Cerebral Ischaemia and Pathogenic Mechanisms: Fundamentals

Question 1

Stroke pathophysiology (cellular level)

Answer 1

Thrombus occludes cerebral artery -minutes> vascular endothelium affected ->astrocyte cell death-> neuronal cell death in cerebral cortex

Question 2

Cellular (pathophysiological) changes that occur in response to stroke?

Answer 2

Cerebral artery: Inflammatory blood cells -> increased perm of vasc endo

Vascular endothelium: adhesion molecules (ICAM, P-selection E); NO relaxation & CBF increase

Inflammation (inflamm cells, cytokines, adhesion molecules), proteases

Question 3

Main events that occur in cerebral ischaemia (and at what time period)?

Answer 3

[stroke]

1. Energy failure (mins)
2. Excitotoxicity (mins)
3. Transcriptional cascade (hours)
4. Inflammation (hours->days)
5. Cell Death (days)
6. Repair (days)

Question 4

Overview of energy failure in stroke?

Answer 4

RMP not maintained -> extracel glutamate

Decreased: ATP, glucose, protein synthesis

Increased: H2O, Na+, K+

Question 5

Overview of excitotoxicity in stroke?

Answer 5

Extracel glutamate -> stimulates AMPA + NMDA -> increased Na+ and Ca2+

Question 6

Effect of increased Na+ and Ca2+ on excitotoxicity?

Answer 6

more intracel Na+ -> pushes K+ out -> peri-infarct depolarisation

more intracel Ca2+ -> activates enzymes (NOS->ROS; proteases-> actin degrad; mitochondria-> apoptosis)

Question 7

Overview of transcription cascade in stroke?

Answer 7

Glutamate activates early response genes:

• CAMKIV-> CREB -> CBP complex -> t. factors -> immediate early genes
• Increased enzymes (e.g. COX 2 -> more prostaglandins)
• HSPs (neuroprotective) to target abnormal proteins for degradation

Question 8

Overview of inflammation in stroke?

Answer 8

BBB disruption -> inflamm cell transmigration (first neutro, then lymp/macro)

Inflammatory mediators (TNF-a and IL-1) -> adhesion molecules

Question 9

Overview of cell death in stroke?

Answer 9

Apoptosis: Cyt C-> apoptosome complex -> pro Cap3 ->Cap3 -> DNA frags

Bcl-2: promotes/prevents mitochond. pore formation for Cyt C release

Question 10

Overview of repair in stroke?

Answer 10

Neurons and glia secrete local growth factors at infarct site

Astrocytes contribute to tissue repair and glial scar

Neuronal sprouting of preserved axons

Glutamate mediated synaptic activity -> increased BDNF

Question 11

Overview of neuroprotective drugs?

Answer 11

• NR1 antibody
• antioxidants
• anti-inflammatories
• anti-apoptotic
• hypothermia
• pre-conditioning