Stroke Flashcards
What is stroke?
Group of disorders involving haemorrhage or occlusion of blood brain vessels
Types of stroke
- Haemorrhagic
- Ischaemic
Typically focal but can be global (i.e in cardiac arrest)
Stroke risk factors
Diabetes; hypertension; atherosclerosis; polymorphisms
Schematic of the brain following stroke
The area where the stroke has occured (greatest loss of blood flow) is the core/infarct and die by rapid necrosis.
Area around it where nerve cells have been deprived of some oxygen is the penumbra where cells die slower, typically by apoptosis
What are the potential causes for delayed cell death (penumbra region, thus target area?)
- Glutamate release (massive)
- influx of Ca2+
- Free radicals
- microglia activation
- apoptotic mechanisms
What is the excitotoxicity theory?
excess activation of glutmate systems in the brain causes cell death
What are the glutamate receptors in the brain
1) ionotropic: AMPA;Kainate; NMDA
2) Metabotropic- G protein linked
AMPA receptors
Link to stroke
LGIC
Causes Na+ influx. Has many subunits GluR1-4.If has Glur2 sodium, if 3, Calcium. Injury can cause downregualtion of 2.
Kainate receptors
GluR5-7
LGIC, causes Na+ influx
NMDA receptors
how do they work
role of Mg2+
Is a ligand and voltage gated channel
Depolarisation+ glutamate and glycine bonding opens the channel causes calcium influx, depolarisation.
Mg2+ occupies and blocks channel, however when depolarised, efflux of it. Hence voltage dependent.
What is significant about the PCP binding site on the NMDA receptor?
PCP (angel dust) binds to a sub unit and blocks the channel. making it a (non competitive) antagonist of the NMDA receptor. Typically NMDA antagonists are neuroprotective (stop large influx of calcium)
What are the two types of metabotropic glutmate receptors?
Group 1- mGluR1 and 5: activate phospholipae C, then IP3 and DAG to release calcium from intracellular stores, depolarise. Antagonists are neuroprotective typically.
Group 2- mGluR2 and 3: Gi linked, Inhibit adenylate cyclase and stop NT release. Agonsist can be neuroprotective
Theory on the ions causing harm in stroke and the time associated with the receptors (hypothesis)
Calcium influx, in turn by NMDA receptors responsible for penumbric region woth apoptotic cell death over hours to days. Calcium causes activation of calcium sensitive enzymes then apoptosis e.g. caspase 3
Na+ influx due to AMPA and Kainate receptors will cause the rapid cell death and necrosis at the core/infarct area
What treatments can we use for stroke?
TPA for ischaemic strokes, for thrombolysis. Must be given within a few hours (short time) after stroke to work.
Glutamate antagonists have failed due to complex nature of NMDA receptor.
How can targeting other brain cells be beneficial?
- Astrocytes involved in neuroprotection so may want to target these
- Pericytes and endothelial cells to re-establish blood flow i.e promoting angiogenesis
