Excitotoxocity

Question 1

What effect does ischemia have on cells?

Answer 1

disrupts Ca2+ levels that initiate cascade of events where cell further compromised

Question 2

What are the 2 types of receptors assoc w/ excitatory AA NTs?

Answer 2

ionotropic (cations)

metabotropic (G protein)

Question 3

What does the NDMA receptor bind & what is the result of that binding?

Answer 3

N-Methyl-D-Aspartate, Aspartate, Glutamate

allows Ca2+ to enter cell (along w/ Na+)

Question 4

What are some of the modulatory sites of the NDMA receptor?

Answer 4

glycine binding site
pH sensitive region
Zn binding site
PCP binding site
Mg2+ binding site

Question 5

How does glycine work on NDMA receptor?

Answer 5

site located near primary agonist binding site (extracell)

glycine acts as co-agonist & potentiates effects of primary ligand

Question 6

How does the pH sensitive region affect the NDMA receptor?

Answer 6

on extracell side of complex

increased H+ ions inhibit the opening of the channel

Question 7

How does the zinc binding side affect the NDMA receptor?

Answer 7

found on inside of channel

modifies Ca2+ current into cell

Question 8

How does the PCP binding site affect the NDMA receptor?

Answer 8

inside the channel

blocks the Ca2+ current

Question 9

How does the Mg2+ site affect the NDMA receptor?

Answer 9

inside the channel & blocks at a physiological level

Mg2+ is bound to site @ resting membrane potential

Mg2+ will LEAVE site & allow Ca2+ current w/ depolarization of cell

Question 10

What are the 2 Non-NMDA receptors?

Answer 10

AMPA receptor

Kainate receptor

Question 11

How does AMPA receptor work?

Answer 11

can bind AMPA, glutamate, aspartate

usually leads to Na+ influx

modulation site for benzodiazipines leads to inhibition of ion influx

Question 12

How does the kainate receptor work?

Answer 12

can bind kainate, glutamate, aspartate

leads to some Ca2+ influx but primarily Na+ influx

Question 13

general mode of action of metabotropic receptors

Answer 13

some decrease cAMP
some increase IP & DAG
1 causes increase in cAMP

Question 14

Rasmussen’s encephalopathy

Answer 14

rare conditions where seizures in childhood that causes brain damage destroying 1 hemisphere of brain

only known treatment is to remove affected hemisphere

some findings of Abs directed v metabotropic receptors in humans suffering from disease

Question 15

Process of removal of EAA @ synapse by astrocytes & neurons

Answer 15

3 different transport systems for removal @ synapse

Na+ dependent secondary active transport
high affinity systems
loss of Na+ gradient will slow uptake down considerably

Question 16

Glutamate-glutamine cycle

Answer 16

in astrocytes-take up glutamate

convert to glutamine by glutamine synthetase (requires ATP)

glutamine released back into extracell space for neuron to take it back up

glutamine is converted back to glutamate in neuron (2nd source)

Question 17

EAA @ non-NMDA receptors

Answer 17

most of primary afferents in spinal cord

general excitatory synaptic transmission

Question 18

EAA @ NMDA receptors

Answer 18

found thru CNS but mostly @ hippocampus

produces long-term changes in synaptic strength
memory
learning

Question 19

EAA @ metabotropic receptors

Answer 19

widely thru CNS

many are presynaptic & serve to modify EAA release

general effect to decrease synaptic excitability

involved in synaptic plasticity assoc w/ learning & memory

Question 20

Where does NO come from?

Answer 20

direct result of NMDA receptor activation

Calcineurin is activated w/ Ca2+ influx & removes PO4 from NOS to activate it

NOS takes arginine & cleaves NO from it

Question 21

actions of Nitric Oxide

Answer 21

increases activation of guanylyl cyclase=increase cGMP

increases Ca2+ dependent K+ channel

effects from increased cGMP

Question 22

effects of cGMP (from NO)

Answer 22

smooth muscle=relaxation

made by endothelial cells=acts on smooth muscle for relaxation

major inhibitory NT in gut causing relaxation

Question 23

effects of NO in CNS

Answer 23

respiratory control
cardiovascular control
memory/learning

Question 24

major non-neural effect of NO

Answer 24

NO is mechanism for dilation in cerebral vasculature

increase in neuronal activity leads to increased blood flow as vasculature dilates

Question 25

Removal of NO from synapse

Answer 25

NO UPTAKE b/c is lipid soluble half life is 5 sec & then degrades

Question 26

what is excitotoxicity?

Answer 26

direct consequence of activation of EAA system following insult to brain proposed to explain neuronal death/damage following ischemic events in brain

Question 27

what are strong examples for evidence implicating excitotoxicity?

Answer 27

cerebral ischemia hypoxia or anoxia mechanical trauma to CNS hypoglycemia

Question 28

in what cases does excitotoxicity have some involvement?

Answer 28

substantial evidence in epileptic seizures good evidence: Huntington's disease AIDS dementia complex neuropathic pain syndromes

Question 29

what is the 1st step with ischemic event?

Answer 29

increase in intracellular calcium

Question 30

what is the 2nd step with ischemic event?

Answer 30

activation of enzymes by excess Ca2+ in cell

Question 31

what is the 3rd step with ischemic event?

Answer 31

deranged cellular metabolism following enzyme activation

Question 32

what is the 4th step with ischemic event?

Answer 32

induction of apoptotic pathways

Question 33

what happens during reperfusion?

Answer 33

re-establishes blood flow & increases O2 levels leads to injury post-ischemic event due to production of peroxide radicals & enzymes not fxning to handle increase in ATP

Question 34

What contributes to reperfusion injury?

Answer 34

increase in O2 levels increase in ATP levels delivery of blood-borne chemicals (epi & WBCs) influx of growth factors alterations in blood flow/vascular permeability

Question 35

what is a specific effect to alterations in blood flow/vasc permeability?

Answer 35

reactive hyperemia due to O2 deprivation leads to vasodilation

Question 36

what is a non-specific effect to alter blood flow/vasc permeability?

Answer 36

lots of NO from neurons w/ activated NMDA receptors & from WBC which cauess smooth muscle relaxation & vasodilation

Question 37

what causes increase in vascular permeability?

Answer 37

direct effect of high conc of NO & indirect damage due to free radical production

Question 38

what is the main result of influx of fluid into damage areas?

Answer 38

EDEMA

Question 39

what is the problem with edema?

Answer 39

swelling can lead to rapid increase in intracranial pressure (b/c brain encased in skull) neurons are sensitive to increase in pressure & may stop function also compromises blood flow to area

Question 40

What might protect a brain from edema?

Answer 40

genetic & enviro factors may contribute to variance genetic variations in non-NMDA & NMDA channels that change amt of cation that can enter cell & limit or accentuate damage that can result from an injury may also relate to conc of anti-oxidants in brain enviro influences like presence of depressants in system prior to event

Question 41

Why was the swelling of Billy's brain so severe?

Answer 41

amount of NO produced by neurons exceeded what could be handled by normal degradation pathways so NO accumulated ischemia will trigger vasodilatory mechanisms & NO accumulates in vasculature b/c absence of normal blood flow enough NO in CNS that parts of brain w/ blood are being ACTED ON by NO so capillaries are leaking fluid & increase volume

Question 42

What was the cause of Billy's initial symptoms?

Answer 42

blood flow thru carotid interrupted by clot so many neurons unable to maintain membrane potentials so depolarized massive release of EAA initiated processes leading to neuronal cell death

Question 43

Why would systemic hypothermia & drug induced comas possibly help people who suffered brain injury?

Answer 43

both treatments decrease metabolism by neurons which should improve neuron's chances for survival