of lots of ion channels
- Voltage gated calcium channel
- Release neurotransmitter and glutamate
- Calcium influx build up in post synaptic neuron
7
Q
Describe Excitotoxic mechanisms – stage 2
A
- Glutamate released excessively as membrane is depolarised
- Activate AMPAr and NMDAr receptors
- AMPAr are sodium permeable and depolarise in post synaptic cell
- Can activate and open VGSC
- Relieves voltage dependent magnesium blocked of NMDAr
- Allows them to signal through there – they are calcium permeable
- Activate VGCC
- More calcium through cell
- Na-Ca exchanger
- Pumps sodium out and calcium in
- Process continues
8
Q
What does Ca2+ do
A
- Ca2+ is important signalling molecule and activates
- Proteases, Lipases, Caspases
- Activate for cancer therapy as induce cell death
- But cause neuronal cell death
- Free radicals
- All lead to membrane and cytoskeletal damage
9
Q
What is Peri-infarct depolarisation
A
- Neurones in core never repolarise -death by necrosis
- Neurones in penumbra repolarise
- repolarisation uses energy (ATP) - energy depletion - depolarisation
- Repeated cycle lasting 6-8 hours
- More excitotoxic death
10
Q
What are some treatments for stroke
A
- Tissue plasminogen activator (tPA) only licensed treatment
- Neuroprotective agents?- often impossible to deal with side effects
- Neuroregeneration? Eg. stem cells
11
Q
What does tPA do
A
- restores blood flow - disperses thrombus
- within 3 hours
- only for ischaemic (thrombotic) stroke
12
Q
What are some Neuroprotective agents that may be used
A
- AMPA/NMDA receptor blockers
- glutamate release blockers
- Na+/Ca2+ blockers
- free radical scavengers
- protease inhibitors
- caspase inhibitors
13
Q
How can you Reduce risk of future strokes
A
- Antihypertensives (eg. ACE inhibitors) – ischaemic and haemorrhagic
- Statins - cholesterol reduction – ischaemic [possible contraindication in haemorrhagic though evidence is scant]
- Antiplatelet drugs (eg. aspirin, clopidogrel) – ischaemic only
- Anticoagulants (eg. warfarin) – ischaemic only
- Stockings?- compression – higher compression further down, help to push blood back up to heart
- Prevents deep vein thrombosis
- Limited evidence that it works with strokes - Obesity, Lack of exercise, Smoking, Alcohol
14
Q
What are TIAs
A
- Transient ischaemic attacks (TIAs) -short-lived neurological signs (aka ‘ministroke’). Initial symptoms identical to stroke
- > 25% of people who have had a stroke have previously had a TIA
- Put on preventative measures to prevent risk of stroke
15
Q
What are other examples of excitotoxicity
A
- Other disease states (eg. Alzheimer’s, Parkinson’s, motor neurone disease)
- Food-induced excitotoxicity
- Amnesic shellfish poisoning
- Neurolathyrism
- Guam disease
