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-
