Flashcards in Cerebral Ischaemia and Pathogenic Mechanisms: Fundamentals Deck (11)
Stroke pathophysiology (cellular level)
Thrombus occludes cerebral artery -minutes> vascular endothelium affected ->astrocyte cell death-> neuronal cell death in cerebral cortex
Cellular (pathophysiological) changes that occur in response to stroke?
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
Main events that occur in cerebral ischaemia (and at what time period)?
1. Energy failure (mins)
2. Excitotoxicity (mins)
3. Transcriptional cascade (hours)
4. Inflammation (hours->days)
5. Cell Death (days)
6. Repair (days)
Overview of energy failure in stroke?
RMP not maintained -> extracel glutamate
Decreased: ATP, glucose, protein synthesis
Increased: H2O, Na+, K+
Overview of excitotoxicity in stroke?
Extracel glutamate -> stimulates AMPA + NMDA -> increased Na+ and Ca2+
Effect of increased Na+ and Ca2+ on excitotoxicity?
more intracel Na+ -> pushes K+ out -> peri-infarct depolarisation
more intracel Ca2+ -> activates enzymes (NOS->ROS; proteases-> actin degrad; mitochondria-> apoptosis)
Overview of transcription cascade in stroke?
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
Overview of inflammation in stroke?
BBB disruption -> inflamm cell transmigration (first neutro, then lymp/macro)
Inflammatory mediators (TNF-a and IL-1) -> adhesion molecules
Overview of cell death in stroke?
Apoptosis: Cyt C-> apoptosome complex -> pro Cap3 ->Cap3 -> DNA frags
Bcl-2: promotes/prevents mitochond. pore formation for Cyt C release
Overview of repair in stroke?
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