Excitotoxicity

Question 1

Glutamate

Answer 1

Most abundant excitatory amino acids but also most toxic

Question 2

Toxic amino acids

Answer 2

Glutamate, aspartate, cysteine, homocysteine, cysteic acid, cysteine sulfonate

Question 3

Glutamate key roles in neurodevelopment and LTP (memoryformation)

Answer 3

Verderio et al., 1999

Question 4

Short exposure to glutamate leads to neuronal cell death. This is dependent on extracellular calcium

Answer 4

Choi et al 1987

Question 5

Removal of extracellular calcium results in LESS excitatory amino acid-induced cortical loss in a variety of neurons (cortical, hippocampal, cerebellar)

Answer 5

Choi et al., 1985, Rothman et al., 1987

Question 6

Glutamate taken up by?

Answer 6

presynaptic glu transporters, or glial transporters. E.g. EAAT2 or GLT1

Question 7

Glutamate is taken up postsynaptically by

Answer 7

kainate, AMPA or NMDA Rs

Question 8

At basal synaptic transmission NMDARs are….

Answer 8

blocked by Mg2+

Question 9

NMDARs open more slowly (slow EPSCs)

Answer 9

Hestrin et al., 1990

Question 10

MoA of domoic acid

Answer 10

Glutamate analogue. Activates kainate/AMPA Rs –> Ca2+ influx –> depolarisation –> glutamate release –> excitotoxicity. Domoic acid not readily removed by transporters

Question 11

In 1987 >100 people in Canada got toxic encephalopathy and the cause was found to be domoic acid from mussels

Answer 11

Perl et al., 1990

Question 12

Domoic acid builds up in

Answer 12

Algae. Then is eaten by shellfish

Question 13

BMAA found…

Answer 13

neurotoxin produced by cyanobacteria and found in cycad plant. This is eaten by flying fox bats which are consumed by the Chamorro people of Guam

Question 14

BMAA consumption may be related to cases of ALS-parkinsons-dementia complex in Guam

Answer 14

Banack + Cox, 2003

Question 15

BMAA MoA

Answer 15

activates AMPA/NMDA/kainate Rs –> excitotoxicity, also ROS production

Question 16

Death of individual cells

Answer 16

Apoptosis

Question 17

Death of group of cells

Answer 17

Necrosis

Question 18

Physiological stimuli e.g. BAX, BAD

Answer 18

Apoptosis

Question 19

Non-physiological stimuli e.g. ischaemia

Answer 19

Necrosis

Question 20

Shrinking of cytosol, consolidation of nucleus

Answer 20

Apoptosis

Question 21

Swelling of cytoplasm + mitochondria

Answer 21

Necrosis

Question 22

Blebbing of plasma membrane without loss of integrity

Answer 22

Apoptosis

Question 23

Loss of membrane integrity

Answer 23

Necrosis

Question 24

Energy dependent

Answer 24

Apoptosis

Question 25

Passive process

Answer 25

Necrosis

Question 26

MoA cell death pathways e.g. BAD, p38

Answer 26

Apoptosis

Question 27

MoA Ca2+ overload

Answer 27

Necrosis

Question 28

NMDA has neuroprotective properties - blockade in neonatal mice produced widespead apoptosis

Answer 28

Ikonomidou et al., 1999

Question 29

Synaptic NMDA effect on Pi3K

Answer 29

Increases

Question 30

Extrasynaptic NMDA mediate cell death; synaptic mediate protection

Answer 30

Hardingham et al., 2002

Question 31

Domoic acid more potent than kainate/glutamate at kainate Rs

Answer 31

Biscoe et al., 1975

Question 32

NR2B promotes death; NR2A promotes survival

Answer 32

Liu et al., 2007

Question 33

NR2B promotes surivial, NR2A promotes death

Answer 33

Martell et al., 2009

Question 34

NMDAR antagonists failed clinical trials for stroke and traumatic brain injury due to poor tolerance and efficacy

Answer 34

Ikonomidou et al., 2002

Question 35

SOD1 mutations affect glu transporters EAAT2 and GLT1 - lower EAAT2 levels in rates leads to neuronal death

Answer 35

Rothstein et al., 1996

Question 36

NMDA enhancement in SMA mouse models promotes survival

Answer 36

Biondi et al., 2008

Question 37

YAC128 mouse model of HD displays increased extrasynaptic NMDAR expression

Answer 37

Milnerwood et al., 2010

Question 38

Low doses of memantine in HD models improves neuropathology and cell death in HD mouse models

Answer 38

Lee et al., 2006

Question 39

Memantine MoA

Answer 39

Preferentially blocks extrasynaptic NMDA

Question 40

Synaptic NMDA in Alzheimers

Answer 40

Reduces production, release and aggregation of amyloid beta. Increases soluble components so promotes protective amyloidogenic pathways