Excitotoxicity

Question 1

After an ischemic event in the brain, there is usually continued damage that is related to EAA, calcium and oxygen. Describe the mechanisms caused by ischemia or anoxia which increases cytoplasmic Ca2+ levels.

Answer 1

During an ischemic or anoxia event, the O2 levels drop causing ATP production to stop, and Na/K ATPase activity to stop

The cell membrane is now depolarized and this triggers an action potential

The action potential triggers the release of EAA, which is nerver re-uptaken because that process is based on the secondary active transport of Na+, leading to an over abundance of EAA

The EAA continuesly binds to the NMDA receptor on the post-synaptic membrane which triggers the release of Ca2+

Question 2

What are the 2 consequences of an over abundance of intracellular calcium that results following an ischemic event in the brain?

Only include the consequences that relate to phospholipase A and u-calpain

Answer 2

1. Increases Phospholipase A activity which triggers the release of arachidonic acid. Arachadonic acid leads to calcium release from the ER and mitochondria causing protein synthesis errors and mitochondrial dysfunction
2. The proteolytic enzyme u-calpain gets activated and further disrupts protein synthesis

Question 3

One of the consequences of high intracellular calcium is the activation of calcineurin. What does this activation lead to

Answer 3

The activation of calcinuerin is it leads to the production of NO, which can produce a lot of free radicals especially when overexpressed

Question 4

The activation of phospholipase A, u-calpain, and calcineurin that result from the over-abundance of intracellular calcium ALL eventually lead to the activation of the apoptotic pathway. Explain the apoptotic pathway that results

Answer 4

The release of calcium from the intracellular stores triggers the mitochondria to release all of its enzymes including cytochrome C and Caspase 9

The release of Caspase 9 leads to the activation of Caspase 3, the pro-apoptotic enzyme

Question 5

Reperfusion is the re-addition of oxygen to an area following an ischemic event. While this process seems like a good idea, explain why it is not so good for the brain

Answer 5

The previous ischemic event damaged mitochondria, and now they are unable to use oxygen efficiently

The un-utilized oxygen gives off free radicals

Question 6

T/F: Phosphorylation of elF2a kinase leads to further decrease in protein synthesis and FURTHER activates caspase 3, which FURTHER INCREASES apoptotic signalling.

Answer 6

True