Stroke and mechanisms of neurodegeneration

Question 1

How do you confirm pathological cell death?

Answer 1

neuropathology(death by necrosis easily detectible) or MRI

Question 2

5 causes of pathological neurodegeneration

Answer 2

• ageing
• stroke
• 2y to disease - diabetes neuropathy, HIV encephalopathy
• neurodegen disease e.g. parkinsons huntingtons
• endog toxins

Question 3

5 necrotic events and 2 apoptotic events that cause nn cell death

Answer 3

prion disorder, free radicals, excessive excitatory receptor activation , HIV , neurotoxic drug insult
mitochondrial damage and no GFs

Question 4

What is excitotoxicity

Answer 4

when depol factors overcome the control of ionic homeostasis –> initiate pathogenesis

Question 5

describe the excitotoxicity cascade

Answer 5

NMDA lets in to much calcium which causes:
-oxidative stress (free rad production)
- calcium dependant enzymes e.g phospholipase (breaks down cell wall) kinase , endonuclease degrade DNA
-damages the mitochondria
causing necrosis and apoptosis

Question 6

describe the two types of NMDA receptors

Answer 6

ionotrophic - ion channel CALCIUM

metabotrophic - g protein

Question 7

when does excitotoxicity occur in epilepsy

Answer 7

after increased neuronal activity a 2nd spread of excitotoxic neuronal death can occur

Question 8

How does noise induce deafness and how can you prevent this

Answer 8

exposing cochlear receptors to beyond withstand causes death of inner and outer nn cells
glutamate antagonist OR interfere apoptotic pathway

Question 9

neuronal death in AIDS

Answer 9

AIDS replicates in microglia. infected microglia presents gp120 on surface to astrocytes which causes both the astrocytes and the microglia to release TNF causing release of glutamate = excitotoxicity

Question 10

what are.. glutathione, ascorbate, vit E, flavanoids

Answer 10

antioxidants

Question 11

descrive how 02 can become pro oxidants

Answer 11

02 –> 02 (-) –> H202 –> H0(-) –> H20

• superoxide anion 02- is removed by superoxide dismutase
• hydrogen peroxide is removed nu reduction to h2- or glutathione
• hydroxyl radicals VERY reactive

Question 12

what is the fenton reaction

Answer 12

h202 –> OH - using Fe2+ or other metals to enable reaction.
means that free iron is very dangerous

Question 13

How can redox stress cause damage - 3

Answer 13

1. lipid peroxidation of fatty acids
2. protein oxidation. can impaire enzymes involved in Ca homeo
3. DNA strand scissors impaired (impaired ATP synthesis )

Question 14

relationship between redox and excitotoxicity

Answer 14

SYNERGISTIC

Question 15

evidence of oxidative stress in parkisons that can be found in a post mortem

Answer 15

increased lipid peroxidation 
increaed free rads
increased brain iron
increased superoxide dismutase activity
decreased glutathione

Question 16

what is parkin gene responsible for

Answer 16

degradation of proteins (ubuiqatin proteosome)

Question 17

How does ALS cause neurodegeneration

Answer 17

mutations in superoxide dismutase activity therefor oxadative stress - loss of motorneurones - weakness and muscle atrophy

Question 18

Two types of strokes?

Answer 18

hemorrhagic - 10% bleeding around/in brain

ischemic - 90% clot blocks blood flow to an area

Question 19

what is a blood flow deficit made up of

Answer 19

core + penumbra (compromised area)

Question 20

describe the main early events in a stroke

Answer 20

hypoxia
failure of aerobic metabolism = LACTATE, neurones and glia CANT maintain ion gradient 
release glutamate 
increased intracellular calcium
cellular oedema brain swelling 
increased ICP

Question 21

what happens 1w after a stroke (beneficial)

Answer 21

endogenous neurogenesis

Question 22

what exodogenous therapy can be used after a stroke

Answer 22

GFs may be used to stim proliferation

stem cells from brain implants may be used to start neurogenesis

Question 23

what are the two main aims of stroke therapy and how do you achieve them

Answer 23

rapid restoration of blood flow
-iv TPA removes clots, surgery, brain cooling
encouraging recovery of surviving
- supportive care, physiotherapy