Molecular pathology of brain injury Flashcards
1
Q
give 4 examples of 4 chronic neurodegenerative conditions
A
alzheimers disease
parkinsons disease
multiple sclerosis
prion disease
2
Q
give 4 examples of acute neurodegenerative conditions
A
traumatic brain injury
stroke
transient ischaemic attack (TIA)(mini stroke)
intracranial haemorrhage
3
Q
what are the two main differences between chronic and acute neurodegeneration?
A
chronic: slow onset, progressive
acute: sudden onset, secondary progression
4
Q
who fraction of stroke sufferers survive?
A
two thirds
5
Q
how many strokes happen every year?
how many are first strokes
A
152,000 strokes every year
(100,000 are first strokes)
6
Q
how many strokes happen every year?
how many are first strokes
A
152,000 strokes every year
(100,000 are first strokes)
7
Q
how many people in the uk are stroke survivors?
A
1 in 53
(1.2 million people)
8
Q
what percentage of those who have strokes need caring for themselves, have speech impediments, or have to be institutionalised?
A
31% need help caring from themselves
71% have speech impediments
16% have to be institutionalised
9
Q
what is the 4th most common cause of death in the UK?
A
stroke
5% men, 8% women
10
Q
incidence of first stroke __ every __ after __
A
incidence of stroke double every decade after 55
11
Q
which ethinic group has the lowest risk of stroke
A
caucasian
12
Q
what reasons underly the reduction of mortality from stroke?
A
improved clinical pathways
wider access to specialist stroke wards
increased public and professional awareness (eg FAST campaign)
13
Q
give four risk factors of stroke
A
hypertension
diabetes (type 2)
hypercholestrolaemia
previous stroke or transient ischaemic attack
14
Q
what are the two major types of stroke
share of all and approx mortality
A
Ischaemic stroke: 85% of all strokes, 30% mortality
Haemorrhagic stroke: 15% of all stroke, 70% mortality
15
Q
what is ischaemia
A
loss of blood supply to areas downstream of the clot
16
Q
neurological deficit of a stroke is determined by what
A
location of the clot
17
Q
what is the most common vessel affected in strokes?
A
Middle cerebral artery (>50% of strokes)
18
Q
breifly describe the mechanims of neurodegeneration following descreased blood supply
A
- a decrease in blood supply results in a descrease in oxygen and glucose levels which leads to energy failure
- energy failure leads to loss of protein synthesis resulting in a decrease in protective protein, failure of Na/K ATPase cause depolarisation and anaerobic metabolism leading to decrease in pH (acidic environment due to lactate).
- depolarisation leads to release of neurotransmitter (glutamate) as well as increase in calcium levels. the acidic environment also causes release of calcium.
- these increased calcium levels lead to oedema, activated proteases and free radicals which all cause cell death
- in addition, reperfusion results in aerobic metabolism and inflammatory response with both add to the free radicals that lead to cell death
19
Q
what is reperfusion?
A
the restoration of blood flow to an organ or tissue after having been blocked
20
Q
what are the four types of glutamate receptors?
A
NMDA
AMPA
Kainate
metabotropic
21
Q
blockage of postsynaptic glutamate receptors is __
glutamate antagonists are __
A
neuroprotective
22
Q
direct application of low concentrations of AMPA/NMDA is highly __
A
neurotoxic
23
Q
why isnt direct application of glutamte not neurotoxic?
A
because glutamate is an endogenous neurotransmitter and the brain already has mechanisms in place to get rid of it
24
Q
under what conditions do physiological concentrations of glutamate become hghly toxic
A
hypoxic conditions
25
In ischaemia why does loss of ATP result in depolarisation and normalisation of transmembrane ionic gradients
loss of ATP means that the sodium potassium ATPase no longer functions, meaning the sodium gradient is no longer present
this means that the cotransport of glutamine with sodium no longer occurs
26
free radicals are natural by products of what parts of cellular metabolism
- oxidative metabolism
- enzyme reactions
- inflammatory cells
27
what regulate free radicals
superoxide dismutases (Cu/ZnSOD, MnSOD)
glutathione peroxidase
28
why are free radicals so reactive
due to an unpaired electron
29
what three things lead to reactive oxygen species in ischaemia
substrate limitation leads to nitric oxide synthase uncoupling
Ca overload leads to mitochondrial depolarisation and NOX/p22
preotease activation leads to xanthine dehydrogenase conversion to xanthine oxidase
30
what are the four types of nitric oxide synthase (NOS)
endothelial eNOS
neuronal nNOS
inducible iNOS
mitochondrial mtNOS
31
nitric oxide formation is mediated by what
| what is the equation
arginine -> NO + citrulline + H2O
mediated by nitric oxide synthase
32
what happens to Nitric oxide when it enters the mitochondria
preferentially reacts with superoxide to form peroxynitrite which is highly toxic
NO + O2- -> ONOO-
33
what is the drug currently used to treat stroke
Tissue plasminogen activator (tPA)
34
why are there so many regulations for who can be given tPA
| what are they
Because of the risk of hemorrhage is thought to outweigh any potential benefits, patients with any absolute contraindication should not be given tPA.
because 6.4% of those who received tPA had an intracerebral haemorrhage within 36 hours
- requires absolute certainty that there is no intracranial bleeding
- very limited time window of efficacy: within 4.5 hours of onset
| ageed between 18-79
## Footnote
- very small percentage (12-20%) of patients actually receive r-tPA
35
excitotoxicity and free radical production onset occurs and ends within what period after onset of ischaemia
3-4 hours
36
describe the progressionof degeneration
37
Expression of what groups of genes are increased following ischaemia
Immediate early genes
Heat shock proteins
Cytokines
Growth factors
Adhesion molecules
Protease inhibitors
Remodelling factors
38
compare the peripheral and CNA inflammatory response
- Perioheral inflammatory response
o Expression of adhesion molecules
o Recruitment and activation of pahgocytes
o Increase vascular permeability
o All driven by cytokines
- In CNS
o Rapid and sustained upregulation of cytokines
o Inflammatory response delayed by hours-days
o Local activation of microglia
o Differential sensitivity of parenchyma and menige
39
what is the predominant form of Interleukin 1 in the brain
Interleukin 1 beta
40
how is interleukin beta fromed
by activation of IL-1 converting enzyme (caspase-1)
41
how is interleukin beta fromed
by activation of IL-1 converting enzyme (caspase-1)
42
what is the selective endogenous antagonist of interleukin 1
Interleukin 1ra
43
what are the effects of interleukin 1 beta in the CNS?
In endothelium - increase in permeability, upregulation of ICAM-1
In glia - astrogliosis, proliferation of microglia, release of neurotoxins
In neurons/other cells - COX-2 induction, NO production, induction of TNFalpha
44
name the contradictory effects of interleukin 1
elevated IL-1 after injury is linked to neurodegeneration
however IL-1 has also been shown to: increase glial activation and proliferation, induce synthesis of nerve growth factor, enhance neuronal sprouting, promote neovascularisation, decrease calcium entry into neurons, enhance GABA activity all of which may be neuroprotective
45
in clinical trials with IL1ra (for strike) what occurred and why didn't they follow through further with it
the proportion of patients in the upper group of the independence scales significantly increased with IL-1ta treatment
however it had no effect at all on the that were more severely affected by their stroke(even increasing the worst outcomes)
46
in clinical trials with IL1ra (for strike) what occurred and why didn't they follow through further with it
the proportion of patients in the upper group of the independence scales significantly increased with IL-1ta treatment
however it had no effect at all on the that were more severely affected by their stroke(even increasing the worst outcomes)
47
why cant the neuroprotective effects of TNFalpha be utilised clinically
because the mechanism that contributes to the neuroprotective effects is needed to be triggered before ischaemia sets in
TNF activation leads to superoxide poduction which increases the superoxide dismutase produced
**pretreatment allows time for production of dismutases to deal with the effects of free radicals**
If there is a delay after a period of ischaemia, TNF actually contributes to more cell death
48
give two examples of independence scales used to monitor patients after brain injury
Barthel index
Modified rankin scale
49
what are the three main cytokines upregulated after head injury
IL-1beta
IL-6
TNF alpha
50
what is the largest cause of death and long term disability in the under 35s in the developed world
traumatic brain injury
51
there is correlation between cytokine production and outcome of traumatic brian injury between only 1 of the cytokines, which is it?
IL-6
52
What is the ischaemic penumbra
an area of constrained blood flow with partially preserved energy metabolisM
53
why is glutamate uptake reduced in stroke
GLutamate uptake is driven by the sodium concentration gradient. If no sodium gradeitns then nothing is driving glutamate uptake so it stays in synapse and builds up moving to the next synapse. killing cells quickly
54
why is glutamate uptake reduced in stroke
GLutamate uptake is driven by the sodium concentration gradient. If no sodium gradeitns then nothing is driving glutamate uptake so it stays in synapse and builds up moving to the next synapse. killing cells quickly
55
Under hypoxic conditions, physiological concentrations of glutamate become highly toxic… WHY
During hypoxia-ischemia, as cellular energy reserves and Na+ gradients fall, increased release and impaired uptake of glutamate mediate a toxic buildup of extracellular glutamate, leading to overstimulation of glutamate receptors and consequent neuronal cell death
56
Under physiological conditions large quantities of ATP required to maintain resting potential, how do they do this?
It mediates activity of the SOdium potassium ATPase pump
channelling 3 sodiums out of the cell and 2 potassiums into it to create a sodium gradient and membrane potential of -60mV
57
how does calcium overload affect mitochondria?
Can drive production of ROS and effect breakdown of other things in the cells like Xanthine
causing over production of ROS
58
how do reactive oxygen species cause cell death?
Excess cellular levels of ROS cause damage to proteins, nucleic acids, lipids, membranes and organelles, which can lead to activation of cell death processes such as apoptosis
59
how do reactive oxygen species cause cell death?
Excess cellular levels of ROS cause damage to proteins, nucleic acids, lipids, membranes and organelles, which can lead to activation of cell death processes such as apoptosis
60
how do cell protect against reactive oxygen species
cells possess a variety of defenses including cell-cycle delay (9–11), the induction of enzymes such as catalases, peroxidases, and superoxide dismutases, and the synthesis of antioxidants such as glutathione, vitamins C and E, and ubiquinol
61
what is nitrosative stress?
Nitrosative stress refers to the joint biochemical reactions of nitric oxide (NO) and superoxide (O2–) when an oxygen metabolism disorder occurs in the body
62
what are the neurotoxic effects of iNOS activation?
the production of NO induced by iNOS leads to brain damage during ischemia reperfusion.
The overexpression of iNOS can promote the secretion of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and subsequently induce secondary inflammatory reaction and the generation of oxygen free radicals.
63
which NOS are have neurotoxic activity and which are neuroprotective?
No plays a dual role in ischemic stroke,
The production of NO in the early stage of transient cerebral ischemia has a positive effect on the neuroprotection of stroke, but nNOS and iNOS play a negative role in the later stage.
eNOS plays a key role in the protection of neurovascular system
64
describe the role of eNOS in stroke
NO derived from eNOS often plays a neuroprotective role in ischemic stroke.
eNOS generates a small amount of NO,
it plays a critical role in the regulation of cerebral microvascular tone, the protection of the blood-brain barrier, the reduction of oxidative stress and the alleviation of procoagulant stimulation.
The NO released can scavenge oxygen free radicals, inhibit the expression of adhesion molecules, and promote the aggregation of platelet and the adhesion of lymphocyte
65
what is the effect of nNOS in stroke?
The synthesis of NO through nNOS is mainly related to calcium overload induced by glutamate in ischemic neurons
66
what happens to the NO levels in ischeamic stroke
In ischemic stroke, the concentration of NO decreases rapidly due to blocked blood flow.
Once the blood flow is restored, the production of NO will increase, which is mainly mediated by nNOS
67
what are the absolute contraindication for using tissue plasminogen activator (tPA)
Significant head trauma or prior stroke in the previous 3 months.
Symptoms suggest subarachnoid hemorrhage.
Arterial puncture at a noncompressible site in previous 7 days.
History of previous intracranial hemorrhage.
Intracranial neoplasm, AVM, or an aneurysm.
Recent intracranial or intraspinal surgery.
active internal bleeding
abnormal blood glucose
68
how does tPA work to improve the outcome of stroke
69
how does tPA work to improve the outcome of stroke
tPA attaches to the fibrin on the clot surface. It activates the fibrin-bound plasminogen. Plasmin is subsequently cleaved from the plasminogen affiliated with the fibrin. The plasmin breaks up the molecules of fibrin, and the clot dissolves
tPA helps to restore blood flow to brain regions affected by a stroke, thereby limiting the risk of damage and functional impairment.
70
give one reason why there was a strong correlation between amount of IL6 produced and good outcome in stroke patients
IL-6 stimulates the production of IL-1 receptor antagonist, which is an anti-inflammatory mediator. IL-6 therefore can have a protective effect.
