Stroke Flashcards
What is stroke?
Group of disorders involving haemorrhage or occlusion of brain blood vessels.
World-wide the 3rd leading cause of death → huge world-wide burden (8000 in NZ per year)
More common with older age
What are the main types of stroke?
Ischemic: blockage of blood vessels more common
Haemorrhagic: rupture of blood vessels ass. with smoking
Strokes are mostly focal (loss of blood-supply to particular area of the brain) but can be global (due to cardiac arrest)
What are the risk factors for stroke?
- Diabetes
- Hypertension
- Atherosclerosis (>50% ischemic strokes)
- Genetic Polymorphisms
Describe the differing regions of cell death around the stroke.
When you have a focal ischaemic stroke, nerve cells in the brain region with the greatest blood-flow loss in the core/infarct zone die rapidly by necrosis.
Surrending this infarct is the penumbra, a region where nerve cells die by a slower 24-72hr death via apoptosis.
draw this diagram *pg 151
Why are most stroke therapies focused around the penumbra?
The infarct region dies via necrosis too quickly to be amenable, whereas the penumbra could potentially be saved due to a larger time-limit.
What are the reasons for the delayed apoptitic cell death at the penumbra?
- Massive glutamate (excitatory) release into brain due to saturation of transporters that usually inactivate glutamate
- Influx of intracellular Ca2+ which are toxic to cells
- Free-radical production
- Activation of brain macrophages (microglia) releasing NO, superoxide, cytokines
- Activation of intrinsic apoptotic mechanisms
How is it that excess glutamate can cause that neuronal cell death?
Excitotoxicity Theory= excessive activation of glutamate systems in the brain → nerve cell death.
Saturation of glutamate transporters may be involved.
We know glutamate is functional to everything.
What are the two main classes of Glutamate receptors?
- Ionotropic: (ion channels) AMPA/kainate, NMDA
- Metabotropic: G-protein linked
AMPA receptor
Ligand (glutamate) gated ion channel
Glutamate binds ⇒ Na+ influx ⇒ neuronal depolarisation
Composed of multiple subunits, ‘GluR1-4’.
Receptors with the GluR2 sub-unit pass Na+ but not Ca2+
Receptors with GluR3 (and not GluR2) can carry Ca2+
Ischaemic brain injury causes a down regulation of the GluR2 sub-unit → increased calcium → higher risk of brain damage
Kainate REceptors
Ligand-gated ion channels
Subunits GluR5-7
Glutamate binds ⇒ Na+ influx ⇒ Neuronal depolarisation
NMDA Receptor
Ligand and voltage-gated ion channel.
Lots of binding sites:
- Glutamate
- Glycine-binding site
- PCP site: a drug of abuse ‘angel dust’. Binds inside the channel as a non-competitve antagonist, model of paranoid schizophrenia
Depolarisation (Glutamate + glycine) ⇒ opens channel ⇒ influx of Ca2+ ⇒ depolarisation of neuron (for memory formation)
Mg2+ can also occupy and block the channel, and the only way to get rid of it is to depolarise the channel
Depol ⇒ efflux of Mg2+ (hence voltage dependent gate!)
PCP binds inside channel ⇒ blocks ion flow
Metabotropic (G-protein-linked receptors)
Group I support apoptosis (mGluR1 and 5):
glutumate → IP3/DAG (2nd messanger) → activate phospholipase C + incr. intracellular Ca2+ → APOPTOSIS/ NECROSIS
Group 1 antagonists are neuroprotective
Group II fight apoptosis! (mGluR2 and 3): Gi linked glutamate binds → inhibit adenylate cyclase + inhibition of neurotransmitter release.
Group II agonists at these are neuroprotective in some model system
***see page 153 for flow diagrams!
Re draw the stroke flow diagram page 154
…
How does Calcium actually lead to cell death?
Ca2+ ⇒ nerve cell death ⇒ Activation of Ca2+ sensitive enxymes ⇒ programmed cell death (apoptosis)
This is because intrinsic biochemical pathways are activated ⇒ initiating cleaving capsases ⇒ cell suicide
***these pathways are being hugely investigated as a way to prevent neurodegeneration
A number of studies suggest that ischaemic neuronal cell death is due to new gene expression that causes activation of caspase enzymes. These caspase enzymes cleave substrates leading to cell death.
Caspases are themselvses cleaved into activation, then they cleave target substrates ⇒ neuronal apoptosis
**Caspase 3 in particular
What are some stroke treatments?
- TPA (only pharmacological treatment)
- Hypothermia
- Free radical scavanger
- Anti-inflammatory mediciations
BUT currently NO effective treatment for stroke (every treatment showing success in animals has failed in humans), probably due to a combo of factors.
Why could combination therapy for stroke potentially be better?
Given that nerve cell death after stroke is cause by muliple mechanisms.
eg; you could target the metabotrophic glutamate receptors with an antagonist, but this will block both the apoptotic group 1 and the apoptotic fighting group 2 at the same time!
What is TPA
Tissue plasminogen activator for thrombolysis (make sure the person is ischaemic to resolve the clot, NOT haemorrhagic stroke) but must be given within a few hours post-stroke to have any benefit.
Are Glutamate antagonists effective?
No, every treatment no matter how successful in the models have failed in human.
Activation of synaptic NMDA receptors ⇒ survival
Activation of extrasynaptic NMDA receptors ⇒ neuronal cell death
How are astrocytes related to stroke?
By tying in the idea of “neuroprotection” or as they are calling it, “astroprotection”.
Astrocytes are hugely important brain cells, linking neuronal activity to blood flow and also promoting neuronal survival/
Therefore Astrocytes may be able to treat stroke, in bykeeping the astrocytes alive we can protect the neuro-vascular unit
**similar idea for pericytes and endothelial cells also
