Stroke Flashcards
Stroke
An acute focal injury by a vascular cause; including cerebral infarction, intracerebral haemorrhage + a subarachnoid haemorrhage
Types of strokes + incidences
Ischaemic stroke - a clot occluding the artery ~ 85%
Intracerebral haemorrhage - bleeding within the brain ~ 10%
Subarachnoid haemorrhage - bleeding around the brain ~ 5%
*** important to distinguish the difference for treatments!
Haemorrhagic strokes = caused by a burst or leaking blood vessel
- Due to an aneurysm on a weakened blood vessel; ruptured aneurysm = caused bleeding
- Or due to an AVM (arteriovenous malformation); cluster of abnormal blood vessels
- Other common causes: HPB, trauma
Identify:
- Use CT/MRI scan to identify where the bleeding is
Symptoms of a stroke
Left-side stroke
- Paralysis on right-hand side
- Speech-language deficits (Wernicke’s/Broca’s area)
- Slow, cautious behavioural style
- Memory deficits
Right-hand stroke
- Paralysis on left-hand side
- Spatial-perceptual deficits
- Quick, impulsive behavioural style
- Memory deficits
Stroke pathology timeline
Minutes/hours = fast onset of symptoms; unlikely rescue of core = necrosis
Hours/days; early intervention = protect penumbra damage (necrosis + apoptosis)
Days/weeks = debris clearance + astrocytic scar formation; apoptosis + inflammation
Months/years = tissue lost due to brain capacity - healthy cortical regions can take over function
ie. Learn to rewalk
6 hours = no visible macroscopic changes
2 days = immune infiltration through BBB
- Through a compromised BBB; due to activation of astrocytes which causes a down-regulation of the tight junction proteins (connexin hemichannels)
2 weeks = apoptosis, macrophages, liquefactive necrosis
4 weeks = gliosis, astrocytic scars, loss of structure
- Glial scar = astrocytes which surround the lesion core + walls of intact neurones; induce the infiltration of immune cells + inflammatory factors (increase EC deposition) which inhibit axonal regeneration, impede recovery + cause neurological complications
Why do cells die?
Core = necrosis due to inhibition of metabolism
Penumbra = apoptosis + necrosis
- Excitotoxicity
- DNA oxidative damage (oxidative radicals = increase GluA3 translation)
- Increased free radicals (hippocampus = increased Team Tac GEF = increased free radical production)
- Dendritic death
*** hippocampus more vulnerable than the cortex!
*** FSC231 = block PDZ domain on PICK1; reduced GluA2 internalisation to reduce Ca-permeability of synapses therefore reduce excitoxicity
SCB:
- down-regulation of ADAR2
- increased translation of REST = Repressor Element Silencing TF (repress GluA2 translation)
- Hippocampus: increased PICK1-GluA2-mediated internalisation
TIAs
Transient Ischaemic Attack
- Similar symptoms but transient; < 1 hour
- Temporary blood blockage through the brain
- Does not lead to permanent brain damage
Neuronal degeneration
Dissipation of ionic gradients - due to Na-K-ATPase failure
- EAAT1/2 reversal
AND
- b-interleukin down-regulates EAAT1/2
Increase EC [glutamate]
- Decrease in glutamine synthethase translation
- Cytokines increase in VGSC expression = increase excitability = increase glutamate release
- Interleukins down-regulates EAAT1/2
Excitoxicity occurs
Blood brain barrier dysfunction = due to activated astrocytes producing a down-regulation of the tight junction proteins
- Increased leukocyte transmigration
- Activated P2X4-microglial = release BDNF - cause hyperexcitability of neurones via collapsing Cl- electrochemical gradient
- Activated P2X7-macrophages = release interleukin - down-regulation of EAAT1/2
Prevention + Therapeutics
Prevention:
- Aspirin = blood thinner - secondary prevention (prophylactic for people with high risk for stroke)
- Controlling BP with propanolol
- Preventing atherosclerosis from occurring
Treatment:
- tPA (tissue plasminogen activator) ie. ALTEPLASE = fibrinolytic - breaks down fibrins in the blood to restore blood flow
Early repurfusion < 3 hours
Preclinical:
- FSC231 = PDZ domain inhibitor of PICK1; in vitro + in vivo = reduce excitotoxicity
Clinical trials which failed:
- VGSC inhibitors
- NMDAR/AMPAR antagonists
- Free radical scavengers = either prevent formation or remove before they cause damage
Oxidative stress
Increased free radical production
- DNA oxidative damage
- Lipid perioxidation
- Histone phosphorylation
DNA oxidative damage = increased translation of GluA3 - increase CP-AMPARs @ synapse
Heat Shock Response
Stroke = heat shock factor (HSF) is P and activated
HSF binds to conserved regulatory sequences = heat shock elements - translation of heat shock proteins (HSPs)
HSPs involved in:
- The correct folding of polypeptides
- Modulating protein activity by changing protein conformation and promoting multi-protein complex assembly/disassembly
- Regulating protein degradation (apoptosis) and directing misfolded proteins to proteolysis via the ubiquitin proteolysis system
HSP70
Regulates apoptosis (occurs in the penumbra)
Apoptosome cleaves + activates caspase-3
(Apoptosome = Apaf1, activated caspase-9, cytochrome c)
*** Apaf1 also acts as a NOX = increase free radicals
HSP70:
- Binds to Apaf1 = prevents formation of the apoptosome
- Inhibits activation of caspase-9
- Binds + prevents AIF-induced chromatin condensation (required for apoptosis to occur)
Endogenous mechanism during stroke (VGKCs)
Kv beta1 subunit = N-type inactivation; ball + chain
= transient A current
Ball = cysteine residues - ischaemic conditions, high [oxidative radicals] = oxidase cysteine residues - therefore cannot cause inactivation of the channel
Transient A-current –> DR current
= decrease excitability via a prolonged K+ efflux
HIF-1
HIF-1 = Hypoxia Inducible Factor-1
Normoxia = degraded via proteosomes (hydroxylases) Hypoxia = hydroxylates require ATP, therefore cannot degrade - HIF-1 = activated
HIF-1 binds to regulatory elements of target genes
Target genes involved with:
- Angiogenesis (targets VEGF)
- Proteolysis
- pH regulation
- Apoptosis
- Cell proliferation + survival
Mixed
Enhancement of this gene within ischaemic patients could promote the vessel proliferation needed for oxygenation
BUT
As HIF-1 allows for survival and proliferation of cancerous cells due to its angiogenic properties, inhibition potentially could prevent the spread of cancer
Current Therapies
Reperfusion therapies = prevent expansion of the penumbra
- tPA Alteplase = fibrinogenolyis - restore blood flow via enzymatic breakdown of fibrinogen
< 3 hours - oxidative radicals build up, do not want to spread these (enhance damage)
Thrombectomy = introduce a canula + remove the clot
< 4.5 hours
Prevention
Statins = reduce cholesterol biosynthesis
Endarterectomy = restore lumen of the intracaratoid artery
