0910 - Cellular Reactions to Cerebral Ischaemia

Question 1

What are the three broad groups of cerebral ischaemia?

Answer 1

Global cerebral ischaemia - e.g. Cardiac arrest, neonatal birth asphyxia, drowning

Focal cerebral ischaemia - e.g. acute stroke/cerebral hemorrhage
Traumatic brain injury - injury evolves faster and more severely.

Question 2

What are the various patterns of cellular injury?

Answer 2

Immediate cell death - anoxic/traumatic. Salvage not possible (minimum deficit from event).

Delayed cell death - occurs during subsequent days, may be affected by therapy (penumbra, secondary cerebral injury)

Late cell death - Occurs weeks-months later, believed to be apoptosis.

Question 3

FOR EXAM - What is likely the mechanism behind late cell death in humans that cannot be explained by animal data?

Answer 3

Believed to be neuro apoptosis - explains difference between animal data and human data. Cell doesn’t die immediately, but undergoes apoptosis over the next 6 months.

Question 4

What is the cutoff cerebral blood flow for functional impairment and membrane failure?

Answer 4

Impairment - 25mL/100g/min. Can progress to membrane failure if prolonged/severe.

Membrane failure - 10mL/100g/min

Normally averages 50-60mL/100g/min

Question 5

What are the three physical components of an infarct?

Answer 5

Core

Ischaemic penumbra (perfusion/diffusion abnormalities) - vulnerable to damage but potentially salvageable depending on treatment.
Benign oligaemia.

Question 6

How does delayed cell death manifest?

Answer 6

Occurs in penumbra in days after the stroke, with reduced ATP and reduced glucose utilisation.

Mechanisms - peri-infarct depolarisations, excitotoxicity, and inflammation

Question 7

FOR EXAM - How can excitotoxicity lead to cell death?

Answer 7

Perinfarct depolarisation/damage buggers the pumps causes increased Ca++ in presynaptic terminal, leading to unregulated glutamate release (excitatory). This interacts with NMDA and AMPA ionic channels, increasing postsynaptic Ca++ and Na+, causing postsynaptic depolarisation and therefore propagation of excitatory waves. Implication is huge amounts of O2 consumption and potentially damaging cations (e.g. Ca++) where they shouldn’t be. Leading to cell death. Put this across a huge number of cells and you have a huge problem.

Question 8

FOR EXAM - What is the time in which the ischaemic penumbra is vulnerable to secondary neuronal injury?

Answer 8

48-72 hours

Question 9

FOR EXAM - What glutamate receptors are responsible for post-synaptic excitotoxicity in neural ischaemia?

Answer 9

NMDA, AMPA - both ionic

Question 10

FOR EXAM - What causes presynaptic depolarisation in neural ischaemia?

Answer 10

(failure of membrane pumps and exchange mechanism) - ultimately pre and post-synaptic membrane depolarisation across the hypoxic tissue. Failure of APT causes increase in intracellular Ca and Extracellular K. O2 sensitive channels open, causing increase in extracellular K+, leading to depolarisation.

Question 11

FOR EXAM - How does inflammation lead to cellular death?

Answer 11

Neural Nitrus Oxide Synthase - nNOS - increased ROS, damaging membranes, protein, and DNA. This leads to PARP (poly-ADP ribose polymerase) activation, and further oxygen consumption.

Glial cell activation and TNF, IL-1 release, leading to leukocyte-mediated injury

Eicosanoid production and COX-2 induction.

Question 12

FOR EXAM - does Leukocyte/neutrophil mediated injury occur in neural ischaemia?

Answer 12

Yes

Question 13

What are the aims of stroke therapy?

Answer 13

Early restoration of blood flow - global return of spontaneous circulation and focally revascularise ASAP.

Cerebral protection - focus on penumbra. Will be compromised for some time before returning to normality if reperfusion is effective.

Question 14

What are the three strategies of cerebral protection?

Answer 14

Increase cerebral O2 delivery - leave MAP, reduce ICP, leave Cerebral Vascular Resistance, increase Hb O2 sat.

Reduce cerebral O2 demand - Hypothermia and pharmacological (various agents, poor evidence).

Improve cellular integrity - Prophylaxis to prevent seizures, control glucose. Other drugs have some promise (NMDA antagonists, EPO).

Question 15

FOR EXAM - What is the cerebral effect of hypothermia?

Answer 15

Non-pharmacological method of cerebral protection.

Dose dependent reduction in cerebral O2 use. 5% per degree Celsius average, but non-linear curve - maximum benefit is early (37 to 35). Best evidence is in global cerebral ischaemia - prophylactically and as therapy.

“All of these are true except” type question - so learn it!