Acute Brain Injury Flashcards
Describe chronic and acute neurodegeneration.
Chronic - slow onset, progressive. Alzheimer’s, Parkinson’s.
Acute - sudden, secondary progression. Stroke
3 Stroke statistics.
- More common in men, but more women die. 2rd/3rd most common cause of death.
- 1 in 53 people in the UK are stroke survivors.
- Incidence doubles every year after 55.
What are the two types of stroke?
Ischaemic - 85% of all strokes, 30% mortality
Haemorrhagic - 15% of all strokes, 70% mortality
Define iscahemia and ischaemic stroke.
How can it be caused?
Ischaemia = a loss of bloody supply to areas downstream of the clot.
Ischaemic Stroke = disease of the vasculature leading to neurological sequelae.
Atherosclerotic or blood clots. Main vessel affected is the middle cerebral artery.
What is the structure of an ischaemic stroke?
The structural lesion forms around the clot, the areas where neurons are only supplied by blood vessels blocked by the clot. Death
Ischaemic penumbra forms around it, neurons supplied only partly by blocked vessels.
Penumbra decreases as some neurons repair and some die, increasing the structural lesion.
Draw the massive diagram.
Draw
How does endogenous glutamate underly neurodegenration?
Glutamate is release calcium dependently.
Ca2+ release, glutamate release, NMDA receptor activation –> neurotoxicity.
Glutamate receptor antagonists are neuroprotective.
Needed together with hypoxia to induce cell death, they do not work individually.
Why does glutamate accumulate in iscahemia?
Because a large quantity of ATP is required to maintain resting potential, when ATP is lost in ischaemia, cells depolarise. Loss of function of the Na+/Glutamate co-transporter. Glutamate accumulates to toxic levels.
Synthesis and function of free radicals in ischaemic stroke.
Nitric Oxide Example
Natural byproduct of cell metabolism.
Usually regulated by superoxide dismutases (Cu/Zn/Mn SOD). If not regulated, react with many parts of the cell to cause cell death.
Arginine forms NO* mediated by nitric oxide synthase. Reacts with superoxide (O2-) to form Peroxynitrite (*ONOO-).
Blocking NOS = decrease in cell death.
Describe tPA as a treatment for ischaemic stroke and why many drugs have little efficacy in ischaemic stroke treatment.
tPA catalyses the reaction to cause increased cerebral blood flow. 12% of people can take tPA.
Drugs have a limited window of efficacy, needs to be used minutes after formation of core lesions.
Usually too late - therapeutic cutoff, FAST increases chance that drug will be administered in window.
Describe the changes in gene expression following iscahemia.
Immediate transient response of early genes.
HSP protective proteins, stops misfolding.
Cytokines, adhesion molecules and growth factors not usually present in the adult brain.
Tissue remodelling genes.
What is the role of IL-1B?
What is IL-1ra?
Is IL-1B always neurodegenerative and should it be blocked in stroke patients?
Formed from caspase-1 activation.
Activation of IL-1 receptor causes increases endothelium permeability and enhances neurodegeneration by promoting the toxicity of other neurodegenerative signals.
IL-1ra is a selective antagonist for IL-1 receptor. Neuroprotective, blocks pro-inflammatory response.
Shown to help post-stroke patients recover faster.
IL-1B is neuroprotective pre-stroke - decreased Ca into cells and glutamate signalling, enhance GABA.
Because of these neurprotective features, IL-1B should not be completely block to treat stroke.
What is the difference of using TNF-a pre and post treatment of ischaemic stroke?
Diagram
Pre-treatment = less cell death
Post-treatment = more cell death
TNF activation is able to activate NFkB and increase the transcription of superoxide dismutases like MnSOD in pre-treatment. However, in post-treatment, MnSOD cannot be produced fast enough and ROS are increased and causes cell death.
The time determines the functional response of TNFa
What is the function of IL-6 in neurodegeneration.
Cytokine IL-6 is strongly neuroprotective and may be a potent endogenous neuronal survival factor. High levels in good outcomes, low in bad outcomes.
Targeting IL-6 activation could be therapeutic.
