5. EAA & Excitoxicity Flashcards by Priyanka Barad

what is neurologically vital for normal fxn

EAA NT system
Ca2+
O2

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what is excitotoxicity?

explains why you have continued brain damage after trauma

= overstimulation of EAA system after ischemia –> damage neurons far/near ischemic region

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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

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what trauma shows strong evidence of involvement of excitoxicity

epilepsy

severe seizures

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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production of DA, NE, E

Tyr (tyrosine hydroylase)–> DA –> (into vesicle via VMAT) –> NE –> (out of vesicle & PMNT)–> E

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what is reserpine

inhibit VMAT (synaptic failure)

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where is E most located

medulla

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where is 5HT found & what is its fxn

hypothalamus/limbic system : mood

raphe nuclei/cerebellum : motor

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reputake, MAO & COMT remove _____ NTs from the synapse

DA/NE/E

5HT

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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

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where is DA located & what is its fxn

basal ganglia: motor (parkinsons if messed up)

hypothal/limbic: endocrine/emotion

cortex

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what are the receptors for DA

all metabotropic

D1 &5 = increase camp - excite

D2, 3, 4 –> decrease camp

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what NT is associated with tuberomammillary nucleus & what is its fxn

Histamine

wakefulness

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how is His removed from the synapse

Study These Flashcards

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

1. M1/3/5 - Gq (M1 = neuronal) 2. M2/4 = Gi (4 = presyn autoreceptor striatum) 3. 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 2. 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

1. glycine binding site: coagonist= required 2. 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 1. neural fxn (hippcam/cerebellum: memory & pons/medulla: heart/resp) 2. immunological fxn: made by macrophage bc its toxiz

5. EAA & Excitoxicity Flashcards

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