19: Excitotoxicity In Ischemic Event

Question 1

Two major molecules in excitotoxicity

Answer 1

O2, Ca

Question 2

What system becomes overstimulated in ischemia in the brain? What effect can that have?

Answer 2

EAA - can damage neurons even if they aren’t in the ischemic area

Question 3

3 steps in an ischemic event that cause membrane depolarization

Answer 3

1. Local event -> immediate loss of blood flow
2. In 4 minutes: O2 levels drop to 0 near mito -> no more ATP
3. Na/K ATPase activity stops -> membrane depol

Question 4

Result of depol in an ischemic event: 3 steps

Answer 4

1. Depol
2. AP
3. EAA released into many synaptic clefts -> too many parts of the brain
4. EAA cant be uptaken by glial cells, so it repeatedly binds same receptors

Question 5

Why cant glial cells uptake excess EAA in ischemia?

Answer 5

They use Na/K ATPase, which wont work without ATP

Question 6

After increased receptor binding due to EAAs, lots of Ca ends up in the post-synaptic cell. What are four main consequences of that?

Answer 6

1. Phospholipase A increases
2. u-calpain activation
3. Calcineurin activation
4. Apoptotic pathway activation

Question 7

What does phospholipase A do?

Answer 7

Acts on membrane, causing release of arachidonic acid

Question 8

Arachidonic acid does what? Three things

Answer 8

Becomes a messenger

1. Ca release from ER/mito
2. Stops the ER from making proteins
3. EI2a-kinase activation

Question 9

What type of protein is u-calpain

Answer 9

Proteolytic enzyme

Question 10

What does u-calpain do?

Answer 10

Proteolysis of structural proteins, eIF4G, and other proteins

Question 11

What does calcineurin do?

Answer 11

Activates NOS -> NO

Question 12

Apoptotic pathway activation

Answer 12

Mito releases caspase 9 -> activates caspase 3 -> pro-apoptosis

Question 13

What happens with reperfusion of O2 into an ischemic system

Answer 13

Mito have an impaired ability to use the O2, so they make free radicals instead