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NMH: Module 2 > Cerebral Ischaemia and Pathogenic Mechanisms > Flashcards

Cerebral Ischaemia and Pathogenic Mechanisms Flashcards

1
Q

What is the best method to improve stroke outcome?

A

Rapid intervention

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2
Q

Current treatments for cerebral ischaemic stroke

A

tpA, mechanical thrombectomy, aspirin, antiplatelets

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3
Q

Stroke prophylaxis examples?

A

statins, ACE inhibitors, antiplatelets, antihypertensives

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4
Q

Difference between ischaemic core and ischaemic penumbra?

A

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)

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5
Q

What is the metabolic outcome of reduced blood flow on the brain

A

[as we approach <22ml/100g/min]

  • Decreased ATP
  • Decreased glucose utilisation
  • Decreased protein synthesis
  • Increased water content (oedema)
  • Increased Na+ & K+
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6
Q

Outcome of administering thrombolysis within 1 hour of stroke?

A

Damage confined to core region, penumbra is spared

[the amount spared decreases until 3 hours, where damage is too great]

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7
Q

Stroke outcomes from energy failure?

A

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

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8
Q

Effect of reduced blood flow on neurotransmitters

A

Glutamate, GABA and Adenosine leak into the extracellular space]- i.e. levels increase

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9
Q

Effect of increased glutamate in stroke

A

Activate receptors: AMPA (-> Na+ influx) and NMDA (-> Na+ & Ca2+ influx)

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10
Q

Describe how stroke causes excitotoxicity?

A

[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

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11
Q

Describe 3 species of nitric oxide synthase (NOS)

A

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

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12
Q

Importance of endogenous antioxidants and free radical scavengers?

A

Can counterract the effects of superoxides

Helps in ischaemic period and in reperfusion when tissue is exposed to high oxygen levels

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13
Q

Examples of endogenous antioxidants and free radical scavengers?

A

Endogenous: Superoxide dismutase, catalase, glutathione peroxidase

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14
Q

Explain NMDA receptor mediated neurotoxicity

for a severe insult

A

SEVERE INSULT [in core]
Ca2+ entry -> Ca2+ uptake into mitochondria -> free radical generation -> severe ATP depletion -> mitochondrial swelling -> necrosis

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15
Q

Explain NMDA receptor mediated neurotoxicity

for a mild insult

A

MILD INSULT [penumbra]
transient depolarisation -> reduced ATP levels -> Ca2+ loaded mitochondria -> Cyt c release from mitochondria -> apoptosis

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16
Q

Experimental evidence of NMDA’s role in stroke?

A
  • 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%
17
Q

Experimental evidence of AMPA’s role in stroke?

A

GluR2 antisense KO increases injury- AMPA receptor more Ca2+ permeable

18
Q

Where are the target sites of NMDA receptor antagonists

A

Targets:

  • glutamate binding site
  • coagulous binding site
  • polyamine site
19
Q

NMDA and AMPA antagonists pros and cons summary

A

Highly effective up to 2 hours after insult but have psychomimetic (NMDA) and respiratory depressive propertiesq

20
Q

Describe the ischaemic cascade in response to glutamate

A

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)

21
Q

Penumbra response to peri-infarct depolarisation by potassium and glutamate

A

Upregulated injury response genes (c-jun, ATF3, heat shock proteins- HSPs) -> these all extend the area of infarct

[these are sensitive to glutamate antagonists]

22
Q

List participants of the transcriptional cascade activated by glutamate

A

inducible transcription factors (IEGs)

enzymes e.g. COX-2

neuroprotective proteins (HSPs)

23
Q

Is chronic treatment w/ COX-2 inhibitors a viable stroke treatment?

A

NO

Although they lack gastric toxicity, they reduce prostacyclin (vasodilator) and lack COX-1 anti thrombotic effects, which potentiates CVS events

24
Q

What are heat shock proteins (HSPs)?

A

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

25
Q

Effect of increasing expression of heat shock proteins (HSPs)?

A

Reduces infarct size (shown in HSP70 and HSP27)

NB: HSPs can be induced through NSAIDS

26
Q

Describe HSPs and ischaemic preconditioning (IPC)

A

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

27
Q

Describe the process of inflammation brought about by stroke

A

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)

28
Q

Effect of IL-1 and TNF-alpha in stroke

A

Upregulation of adhesion molecules -> neutrophil migration

29
Q

Relevance of CSF levels of IL-1, IL-6 and TNF-alpha

A

Correlate w/ infarct size

30
Q

Relevance of chemokines (CINC, MCP-1) ]- produced several hours following ischaemia

A

Attract neutrophils and infiltration

31
Q

Relevance of apoptosis in stroke

A

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

32
Q

Stroke treatment targeting apoptosis pathway?

A

Caspase 3 inhibitors (zDEVD, FMK)]- effective up to 9hrs after reversible ischaemia

Broad specificity caspase inhibitors (zVAD)/caspase 1 deletion protects against ischaemia

33
Q

Stroke and late stage repair

A

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

34
Q

Blood flow restoration by thrombolysis and thrombectomy outcomes clinically?

A

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

35
Q

Best time to administer intravenous thrombolysis

A

3 hours

- associated w/ improved functional outcome

36
Q

How to reduce the demands of the penumbra, immediately following stroke?

A
  • 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

NMH: Module 2 (33 decks)

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