Cerebral Ischaemia and Pathogenic Mechanisms Flashcards Preview

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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]
XDH, PLA2-> increased free radicals -> loss of membrane integrity
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

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


- 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?


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]
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