Brain Killers
Lecture 20 - Excitable Cells - 27/04/18
STROKE:
- Reduced blood flow and oxygen to the brain
- Third greatest killer
- Causes:
 Brain artery blocks
 Brain artery bleeds
 Poor general circulation
 Heart failure
 Drowning
Low oxygen at birth
- Limited treatment

PRECLINICAL AND CLINICAL STROKE STUDIES:Over 1000 agents have been tested in experimental stroke models
Over 100 have made it to clinical trial
But nearly all of them have failed
There is still no widely effective pharmaceutical treatment for stroke in the clinic
It is considered a high risk area for research companies and is very expensive so it is difficult to take things forward

INFLAMMATION:
- Most of the agents that have been used so far in treating stroke influence neuronal damage - the main one being inflammation
- Inflammation is a normal defence response to infection - Response of immune system to infection
- First defined by Cornelius Celsus (ca. AD25)
- Characterised by the following
 Heat (calor)
 Redness (rubor)
 Swelling (tumor)
 Pain (dolor)
 Loss of function (functio laesa)

INFLAMMATORY MEDIATORS:Glial cell activation (astrocytes, microglia - act as immune cells of the brain)
Oedema
Systemic acute phase response - the classical immune response outside of the brain
Expression of adhesion molecules
Invasion of immune cells - not as extensively as in the rest of the body
Synthesis of inflammatory mediators - cytokines, free radicals, prostaglandins

INFLAMMATORY EVENTS AFTER A STROKE:Occur in waves
In the very early wave there is expression of early genes and proteins, as well as the invasion of immune cells and activation of the brains own immune system
Key to all inflammatory responses is a group of molecules called cytokines

These are not believed to have a role in normal function - therefore are good targets for intervention in disease

CYTOKINES:Small proteins involved in all forms of disease and injury, they are produced by damaged cells and act on the brain by communicating between cells
Include:
 Interleukins - a class of glycoprotein produced by damaged cells or extreme activation by excitatory cells
 Interferons - inhibits virus replication, used to treat MS
 Tumour necrosis factors - produced by cancers and are the main cause of wasting and loss of appetite in cancer
 'Growth' factors - help repair and recoveryGrowth' factors - help repair and recovery
 Chemokines - involved in adhesion

CYTOKINES IN STROKE:Can be produced in the brain
Particularly after brain injury
Microglial cells are a main source
Interleukin-1 particularly important

EFFECTS OF CYTOKINES IN THE BRAIN:

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