5. EAA & Excitoxicity Flashcards
what is neurologically vital for normal fxn
- EAA NT system
- Ca2+
- O2
what is excitotoxicity?
explains why you have continued brain damage after trauma
= overstimulation of EAA system after ischemia –> damage neurons far/near ischemic region
what kind of trauma shows susbtantial evidence of involvement of excitotoxicity?
anything that impairs abiity to maintain ATP levels
- stroke
- global hypoxia or anoxia
- traumatic injury to brain
- hypoglycemia
what trauma shows strong evidence of involvement of excitoxicity
epilepsy
severe seizures
what is the first step of overstimulation of EAA
loss of blood flow –> w/i 4 mins O2 level in mitochondria drop to zero –>
NO MORE ATP PRODUCTION
-Na/K ATPase activity decreases & cell DEPOLARIZES
what happens after the cell has depolarized due to reduced activity of Na/K ATPase
neurons reach threshold –> get tons of APs –> release a ton of NTs
-still get AP in hypoxic condition, but not able to maintain RMP
How are cells distant from the ishcemic lesion affected
neurons were activated, traveled thru-out brain and release NTs in to synaptic clefts close/far from ischemic site
Why is the increased EAA (NT) release so bad, can’t glial cells reuptake & remove them from the cleft?
NO!
reuptake is dependent on secondary active transport of Na+ (no ATP b/c hypoxic!) –> so EAA continue to accumulate and bind a bunch of receptors
what causes more Ca2+ to enter into postsyn cells?
non-NMDA activation –> depolarization –> force Mg2+ out of Ca2+ cell ==> allows Ca2+ to enter post synaptic cell
what is a normal fxn of Ca2+ that is dangerous in these cases of overstimulation
increases Phospholipase A activity (PLA) –> acts on membrane & release arachnoid acid ==> physical damage
arachnoid acid also = messenger –> cause release of Ca2+ from ER & mito ==> unfolded protein response (ER stops making protein)
==> eIF2a-kinase activated (alter transcription/translation)
==> mito dysfxn
Which enzyme is activated by Ca2+ & leads to proteolysis of structural proteins?
mu-calpain
= proteolysis of structural proteins and other enzymes like eIF4G (stop making RNA for protein synthesis)
==> metabolic & structural impairment of neurons that are not near hypoxic region
Ca2+ also activates __________, which increases production of NO
calcineurin
-uses nitric oxide synthase to make tons of NO ==> vasodilator
NO –> free radicals (damage vasculature further)
rmr: NO = (g) & very soluble across lipid membranes
What is activated when Ca2+ released from intracellular stores
activate PLA
activate mu-calpain
activate calicinurin
mitochondira releases enzymes like Caspase 9 –> which activates Caspase 3 = pro-apototic ==> activate apoptotic pathway
Why is it bad to administer O2 after a certain amount of time
- Mitochondria no longer has enzymes –> cant use O2 to make ATP
O2 –> made into free radicals ==> further damage
- If ATP is made –> will be used by apoptotic cells bc these are the active cells in body now
- if ATP is made –> phosphorylation –> phosphorylate eIF2a kinase (decrease protein synthesis even more) & activate more Caspase 3 (more apoptosis)
production of DA, NE, E
Tyr (tyrosine hydroylase)–> DA –> (into vesicle via VMAT) –> NE –> (out of vesicle & PMNT)–> E
what is reserpine
inhibit VMAT (synaptic failure)
where is E most located
medulla
where is 5HT found & what is its fxn
hypothalamus/limbic system : mood
raphe nuclei/cerebellum : motor
reputake, MAO & COMT remove _____ NTs from the synapse
DA/NE/E
5HT
what are the receptors for 5HT
5HT3 = ionotopic –> Na into cell
5HT 1,2c,4,5,6,7 = metabotopic
-3 for area postrema
6 for antidepressent
where is DA located & what is its fxn
basal ganglia: motor (parkinsons if messed up)
hypothal/limbic: endocrine/emotion
cortex
what are the receptors for DA
all metabotropic
D1 &5 = increase camp - excite
D2, 3, 4 –> decrease camp
what NT is associated with tuberomammillary nucleus & what is its fxn
Histamine
wakefulness
how is His removed from the synapse
reuptake & COMT & diamine oxidase
