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Drugs: from molecules to man > Stroke and brain killers 2 > Flashcards

Stroke and brain killers 2 Flashcards

1
Q

Why are there so many failures in terms of stroke treatments?

A
    • Laboratory studies may be too narrow and irrelevant
  • Imbalance between preclinical studies and clinical studies
  • The targets of the drug interventions to treat stroke were limiting processes which are critical for normal brain function
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2
Q

What specific stroke response can we target?

A

Inflammation?

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3
Q

What is inflammation?

A
  • Response of immune system to infection
  • First defined by Cornelius Celsius
  • Characterised by:
  • Heat (calor)
  • Redness (rubor)
  • Welling (tumor)
  • Pain (dolor)
  • Loss of function (function laesa)
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4
Q

What are inflammatory mediators?

A
  • Glial cell activation (astrocytes, microglia)
  • Oedema
  • Systemic acute phase response
  • Expression of adhesion molecules (within brain)
  • Invasion of immune cells (move into tissues and the brain)
  • Synthesis of inflammatory mediators – cytokines, free radicals, prostaglandins (all implicated in stroke)
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5
Q

What are the inflammatory events after a stroke?

A
  • The very early phase after a stroke (III) we get reduction of inflammatory mediators: cytokines, adhesion molecules and others
  • Good circumstantial evidence that inflammation happens after a stroke
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6
Q

What are cytokines?

A 
- Small proteins involved in all forms of disease and injury 
 Interleukins
 Interferons 
 Tumour Necrosis Factors 
 ‘growth’ factors 
 Chemokines
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7
Q

What are cytokines produced by, where do they act and what do they communicate between?

A
  • Produced by damaged cells
  • Act on the brain
  • Communicate between the cells
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8
Q

Give features of cytokines in stroke

A
  • Can be produced in the brain
  • Particularly after brain injury
  • Microglial cells are a main source
  • Interleukins-1 particularly important
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9
Q

What are the effects of cytokines in the brain?

A
  • Fever, weight loss
  • Altered appetite
  • Hormonal changes
  • Activation of sympathetic nervous system
  • Altered immune system
  • Sleepiness Lethargy Fatigue
  • The amounts of some cytokines that are needed are a thousand fold less in the brain than in other parts of the body, suggesting there is direct control by the brain of many aspects of immune functions
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10
Q

Give features of fever and how it helped to recognise Interleukin-1?

A
  • Helped to recognise Interleukin-1
  • Due to change in increase of regulatory set point of body temperature
  • Found cause of fever by collecting many samples of urine from many people that had an infectious disease at the same time
  • Found IL-1 in this
  • Caused by pyrogens (I think)
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11
Q

Give features of Interleukin-1?

A
  • ‘Master cytokine’
  • Key inflammatory mediator
  • Major disease target
  • Produced rapidly in the brain
  • Naturally occurring and highly selective antagonist, IL-1Ra
  • IL-1B is more prominent in the brain
  • IL-1B precursor is inactive, Caspase-1 cleaver the precursor (Pro IL-1B) to form IL-1B
  • IL-1a precursor is active
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12
Q

If IL-1 levels are increased what do we see in regards to stroke?

A

A worsening of damage

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13
Q

What do we see with an inhibition of IL-1?

A

an inhibition of injury

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14
Q

What can be used to reduce stroke damage?

A

IL-1Ra

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15
Q

What is a major mediator of ischaemic brain damage following a stroke?

A

glutamate

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16
Q

Give features of inflammatory burden and stroke

A
  • Inflammatory background may cause a stroke
  • Inflammation tends to increase with age
  • When there are episodes of infection inflammatory response increase
  • In older people, 3 or 4 weeks after inflammatory response there is an increased likelihood of getting a heart attack of stroke
  • Reduced inflammation -> reduced incidence of stroke?
17
Q

What does inhibition of IL-1 reduce?

A
  • Focal, global ,permanent, reversible ischaemia
  • Traumatic injury
  • Excitotoxic damage (NMDA, AMPA/KA)
  • Clinical symptoms of EAE
  • Heat stroke damage
  • Epileptic seizures
18
Q

What are cellular targets of IL-1?

A
  • Neurones
  • Glia
  • Endothelial cells
  • IL-1 may act peripherally
19
Q

What is systemic inflammation linked to?

A

Cardiovascular disease

20
Q

What does IL-1 expression peripherally induce?

A

CNS responses - systemic IL-1 exacerbates brain damage

21
Q

What does infection outside the brain cause?

A
  • Infection outside the brain causes peripheral inflammation and vascular disease
  • Peripheral inflammation affects the brain through humoral/neuronal and cellular actions because peripheral inflammation causes the release of many immune molecules such as neutrophils which then travel to the brain and target the brain
22
Q

What do we think are the main targets for Interleukin-1?

A

Glia

23
Q

What are the beneficial effects of IL-1?

A

Increased growth factors

24
Q

What are the detrimental effects of IL-1?

A
  • Activation of glia release toxins (assume this is most important)
  • Direct effects on Neurones
  • Cerebrovascular actions both to activate blood vessels in brains, activate adhesion molecules
  • Physiological functions such as fever and causing breakdown of extracellular breakdown
25
Q

What does imaging show regarding microglia?

A

Imaging shows that microglia are particularly activated surrounding the damage caused by stroke

26
Q

What happened with the first clinical trial of IL-1Ra in acute stroke?

A
  • Small phase II study
  • Double blinded, placebo controlled, randomised
  • Primary outcomes: safety, feasibility, is there a signal that the drug we’re using is working:
  • IL-1Ra was found to reduce circulating inflammatory biomarkers
27
Q

What is hibernation?

A

Hibernation is a physiological method of conserving energy when there is little food available and is associated with a dramatic drop in body temperature and heart rate and very low metabolic rates.

28
Q

What are reperfusion injuries caused by and responsible for?

A
  • Reperfusion injuries are mainly caused by inflammatory and oxidative stress responses that occur when the oxygen supply is restored to an area of ischaemic brain tissue.
  • Reperfusion injuries are responsible for a significant component of the brain damage caused by a stroke
29
Q

What mechanisms have hibernating animals evolved?

A

Hibernation involves the brain (and other organs) operating at very low oxygen levels, so hibernating animals have evolved mechanisms to avoid reperfusion injuries.

30
Q

What is thought to play a role in triggering hibernation?

A

It is thought that the body’s opioid peptide system may play a major role in triggering hibernation and that the delta opioid receptor might be particularly important.

31
Q

what was found in the study where strokes were induced in mice by blocking their middle cerebral arteries. They were then given either saline (control), serum from active ground hogs, serum from hibernating groundhogs or an agonist at the delta opioid receptor?

A

It was found that animals treated with delta opioid agonist, or with serum from hibernating groundhogs suffered significantly less brain damage than the control group or those treated with serum from active groundhogs. The mechanism by which this effect occurs is still being unravelled, but may involve a decrease in nitric oxide production

32
Q

What structural changes take place during hibernation of a ground squirrel?

A

it’s neurones undergo dendritic ‘die-back’. When the ground squirrel emerges from hibernation, the dendrites rapidly grow back to re-establish lost synapses. This plasticity is thought to be an energy saving adaptation. However, dendritic die-back in ground squirrels is accompanied by an additional structural change to neurones: the build-up of a heavily phosphorylated protein called tau. When the ground squirrel comes out of hibernation and dendritic regrowth occurs, the phosphorylated tau is simultaneously removed from its brain.

33
Q

What effect does tau have in humans?

A

In humans, the accumulation of hyperphosphorylated tau is thought to be one of the main reasons why brain cells die in Alzheimer’s disease (AD). For this reason, it has been suggested that hibernating ground squirrels may make a good model of AD.

Drugs: from molecules to man (22 decks)

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