EAA and excitotoxicity Flashcards
What are two major players in Excitotoxicity
EAA neurotransmitter system
Calcium (NMDA receptors)
Oxygen
When does overstimulation of the EAA system occurs?
it occurs after an ischemia in the brain and is responsible for damage to neurons whether or not they were exposed to the ischemia or not
evidence in:
Strokes
global hypoxia or anoxia
traumatic injury to the brain
hypoglycemia
What occurs in Step 1 of Excitotoxicity
Depolarization of the membrane
starts with the localized event
- loss of blood flow
- 4 minutes no O2
- ATP production stops in the mitochondria
- Na/K ATPase activity drops quickly
- Causes depolarization of neuronal cell membrane
What occurs in Step 2 of Excitotoxicity
Action Potentials
As the neurons depolarize they reach threshold and the voltage-gate sodium channels open leading to action potentials
(have difficulty to repolarize)
What occurs in Step 3 of Excitotoxicity
Releasing of the EAA
after the Action potentials reach a presynaptic terminal a release of NT into the clefft
Since there are so many synapses that use EAA, lots of EAA is being released into many different parts of the brain
THese will cause damage to neurons because they are recieving so much input from so many different places
What is problematic in the uptake of EAA
since Gilal cells need ATP to uptake EAA (secondary active transport of Na+) and all of the Mitochondrias cant produce it, Thee EAA in the cleft cant get uptoke
What occurs in step 4 of Excitotoxicity
Increase of Calcium levels in the post-synaptic cell
Activation if the non-NMDA produces the depolarization that will force the Mg++ out of the calcium channel
Allows calcium to enter the post synaptic cell
What are the 4 consequences of high intracellular calcium
1) increase in phospholipase A activity
2) Activation of u-calpain (a proteolytic enzyme)
3) Activation of calcineurin
4) Activation of the apoptotic pathway
Why is increase activation of Phospholipase A problematic via high intracellular Calcium
releases arachidonic acid which physically damages the membrane
Arachidonic acid will also increase the release of Ca++ from the ER and mitochondria but these wont be properly folded so their will be an unfolded protein response
then an eIF2a-kinase activation and a mitochondrial dysfunction
What happens when u-calpain becomes activated via high amounts of intracellular Ca++
since u-calpain is a proteolytic enzyme:
Proteolysis of structural proteins including spectrin
proteolysis of other enzymes, proteins, including eIF4G (further disruption of protein synthesis)
Leads to metabolic and structural impairment of neurons
What happens with activation of Calcineurin via high levels of intracellular calcium
Excess production of Nitric oxide via activation of nitric oxide synthesis
Nitric oxide is a vasodilater and at high levels can be toxic via oxidative stress
What happens with the activation of the apoptotic pathway via high levels of intracellular calcium
high levels of calcium causes the mitochondria to release enzymes including cytochrome C, and caspase 9
caspase 9 will then lead to release of Caspase 3 which is pro-apoptotic
why is reperfusion bad after ischemia
since the mitochondria has released many of their enzymes, they cant use O2 to make ATP
therefore the O2 will float around as free radicals and damage the cells
why even if some Mitichondria are functional is reperfusion bad
the mitichondria may be activating a different set of proteins compared to when they are in their healthy state:
Kinases that make ATP to ADP + PO4
which will phosphorylate eIL2a kinase which will further activate caspase 3 and the apoptotic signaling
