Cerebral Ischaemia and Pathogenic Mechanisms Flashcards
What is the best method to improve stroke outcome?
Rapid intervention
Current treatments for cerebral ischaemic stroke
tpA, mechanical thrombectomy, aspirin, antiplatelets
Stroke prophylaxis examples?
statins, ACE inhibitors, antiplatelets, antihypertensives
Difference between ischaemic core and ischaemic penumbra?
Ischaemic Core: area supplied by MCA which experiences cell death
Ischaemic Penumbra: area that surrounds ischaemic core]- where tissue viability may be sustained (<22ml/100g/min)
What is the metabolic outcome of reduced blood flow on the brain
[as we approach <22ml/100g/min]
- Decreased ATP
- Decreased glucose utilisation
- Decreased protein synthesis
- Increased water content (oedema)
- Increased Na+ & K+
Outcome of administering thrombolysis within 1 hour of stroke?
Damage confined to core region, penumbra is spared
[the amount spared decreases until 3 hours, where damage is too great]
Stroke outcomes from energy failure?
reduced blood flow-> ATP reduced -> Na+ pump fails (ion gradient)-> membrane potential NOT maintained -> elevated extracellular glutamate (GLU) -> GLU transporters inactivated (energy dependent)-> acidosis -> Na+ and Cl- entry accompanied w/ H20 -> oedema
Effect of reduced blood flow on neurotransmitters
Glutamate, GABA and Adenosine leak into the extracellular space]- i.e. levels increase
Effect of increased glutamate in stroke
Activate receptors: AMPA (-> Na+ influx) and NMDA (-> Na+ & Ca2+ influx)
Describe how stroke causes excitotoxicity?
[increased Na+ and Ca2+ from AMPA+NMDA]
Na+ -> cell swelling & potassium loss -> peri-infarct depolarisation
Ca2+ -> XDH, PLA2. NOS, proteases&nucleases [all of these are calcium-dependent]
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XDH, PLA2-> increased free radicals -> loss of membrane integrity
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NOS->NO-> increased free radicals -> loss of membrane integrity
Ca2+ -enter mitochondira> leaky mitochondira -> Cyt C release -> apoptosis
Describe 3 species of nitric oxide synthase (NOS)
nNOS/neuronal NOS: retrograde messenger-> toxic levels of NO free radicals ->neuronal lesion
eNOS/ endothelial NOS: vasodilator -> improves cerebral blood flow
iNOS/ inducible NOS: immune mediator -> toxic effects enhanced in ischaemia
Importance of endogenous antioxidants and free radical scavengers?
Can counterract the effects of superoxides
Helps in ischaemic period and in reperfusion when tissue is exposed to high oxygen levels
Examples of endogenous antioxidants and free radical scavengers?
Endogenous: Superoxide dismutase, catalase, glutathione peroxidase
Explain NMDA receptor mediated neurotoxicity
for a severe insult
SEVERE INSULT [in core]
Ca2+ entry -> Ca2+ uptake into mitochondria -> free radical generation -> severe ATP depletion -> mitochondrial swelling -> necrosis
Explain NMDA receptor mediated neurotoxicity
for a mild insult
MILD INSULT [penumbra]
transient depolarisation -> reduced ATP levels -> Ca2+ loaded mitochondria -> Cyt c release from mitochondria -> apoptosis
Experimental evidence of NMDA’s role in stroke?
- KO of NR2A decreases infarct size
- signal interruption using 2B subunit antibody that affects PSD95 interaction reduces ischaemic damage
- NR1 antibody given 4 hrs after MCAO reduces infarct size from 25%->15%
Experimental evidence of AMPA’s role in stroke?
GluR2 antisense KO increases injury- AMPA receptor more Ca2+ permeable
Where are the target sites of NMDA receptor antagonists
Targets:
- glutamate binding site
- coagulous binding site
- polyamine site
NMDA and AMPA antagonists pros and cons summary
Highly effective up to 2 hours after insult but have psychomimetic (NMDA) and respiratory depressive propertiesq
Describe the ischaemic cascade in response to glutamate
NMDA receptor causing Ca2+ entry -> CAMKIV (CAM kinase IV) -> phosphorylation of CREB -? CREB/CREB binding protein (CBP_ complex activates transcription facotrs and neurotrophic factors -> cell survival OR death (depends on t. factors)
Penumbra response to peri-infarct depolarisation by potassium and glutamate
Upregulated injury response genes (c-jun, ATF3, heat shock proteins- HSPs) -> these all extend the area of infarct
[these are sensitive to glutamate antagonists]
List participants of the transcriptional cascade activated by glutamate
inducible transcription factors (IEGs)
enzymes e.g. COX-2
neuroprotective proteins (HSPs)
Is chronic treatment w/ COX-2 inhibitors a viable stroke treatment?
NO
Although they lack gastric toxicity, they reduce prostacyclin (vasodilator) and lack COX-1 anti thrombotic effects, which potentiates CVS events
What are heat shock proteins (HSPs)?
Act as protein chaperones that facilitate protein transfer between subcellular compartments
Induced following a noxious stimulus (ischaemia), they target abormal proteins for degradation
They are anti-apoptotic and anti-oxidant
Effect of increasing expression of heat shock proteins (HSPs)?
Reduces infarct size (shown in HSP70 and HSP27)
NB: HSPs can be induced through NSAIDS
Describe HSPs and ischaemic preconditioning (IPC)
IPC is where brief ischaemia provides protection against subsequent, prolonged ischaemia]- shown in cardiac and cerebral iscaemia
[meditated through the NF-kB pathway]
can promote neuronal survival and reduce infarct size
Describe the process of inflammation brought about by stroke
Brain parenchyma entered by
- neutrophils, then lymphocytes and macrophages
- iNOS elevated
[allowed by disruption of BBB]
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Inflammatory mediators (TNF alpha, PAF, IL-beta, adhesion molecules, ICAM-1, p & e selectins)
Effect of IL-1 and TNF-alpha in stroke
Upregulation of adhesion molecules -> neutrophil migration
Relevance of CSF levels of IL-1, IL-6 and TNF-alpha
Correlate w/ infarct size
Relevance of chemokines (CINC, MCP-1) ]- produced several hours following ischaemia
Attract neutrophils and infiltration
Relevance of apoptosis in stroke
Delayed cell death in penumbra
Triggered by free radicals, death receptor, DNA damage, proteases, ion imbalance
Cyt-C release from mitochondira -> apoptosome formation (APAF1 + procaspase 9) and caspase 3 activation -> DNA fragmentation
Stroke treatment targeting apoptosis pathway?
Caspase 3 inhibitors (zDEVD, FMK)]- effective up to 9hrs after reversible ischaemia
Broad specificity caspase inhibitors (zVAD)/caspase 1 deletion protects against ischaemia
Stroke and late stage repair
Growth factors secreted by neurons, astrocytes, microglia..etc
Glutamate-mediated synaptic activity increases BDNF transcription and secretion
Neuronal spouting occurs in an attempt to form contacts
Blood flow restoration by thrombolysis and thrombectomy outcomes clinically?
Had the greatest impact on salvaging ischaemic brain tissue (needs rapid administration)
intravenous thrombolysis can salvage penumbra if given early; low recanalisation rate
endovascular thrombectomy increases likelihood of salvaging penumbra; half pts with successful recanalisation don’t achieve functional independence
Best time to administer intravenous thrombolysis
3 hours
- associated w/ improved functional outcome
How to reduce the demands of the penumbra, immediately following stroke?
- Fast MAG administered in the field
- early application of neuroprotective drugs
- hypothermia to reduce energy demands of penumbra
- remote ischaemic preconditioning (e.g. limb/sensory stimulation)
- cathodal transcranial direct cortical stimulation to inhibit peri-infarct depolarisation
