Lecture 28: stroke

Question 1

Main types of strokes?

Answer 1

Ischemic - blockage of blood vessel (most common)

Haemorhagic - rupture of blood vessel (associated with smoking)

Stroke is mostly focal (loss of blood supply to a particular area of the brain) but can be global (eg. caused by cardiac arrest)

Question 2

Risk factord for stroke?

Answer 2

1. Diabetes
2. Hypertension
3. Athersclerosis (contributes to 50% of ischemic strokes)
4. Genetic polymorphisms

Question 3

Process of neuron cell death in a stroke?

Answer 3

The area of greatest loss of blood flow in focal ischeamia the Core or Infarct zone die rapidly by necrotic cell death.

Arounf this region in an area called the Penumbra cells die slower 24-72h by processess involving apoptosis.

Most therapy is involved with trying to stop this apoptotic cell death as the necrotic cell death is too fast.

Question 4

Causes of necrosis?

Answer 4

cell lysis - swelling and bursting of the cell

Question 5

Causes of delayed cell death (eg in the penumbra region)

Answer 5

1. Massive release of glutamate (saturation of transporter)
2. Influx of intra-cellular calcium ions in cells producing free-radicle
3. Activation of brain macrophages (microglia) releasing NO, superoxide, cytokines
4. Activation of intrinsic apoptotic mechanisms

= Excitotoxicity theory

Question 6

Types of Glutamte receptors?

Answer 6

1. Ionotropic (ion channels) - AMPA/kainate, NMDA
2. Metabotropic - G-protein linked

Question 7

AMPA receptor features, potential clinical relevance?

Answer 7

• They are Ligand-gated ion channels
• Open when glutamate binds causing Na+ influx and neuronal depolarisation
• Composed of multiple sub-units (GluR1-4)
• GluR2 confers Na+ permeability
• GluR3 but no 2 you get a Ca2+ permeability

Therefore because after ischemic brain injury there is seen to be a loss of GluR2 receptors it is thought there is an increase in Ca2+ permeability/flux.

Question 8

Kainate Receptor features

Answer 8

• Ligand-gated ion channel
• Composed of GluR5-7 sub-units
• Na+ flux from glutamate binding causing depolarisation.

Question 9

NMDA receptor features, sites of binding?

Answer 9

• N-methyl-d-aspartate
• Ligand and voltage gated channel (by depolarisation, glutamate and glycine)
• Mg2+ occupies and blocks channel and must be first removed by a depolarisation before glycine and glutamate can bind to provide maximum response.
• PCP site, Glutamate site and Glycine site (co-agonist)

Question 10

Phenylcyclidine effect in NMDA receptor?

Answer 10

• aka Angel dust or PCP
• binds inside the channel and blocks ion flow non-compeditively
• NMDA antagonists are complex but normally neuroprotective.

Question 11

Metabotropic receptors (G-protein linked receptors) groups, features and relevance of agonists/antagonists?

Answer 11

Group I (mGluR1 and 5)

• Activate phospholipase C and depolarise neurons. Group I antagonists are neuroprotective in some model systems

Group II (mGluR2 and 3)

• Gi-linked and inhibit adenylate cyclase and cause inhibition of neurotransmitter release. Agonists at these receptors are neuroprotective in some model systems.

Question 12

Flow chart of what happens after a stroke to cause fast and delayed cell death

Answer 12

Question 13

Treatments for stroke?

Answer 13

TPA (tissue plasminogen activator) for thrombolysis, but must be given within a few hours of stroke for efficacy

Glutamate antagonists, hypothermia, free-radicle scavengers, anti-inflammatory, blockers and caspases ALL have not worked