Excitotoxicity

Question 1

What did Pulido 2008 say?

Answer 1

Talks about amnesic shellfish poisoning which was identified in canada in 1980s as a result of human poisoning by domoic acid because of blue mussel consumption and post mortem analysis showed necrosis in the hippocampus and amygdala

Question 2

What are the two glutamate transporters?

Answer 2

plasma membrane glutamate transporters and cytosolic glutamate is transported by vesicular transporters which are both ATP dependent

Question 3

What is the mechanism of action of domoic acid?

Answer 3

acts on the non-NMDA receptors AMPA and kainate and causes increase in the levels of intracellular calcium because the AMPA will eventually gets depolarized which alleviates the magnesium block in NMDA

Question 4

What is the mechanism of action of BMAA?

Answer 4

product of cyanobacteria in cycad seeds and fruit bats – seen in the guam people , produces ALS and PD because it kills motor neurones by increasing the raical oxygen species through activation of AMPA-kainate glutamate receptors

Question 5

Why do extracellular levels of glutamate increase in ischaemia?

Answer 5

Because there’s no ATP and the glutamate transporters are ATP dependent and so glutamate doesnt get cleared

Question 6

Apoptosis vs necrosis?

Answer 6

apoptosis- destroys individual cells induce by physiological stimuli , cell death pathways and ATP dependent

Necrosis- inflammation, affects groups of cells and evoked by non physiological events, calcium overload

Question 7

Describe the apoptosis pathway

Answer 7

mild excitotoxic insults
NMDAR activation
Increased mitochondrial calcium and free radical production
mitochondria release cytochrome c , caspase 9, apoptosis inducing factor

Question 8

What are the neuroprotective mechanisms of NMDAR?

Answer 8

cell survival
suppressed pro-death genes
enhanced anti-oxidant defences
mitochondrial function 
enhanced trophic support

Question 9

what are the neurotoxic mechanisms of NMDAR?

Answer 9

mitochondrial dysfunction
calpain activation
stress activated protein kinases

this all happens cause of calcium influx via NMDAR

Question 10

What does calpain activation result in?

Answer 10

Excess calcium activates calpain which then impairs PMCA and NCX3 mediated calcium efflux

Question 11

What are stress activated protein kinases?

Answer 11

P38 MAPK
JNK
these contribute to neuronal cell death

Question 12

define Excitotoxicty

Answer 12

cell death resulting from toxic actions of excitatory amino acids such as glutamate, cysteine, aspartate

Question 13

What are the implications of excitotoxicity?

Answer 13

stroke, cns infections, brain tumours

Question 14

name all the glutamate receptors

Answer 14

ionotropic receptors- kainate, ampa, nmda- mediate opening of ion channels
metabatropic receptors- modulation of intracellular signal transduction

Question 15

how can calcium cause oxidative stress?

Answer 15

increased calcium is mopped up by mitochondria which gets fucked in the process thus causing oxidative stress

Question 16

define oxidative damage

Answer 16

imbalance in ROS production and cells capacity to neutralize ROS

Question 17

How does NMDAR activation result in enhanced trophic support?

Answer 17

synaptic activity regulates neurotrophic factors that have neuroprotective actions such as BDNF, pro-NGF, FGF2

Question 18

how is NMDAR and the PI-3 kinase/AKT pathway related?

Answer 18

promotes cell survival through BAD, P53, FOXO

Question 19

NMDAR and anti-oxidation?

Answer 19

activity regulates the thioredoxin peroxiredoxin system which promotes gene expression changes that boost anti-oxidant defences

Question 20

What did Liu et al 2007 say vs Martell et al 2009?

Answer 20

Liu et al 2007- NR2B extrasynaptic receptor causes cell death whereas NR2A promotes survival
Martell et al 2009- NR2B receptor causes survival and NR2A causes cell death

Question 21

NR2B vs NR2A?

Answer 21

NR2B- extra-synaptic

NR2A- synaptic