Lecture 19 – Strokes Flashcards
Overview:
- 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 treatments
Preclinical & clinical stroke studies:
- Over 1000 agents have been tested in experimental stroke models
- Over 100 have made it to clinical trial
- Still no widely effective pharmaceutical treatment for stroke in the clinic
Recent failures: (high risk disease area – expensive clinical evaluation)
- NXY059 (anti-oxidant spin trap inhibitor)
- Gavestinel (glycine Co-receptor antagonist)
- Cerestat (non-competitive NMDA blocker)
- Selfotel (competitive NMDA blocker)
- Clomethiazole (anti-epileptic; GABA agonist)
- Citicoline (membrane tabilization, reduces free radicals)
- Lubeluzole (Na+ channel blocker)
- Anti-ICAM1 (anti-adhesion molecule)
Inflammation:
¥ Response of immune system to infection ¥ First defined by Cornelius Celsus (ca. AD25) ¥ Characterised by the following Ð Heat (calor) Ð Redness (rubor) Ð Swelling (tumor) Ð Pain (dolor) Ð Loss of function (functio laesa)
Inflammatory mediators:
¥ Glial cell activation (astrocytes, microglia) – scavenge bacteria and kill them, act like macrophages in bone marrow and kill off many inflammatory cells
¥ Oedema - Swelling occurs in the cranium which creates a high pressure, stressing on the brain stem, causing respiration to stop
¥ In haemorrhages, fluid is drained to stop a built up of pressure
¥ Systemic acute phase response – immune system to combat the infection
¥ Expression of adhesion molecules – lead to immune cells that adhere to the brain
¥ Invasion of immune cells – cytokines
¥ Synthesis of inflammatory mediators
Ð cytokines, free radicals, prostaglandins
Cytokines: - don’t readily diffuse into the brain
Small proteins involved in all forms of disease and injury
- INTERLEUKINS, INTERFERONS, TUMOUR NECROSIS FACTORS, “GROWTH” FACTORS, CHEMOKINES
- Produced by damaged cells – activated and can be slightly toxic
- Act on brain – communicate with cells locally (low levels) and act on a small region
- Communication between cells
Cytokines in stroke:
- Can be produced in the brain
- Particularly after brain injury
- Microglial cells are a main source
- Interleukin-1 (IL-1) particularly important
- Cause fevers (high metabolic demand from the brain which can reduce and increase temperatures making the damage worse), weight loss (right)
- When activated in a stroke is bad but otherwise can be good
Interleukin-1 (IL-1):
¥ ‘Master cytokine’
¥ Key inflammatory mediator
¥ Major disease target for therapeutic intervention
¥ Produced rapidly in the brain, particularly after a stroke
¥ Naturally occurring and highly selective antagonist, IL-1Ra to glutamate
- IL-1beta and alpha work on lots of receptors
- R1 antagonist works at the same receptor but blocks signalling and is used to maybe treat patients
- Body produces an antagonists IL-1 can remain for longer as it blocks the IL-1 where it is signalling and periods after as the stroke works locally
- Need gene expression of IL-1 and then an enzyme to cleave IL-1 and then the antagonist to block the actions, such as binding proteins
Middle Cerebral Artery Occlusion:
in rodents filament artery is damaged making it severe
Developing a good drug:
- is it produced in the right place/ time?
- Does increasing the level of the mediator make the effect change
- Does blocking reduce the effects?
Does IL-1 contribute to or limit neuronal injury?
- Expression
- Increasing IL-1
- Inhibition of IL-1
IL-1 mediates brain injury:
¥ Rapid upregulation of IL-1α, IL-1β, IL-1Ra spatial temporal pattern consistent with contribution to injury – cells produced by the brain or CSF
¥ Exogenous or endogenous IL-1 enhances brain injury – strokes causes infections which makes neuronal aspects worse too
¥ Inhibition of IL-1 markedly inhibits injury
IL-1 and ischaemic brain damage
vehicle treated rodents
IL-1Ra reduces stroke damage
antagonists blocks the effects of endogenous
also shown is the transgenic damage
Inflammatory burden and stroke:
reduce inflammation = reduce stroke
- burden increases with age
- if patient is at risk, inflammation can contribute to a stroke and the damage that results from a stroke
Inhibition of IL-1 reduces:
¥ Focal, global, permanent, reversible ischaemia ¥ Traumatic injury ¥ Excitotoxic damage (NMDA, AMPA/KA) ¥ Clinical symptoms of EAE ¥ Heat stroke damage ¥ Epileptic seizures
