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BioMed Season Finale Part 1 > neurodegeneration > Flashcards

neurodegeneration Flashcards

1
Q

what is the difference between the manner in which chronic/acute neurodegeneration occurs

A

chronic - slow onset progressive
acute - sudden onset, secondary progression

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2
Q

what are some chronic neurodegenerative diseases

A

Alzheimer’s
Parkinson’s
MS
Prion disease

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3
Q

what are examples of acute neurodegeneration

A

TBI
stroke TIA
Intracranial haemorrhage

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4
Q

what is the occurrence and mortality rate of ischaemic strokes

A

occurrence - 85% of all strokes
mortality - 30% mortality of all strokes

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5
Q

what is the occurrence and mortality of haemorrhagic strokes

A

occurrence - 15% of strokes
mortality - 70% of all stroke deaths

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6
Q

what does ischaemia mean

A

loss of blood downstream of the clot event

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7
Q

what is an ischaemia stroke

A

disease of brain vasculature leading to neurological sequelae

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8
Q

what is the neurological deficit of an ischaemia stroke governed by and what is the most common location

A

neurological deficit is determined by the location of the clot
>50% occur in the middle cerebral artery

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9
Q

what is glutamate release dependent on

A

calcium

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10
Q

what is the purpose of reducing glutamate

A

reducing glutamate via blockade of calcium entry
shown to reduce neurodegeneration and infarct size

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11
Q

what are the glutamate receptors

A

NMDA
AMPA
KAINATE
Metabotropic

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12
Q

what does glutamate mediated NMDA signalling result in

A

Ca2+ and Na+
slow depolarisation

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13
Q

what does AMPA and KAINATE signalling result in

A

Ca2+, Na+, K+
fast depolarisation

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14
Q

what does metabotropic signalling result in

A

G-rotein coupled receptors
slow secondary messengers

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15
Q

what is MK-801 and what theory does it support

A

a NMDA receptor antagonist - blockade of glutamate is neuroprotective
supports theory that endogenous glutamate release is complicit in neurodegeneration

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16
Q

direct application of low concentrations of AMPA to the brain causes what

A

potent neurotoxicity

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17
Q

what effects does physiological concentration glutamate have under hypoxic conditions

A

becomes highly neurotoxic

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18
Q

how does ischaemic stroke lead to depolaristation

A

loss of blood leads to loss of oxygen and glucose
leads to loss of ATP
without ATP the resting potential of -60mV cannot be maintained
leads to depolaristion and a transmembrane ionic gradient of 0mV

19
Q

how does ischaemic stroke result in glutamate toxicity

A

under normal conditions glutamate uptake is performed by cells (astrocytes) using ATP-mediated transport
no ATP after a stroke means glutamate builds up extracellularly - neurotoxic

20
Q

what are the function of free radicals

A

oxidative metabolism
used by inflammatory cells
enzyme reactions

21
Q

what regulates free radicals

A

superoxide dismutase
glutathione peroxidase

22
Q

how can ischaemia lead to ROS

A

NOS uncoupling and mitochondrial depolarisation via Ca2+ increase
protease activation - XDH to XO

23
Q

for nitric oxide formation what is arginine turned into

A

arginine —-> NO + citruline + H20

24
Q

function of nitric oxide synthase (NOS)

A

.NO + O2- ——> .OnOO-

25
Q

what can be used for acute neurodegeneration treatment

A

tissue plasminogen activator (tPA)
breaks down clots by converting plasminogen into plasmin
leads to fibrinolysis
leads to increase cerebral blood flow

26
Q

what is the peripheral immune response

A

expression of adhesion molecules
recruitment/activation of phagocytes
increase vascular permeability

27
Q

what is the CNS immune response

A

recruitment of microglia
upregulation of cytokines
inflammatory response delayed by hours-days
differential sensitivity to parenchyma/meninges

28
Q

what are the interleukin-1 isoforms and which one is predominant in the brain and activated by what

A

IL-1alpha and IL-1beta
IL-1beta is predominant in the brain
activated by caspase-1

29
Q

what does IL-1beta target and what is it’s antagonist

A

activates IL-1 receptor (R)
IL-1ra is an antagonist of IL-R

30
Q

what is the IL-1beta mediated activation of IL-1R endothelial response

A

increase in endothelial permeability
upregulation of ICAM

31
Q

what is the IL-1R glial response

A

astrogliosis
proliferation of microglia
release of neurotoxins

32
Q

what is the neurones and other cells responses’ to IL-1R activation

A

COX-2 induction
NO production
Induction of TNF-alpha

33
Q

what does activation of IL-1R ultimately lead to

A

brain damage

34
Q

what are the effects of exogenous IL-1 compared to IL-1ra

A

IL-1 - neurodegenerative
IL-1ra - neuroprotective

35
Q

although IL-1 is linked to neurodegeneration, what are neuroprotective aspects of it

A

increase glial proliferation
synthesis of nerve growth factor
enhance neuronal sprouting
promote neovascularisation
decrease Ca2+ entry into neurones
enhance GABAergic activity

36
Q

what are the neuroprotective observations of tumour necrosis factor alpha (TNF-alpha)

A

TNF receptor null mice have increased infarctions
TNF-alpha leads to decreased glutamate toxicity

37
Q

what are the neurodegenerative observations of TNF-alpha

A

TNF-alpha leads to increase in infarct volume
TNF binding protein led to decreased infarct volume

38
Q

what is an explanation for the contradictory effects of TNF-alpha

A

dependent on temporal application of TNF-alpha
before ischaemic event - neuroprotective
after ischaemic event - neurodegenerative

39
Q

function of IkappaB

A

one of the driving transcription factors for inflammation

40
Q

how does pre-treatment activation of TNF receptor lead to neuroprotection

A

TNF signals to the mitochondria
leads to release of ROS
ROS interacts with IkappaB
IkappaB travels to the nucleus
initiates synthesis of manganese superoxide dismutase (MnSOD)
MnSOD detoxifies free radicals in the mitochondria
neuroprotective

41
Q

what is the difference in the post to pre-treatment of TNF-alpha in response to ischaemia

A

during or after an ischaemic event, TNF signalling to the mitochondria release much more ROS
not enough time to produce protective proteins that counteract this
neurodegenerative

42
Q

what is the difference in cytokines between a normal brain and a traumatic one

A

IL-1/6 and TNF-alpha hardly detectable in normal brain
in traumatic brain upregulation is rapid and sustained

43
Q
A
44
Q
A

BioMed Season Finale Part 1 (13 decks)

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