Excitotoxicity (Karius) Flashcards
What causes damage to prevously unaffected neurons after brain damage (ischemia/trauma etc)
Excitotoxicity. Overstimulation of the EAA system damages the neurons.
What happens shortly after O2 drops to 0 in the neuron MT as a result of ischemia?
Everything ceases. No ATP production, or Na/K ATPase activity. Now nothing maintains the RMP and thus causes depolarization of the neuronal cell membrane
Can hypoxic neurons still create action potentials?
Yes. Maintaining RMP is the one that requires a lot of work (rolling the ball up a hill). The energy from that is used to depolarize the membrane. Depolarization and letting ions enter is the “default” action.
What happens after the action potential is generated?
AP reaches the terminal axon and releases NTs. Lots of EAA are released to different parts of the brain, not just the ones that originally got ischemic.
What other problem does EAA pose once it is released in the synaptic cleft under these conditions?
EAA needs to be reuptook in to the Glial cells via Na+ dependent mechanism. There is no O2 = no ATPase activity = no reuptake. EAA accumulates in the synapse and binds to another receptor to repeat the process.
How does the release of EAA damage neurons?
Synapses have both non-NMDA and NMDA receptors. Non-NMDA activation produces depolarization that forces Mg out of the calcium channel and clear the way for Ca to enter the cell.
Why is Calcium release a big player in excitotoxicity?
Ca is a good second messenger that activates a bunch of enzymes in the cell.
What happens when there is increased intracellular Ca?
Phospholipase A activation > release of arachidonic acid off the membrane (aka damaging it).
What does arachidonic acid do after it is released from the membrane?
Ca release from the ER and MT > causes ER to stop making proteins > eIF2a kinase activated > MT dysfunction
What other thing happens due to increased intracellular Ca?
U-calpain (proteolytic enzyme) activation. Structural proteins (e.g. spectrin) and other proteins like eIF4g (responsible for protein synthesis) are proteolyzed > metabolic and structural impairment of neuron
What is another thing that happens if intracellular Ca is high?
Calcineurin is activated > Excess NO production via NOS (Nitric oxide synthase). NO is lipid soluble and can diffuse through the brain cells. Can damage any neuron in the system.
What is yet another thing that happens due to high intracellular Ca?
Apoptotic pathway activation. Release of Capsase 9 > capsase 3 > apoptosis
What happens after oxygen is brought back to the ischemic area?
MT has lost a lot of the enzymes, so their ability to make ATP is now impaired. They make free radicals instead.
Will some cells still be able to make ATP?
Yes, but the enzymes available are now different. So ATP can be used to destroy the cell instead.
How does ATP production after reperfusion damage the neurons?
Kinases take the ATP converts it to ADP and PO4. eIF2a kinase is phosphorylated > decrease in protein synthesis = activation of capsase 3 = increase in apoptosis
