neurodegeneration Flashcards
what is the difference between the manner in which chronic/acute neurodegeneration occurs
chronic - slow onset progressive
acute - sudden onset, secondary progression
what are some chronic neurodegenerative diseases
Alzheimer’s
Parkinson’s
MS
Prion disease
what are examples of acute neurodegeneration
TBI
stroke TIA
Intracranial haemorrhage
what is the occurrence and mortality rate of ischaemic strokes
occurrence - 85% of all strokes
mortality - 30% mortality of all strokes
what is the occurrence and mortality of haemorrhagic strokes
occurrence - 15% of strokes
mortality - 70% of all stroke deaths
what does ischaemia mean
loss of blood downstream of the clot event
what is an ischaemia stroke
disease of brain vasculature leading to neurological sequelae
what is the neurological deficit of an ischaemia stroke governed by and what is the most common location
neurological deficit is determined by the location of the clot
>50% occur in the middle cerebral artery
what is glutamate release dependent on
calcium
what is the purpose of reducing glutamate
reducing glutamate via blockade of calcium entry
shown to reduce neurodegeneration and infarct size
what are the glutamate receptors
NMDA
AMPA
KAINATE
Metabotropic
what does glutamate mediated NMDA signalling result in
Ca2+ and Na+
slow depolarisation
what does AMPA and KAINATE signalling result in
Ca2+, Na+, K+
fast depolarisation
what does metabotropic signalling result in
G-rotein coupled receptors
slow secondary messengers
what is MK-801 and what theory does it support
a NMDA receptor antagonist - blockade of glutamate is neuroprotective
supports theory that endogenous glutamate release is complicit in neurodegeneration
direct application of low concentrations of AMPA to the brain causes what
potent neurotoxicity
what effects does physiological concentration glutamate have under hypoxic conditions
becomes highly neurotoxic
how does ischaemic stroke lead to depolaristation
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
how does ischaemic stroke result in glutamate toxicity
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
what are the function of free radicals
oxidative metabolism
used by inflammatory cells
enzyme reactions
what regulates free radicals
superoxide dismutase
glutathione peroxidase
how can ischaemia lead to ROS
NOS uncoupling and mitochondrial depolarisation via Ca2+ increase
protease activation - XDH to XO
for nitric oxide formation what is arginine turned into
arginine —-> NO + citruline + H20
function of nitric oxide synthase (NOS)
.NO + O2- ——> .OnOO-
what can be used for acute neurodegeneration treatment
tissue plasminogen activator (tPA)
breaks down clots by converting plasminogen into plasmin
leads to fibrinolysis
leads to increase cerebral blood flow
what is the peripheral immune response
expression of adhesion molecules
recruitment/activation of phagocytes
increase vascular permeability
what is the CNS immune response
recruitment of microglia
upregulation of cytokines
inflammatory response delayed by hours-days
differential sensitivity to parenchyma/meninges
what are the interleukin-1 isoforms and which one is predominant in the brain and activated by what
IL-1alpha and IL-1beta
IL-1beta is predominant in the brain
activated by caspase-1
what does IL-1beta target and what is it’s antagonist
activates IL-1 receptor (R)
IL-1ra is an antagonist of IL-R
what is the IL-1beta mediated activation of IL-1R endothelial response
increase in endothelial permeability
upregulation of ICAM
what is the IL-1R glial response
astrogliosis
proliferation of microglia
release of neurotoxins
what is the neurones and other cells responses’ to IL-1R activation
COX-2 induction
NO production
Induction of TNF-alpha
what does activation of IL-1R ultimately lead to
brain damage
what are the effects of exogenous IL-1 compared to IL-1ra
IL-1 - neurodegenerative
IL-1ra - neuroprotective
although IL-1 is linked to neurodegeneration, what are neuroprotective aspects of it
increase glial proliferation
synthesis of nerve growth factor
enhance neuronal sprouting
promote neovascularisation
decrease Ca2+ entry into neurones
enhance GABAergic activity
what are the neuroprotective observations of tumour necrosis factor alpha (TNF-alpha)
TNF receptor null mice have increased infarctions
TNF-alpha leads to decreased glutamate toxicity
what are the neurodegenerative observations of TNF-alpha
TNF-alpha leads to increase in infarct volume
TNF binding protein led to decreased infarct volume
what is an explanation for the contradictory effects of TNF-alpha
dependent on temporal application of TNF-alpha
before ischaemic event - neuroprotective
after ischaemic event - neurodegenerative
function of IkappaB
one of the driving transcription factors for inflammation
how does pre-treatment activation of TNF receptor lead to neuroprotection
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
what is the difference in the post to pre-treatment of TNF-alpha in response to ischaemia
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
what is the difference in cytokines between a normal brain and a traumatic one
IL-1/6 and TNF-alpha hardly detectable in normal brain
in traumatic brain upregulation is rapid and sustained
