Stroke and neurodegeneration Flashcards
Suggest 6 things that cause neurodegeneration
redundancy old age poor circulation neurodegenerative disease other neurons (excitotoxicity) toxic chemicals
Which type of neurological death is easily detected and which is only transiently expressed
necrosis is easily detected
Apoptosis is only transiently expressed
When is neuronal loss physiological
Pruning during brain development. more synapses are formed than needed, numbers trimmed between 1-20 years
Why do nerve cells die
loss of intracellular Ca2+ homeostasis
What is loss of intracellular calcuim homeostasis triggered by
necrotic events- neurotixic drug insult, excessive excitatory receptor activation, mis-metabolism of APP, viral infection, prion disorders, excessive free radical fromation
apoptotic events- deprivation of growth factor, mitochondrial damage
What things cause the depolarising factors to overcome control of ionic homeostasis
epilepsy- spontaneously hyperactive cells (genetic or post traumatic)
stroke- lack of oxygen or glucose= glutamate release
toxicity- agonists of excitatory transmitters reach the brain
Which receptor is most important for excitotoxicity
NMDA receptors (voltage dependant cation channels)
What are the glutamate receptors
ionotropic- AMPA/kinase and NMDA
metabatropic- GPC receptor
Explain the excitotoxic cascade
Calcuim activated proteolytic enzymes (calpains) degrade essential proteins
calmodulin calcuim kinase 11 is activated and enzyme phosphorlyation further increases activity
transcription factors c-jun c-fos and c-myc expression increases calcuim dependant endonucleases- degrade dna
In epilepsy where are the seondary lesions of excytotoxic cell death seen
opposite side of brain to primary site of damage
Explain noise induced deafness
Exposure to high sound levels stimulates the cells of the cochlear beyond what they can withstand
How can noise induced deafness be prevented
glutamate antagonists or interferance with pro-apoptotic pathways
How does AIDS cause neuronal cell death
invades microglia, which then activate an inflammatory response, present viral coat, attractng astrocytes
release of TNFalpha =apoptotic
also cause astrocte processes to release additional glutamate
Explain neuronal death by oxidative stress
disturbance in the pro-oxidant to antioxidant balance ( in favour or pro oxidant
Why is the brain particularly vulnerable to oxidative stress
high rate of oxygen demand and metabolism means that more reactive oxygen species are formed
name 3 anti-oxidants
Ascorbate
vit.e
flavanoids
fenton-metal binding proteins
Name three rective oxygen species formed in normal metabolism and suggest the most reactive
o2-
H2O2
OH most reactive
Why is free iron (or copper colbolt manganese) potentially dangerous in the unbound state
Because it can react with hydrogen peroxie and for hydroxyl radical
What do oxygen free radicals target
Lipid (membrane)
Protein (activation or inhibition of enzymes)
DNA (strand scission)
What are lewy bodies
aggregates of alpha synuclien
The damage done by reduced blood flow in strokes is defined by what two areas
the core, dependant on the occulded artery
and the penumbra, the area of potential damage
List the main early events of a stroke
Vascular damage
local ischaemia
local hypoxia
failure of aerobic metabolism =lactose
inability to maintain ion gradients
release of glutamate and increase in intracellular caluim
cellular oedema, necrosis and brain swelling
increased intercranial pressure and decreased blood flow
damage worsened by re-perfusion
Which scan detects oedema and which one detects interrupted blood flow
oedema= proton MRI blood= functional MRI
What two things are the main focuses of immediate stroke therapy
restoration of blood flow
encoragement of survival of remaining tissue
How is restoration of blood flow achieved
iv, recombinant plasminogen
surgery
brain cooling
What can be done to encourage the surviving tissue
Supportive care
physiotherapy
pharmacological approaches to reduce excitotoxcity and oxidative stress
