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
what are the histamine receptors
H1- PLC - wakeful
H2- increase camp
H3 - decrease His into presyn
what areas are assocaited with Ach & what are their fxns
striatum -voluntary movement
midbrain/pons - brain arousal, sleep/EEG
how is Ach
- put into vesicles?
- removed from synaptic cleft
into vesicle VAchT
removed via AchE
what are the receptors for Ach
- M1/3/5 - Gq (M1 = neuronal)
- M2/4 = Gi (4 = presyn autoreceptor striatum)
- nicotinic (can change amount of Ca2+ allowed in by changing subunits of the channel)
what are the purine NTs & where are they found
ATP, ADP, adenosine (everywhere)
esp: cortex
cerebellum
hippocampus
basal ganglia
what is VNUT
protein that stores purine NTs in vesicles until ready for release
P1 receptor -
ligand = adenosine
on presyn: inhibit NT release
but on postsyn: sleep/general inhibiton
P2-
P2x - ligand - ATP -> ionotopic
P2y- metabotropic; ligand = ADP/ATP/UDP/UTP = Gi/Gq coupled ==> learning & memory
how is gaba transported into vesicles
VGAT
how is gaba removed from the synapse
GAT
1- on presyn = recycle
- on glial cell - break down - release & then presyn recycles
GABA-A receptor
ionotropic (IPSP)
modulate benzodiazepine site, ethanol, steroid, general anesthtics (propofol)
GABA-B receptor
metabotropic
Gi/Go couples - activate GIRK (K channel) & turn off Ca channel
on presyn; to regulate NTs
on postsyn: to inhibit postsyn cell
what is the receptor for glycine
ionotropic - Cl- = IPSP
= spinal inhibiton
=blocked by stychnine
what are names of opiods & where are they found
endorphins, enkephalins, dynerphins, nocicpetins
basal ganglia, hypothal, pontine & medullary sites
what is the precursor for beta-endorphins
POMC (proopiomelanocotinin)
what makes met- enkephalin & leu-enkephalin
proenkephalin ( 5 AAs; first 4 = YGGF_)
5th determines what itll be
M: met
L: leu
what do prodynorphins make
leu enkaphalins
dynorphins
what is orphanim FQ
makes nociceptin
how are opiods removed from the synapse
enkephalinase
aminopeptidase
mu-receptor
opiods metabotropic Gi/Go)
–> increased K efflux
causes: analgesia
resp. depression
euphoira
constipation
sedation
kappa receptors
opiod metabotropic (Gi/Go)
–> decease Ca influx
cause analgesia
dysphoria
diuresis
miosis
delta receptors
opiod: metabotropic - Gi/Go
- decrease Ca influx
cause analgesia
what are exogenous endocannabinoids
THC
what are endogenous cannabinoids
anandimide
2 arachidomyl- glyceral
where are endocannabinoids located & what are the fxns
basal ganglia: motor/mood
sp cord: nociception modification
cortex: neuroprotection
hippocampus: memories
hypothal: energy/hunger
how do endocannabinoids degrade
hydrolysis (anadamide - FAAH & 2AG - MAGL)
oxidation: cycloxgenase & lipoxygenase
C1 receptor
endocannibinoids
- bind AEA & 2AG with high affinity
- striatum, thalamus, hypotha, cerebellum & lower Br.st
in presyn terminal of EAA & GABA releasing cells –> decrease release by Gi
C2 receptor
endocannabinoids
microglia & macrophages = modulate inflam/injury
dendrites/soma - assocaited w/ N injury
bind 2AG > AEA
EAA examples
glutamate
aspartate
NMDA receptor
influx of Ca ==> long EPSP
ligand & Vg gated
NMDA (exogenous), Glu & Asp (endogenous)
short/long term memory & synaptic plasticity
how are NMDA receptors modulated
- glycine binding site: coagonist= required
- Mg binding site- w/i channel, must be removed to open (even if gly & NT bind) (often open after slight EPSP from Non-NMDA receptors
Non-NMDA receptors
influx Na –> short EPSP
AMPA (exogenous) glu & asp (endogenous)
sensory, upper MNs
modulated by: benzodiazepine : decease amount of EPSP
metabotropic receptors of EAA
mGlu1 - Gq
mGlu2&3 - Gi
how is NO formed from NMDA activation
Ca2+ into cell –> bind calcinurum –> actiavte NOS –> make NO –> lipid soluble so out of cell & effect neurons
-needed for
- neural fxn (hippcam/cerebellum: memory & pons/medulla: heart/resp)
- immunological fxn: made by macrophage bc its toxiz
