Stroke and neurodegeneration

Question 1

Suggest 6 things that cause neurodegeneration

Answer 1

redundancy
old age
poor circulation
neurodegenerative disease
other neurons (excitotoxicity)
toxic chemicals

Question 2

Which type of neurological death is easily detected and which is only transiently expressed

Answer 2

necrosis is easily detected

Apoptosis is only transiently expressed

Question 3

When is neuronal loss physiological

Answer 3

Pruning during brain development. more synapses are formed than needed, numbers trimmed between 1-20 years

Question 4

Why do nerve cells die

Answer 4

loss of intracellular Ca2+ homeostasis

Question 5

What is loss of intracellular calcuim homeostasis triggered by

Answer 5

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

Question 6

What things cause the depolarising factors to overcome control of ionic homeostasis

Answer 6

epilepsy- spontaneously hyperactive cells (genetic or post traumatic)
stroke- lack of oxygen or glucose= glutamate release
toxicity- agonists of excitatory transmitters reach the brain

Question 7

Which receptor is most important for excitotoxicity

Answer 7

NMDA receptors (voltage dependant cation channels)

Question 8

What are the glutamate receptors

Answer 8

ionotropic- AMPA/kinase and NMDA

metabatropic- GPC receptor

Question 9

Explain the excitotoxic cascade

Answer 9

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

Question 10

In epilepsy where are the seondary lesions of excytotoxic cell death seen

Answer 10

opposite side of brain to primary site of damage

Question 11

Explain noise induced deafness

Answer 11

Exposure to high sound levels stimulates the cells of the cochlear beyond what they can withstand

Question 12

How can noise induced deafness be prevented

Answer 12

glutamate antagonists or interferance with pro-apoptotic pathways

Question 13

How does AIDS cause neuronal cell death

Answer 13

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

Question 14

Explain neuronal death by oxidative stress

Answer 14

disturbance in the pro-oxidant to antioxidant balance ( in favour or pro oxidant

Question 15

Why is the brain particularly vulnerable to oxidative stress

Answer 15

high rate of oxygen demand and metabolism means that more reactive oxygen species are formed

Question 16

name 3 anti-oxidants

Answer 16

Ascorbate
vit.e
flavanoids
fenton-metal binding proteins

Question 17

Name three rective oxygen species formed in normal metabolism and suggest the most reactive

Answer 17

o2-
H2O2
OH most reactive

Question 18

Why is free iron (or copper colbolt manganese) potentially dangerous in the unbound state

Answer 18

Because it can react with hydrogen peroxie and for hydroxyl radical

Question 19

What do oxygen free radicals target

Answer 19

Lipid (membrane)
Protein (activation or inhibition of enzymes)
DNA (strand scission)

Question 20

What are lewy bodies

Answer 20

aggregates of alpha synuclien

Question 21

The damage done by reduced blood flow in strokes is defined by what two areas

Answer 21

the core, dependant on the occulded artery

and the penumbra, the area of potential damage

Question 22

List the main early events of a stroke

Answer 22

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

Question 23

Which scan detects oedema and which one detects interrupted blood flow

Answer 23

oedema= proton MRI
blood= functional MRI

Question 24

What two things are the main focuses of immediate stroke therapy

Answer 24

restoration of blood flow

encoragement of survival of remaining tissue

Question 25

How is restoration of blood flow achieved

Answer 25

iv, recombinant plasminogen
surgery
brain cooling

Question 26

What can be done to encourage the surviving tissue

Answer 26

Supportive care
physiotherapy
pharmacological approaches to reduce excitotoxcity and oxidative stress