Cerebral Ischaemia Flashcards
Describe the main events that occur in cerebral ischaemia including energy failure, excitotoxicity, inflammation, and cell death, and the relevant localisation and timescale of these events Understand the transcriptional changes that contribute to endogenous neuroprotective processes and delayed cell death Identify the main molecular targets that could improve outcome but also appreciate the problems encountered in developing treatments
How did the incidence of stroke change between 1990 and 2010?
It decreased 25%
Define cerebral ischaemia
A transient or permanent reduction in cerebral blood flow
Give at least 3 ways of improving blood flow in acute ischaemic stroke
Tissue plasminogen activator, mechanical thrombectomy, aspirin, anti-platelet drugs
Describe how occlusion causes cell death
Occlusion leads to the activation of adhesion molecules in the vascular endothelium, enhancing the penetration of inflammatory cells into the brain. This is enhanced by release of proteases and cytokines
Describe one way in which the vascular endothelium promotes recovery
It releases nitric oxide, which causes vessel relaxation and increases blood flow
What is the normal rate of blood flow in the brain?
Above 50ml/100g/min
At what perfusion level does olighaemia occur from hypoperfusion?
22-50ml/100g/min
What is the perfusion level in the ischaemic penumbra?
10-22ml/100g/min
Define the ischaemic penumbra
Tissue at risk of infarction where perfusion is adequate to maintain cell viability but inadequate for normal neuronal function
Describe the effects of focal ischaemia on brain metabolism
Decreased ATP, decreased glucose utilisation, decreased protein synthesis, increased cell water content, increased sodium and potassium ion concentration
Describe what happens to the affected area within minutes of cerebral ischaemia
Energy failure and excitotoxicity
Describe what happens to the affected area within hours of cerebral ischaemia
Induction of immediate early genes
Describe the cause and consequences of energy failure
The reduction in blood flow reduces the amount of ATP, causing the sodium-potassium pump to fail and the membrane potential to not be maintained. Energy-dependent glutamate transporters are inactivated, so extracellular glutamate increases, and sodium and chloride ions enter the cell. Water diffuses after the ions, causing oedema
How long does it take for glutamate changes to be detected in the blood plasma after a stroke?
6 hours
Name 3 neurotransmitters affected by ischaemia
Glutamate, GABA, adenosine
Describe the process of excitotoxicity after cerebral ischaemia?
High levels of glutamate interact with AMPA and NMDA receptors on the neuronal surface, leading to sodium and calcium entry and activation of calcium-dependent enzymes like xanthine dehydrogenase and PLA2. This leads to free radical production, loss of cell membrane integrity, and cytochrome c release leading to apoptosis
Summarise the consequences of excitotoxicity and calcium overload
1) Actin degradation due to activation of proteolytic enzymes
2) Free radical generation due to activation of COX
3) Nitric oxide generation
4) Mitochondrial dysfunction causing cytochrome c release and triggering apoptosis
Name the three substances produced by nitric oxide synthase
1) nNOS - retrograde messenger, leading to toxic levels of NO free radicals
2) eNOS - vasodilator, improves cerebral blood flow
3) iNOS - immune mediator
Name at least 3 endogenous antioxidants and free radical scavengers
Superoxide dismutase (SOD), catalase, glutathione peroxidase, alpha-toxopherol, ascorbic acid
Describe the effect of iNOS and nNOS knockout on mice
Neuroprotective against stroke
Describe the effect of giving exogenous superoxide dismutase to mice
Neuroprotective against stroke
How does NMDA receptor mediated toxicity vary with the severity of the insult?
In a mild insult, transient depolarisation occurs with reduced ATP, calcium-ion loaded mitochondria, and cytochrome c release leading to apoptosis. In a severe insult, calcium ions enter and are taken up by the mitochondria, with free radical generation, severe ATP depletion, and mitochondrial swelling leading to necrosis
