Excitotoxocity Flashcards
What effect does ischemia have on cells?
disrupts Ca2+ levels that initiate cascade of events where cell further compromised
What are the 2 types of receptors assoc w/ excitatory AA NTs?
ionotropic (cations)
metabotropic (G protein)
What does the NDMA receptor bind & what is the result of that binding?
N-Methyl-D-Aspartate, Aspartate, Glutamate
allows Ca2+ to enter cell (along w/ Na+)
What are some of the modulatory sites of the NDMA receptor?
glycine binding site pH sensitive region Zn binding site PCP binding site Mg2+ binding site
How does glycine work on NDMA receptor?
site located near primary agonist binding site (extracell)
glycine acts as co-agonist & potentiates effects of primary ligand
How does the pH sensitive region affect the NDMA receptor?
on extracell side of complex
increased H+ ions inhibit the opening of the channel
How does the zinc binding side affect the NDMA receptor?
found on inside of channel
modifies Ca2+ current into cell
How does the PCP binding site affect the NDMA receptor?
inside the channel
blocks the Ca2+ current
How does the Mg2+ site affect the NDMA receptor?
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
What are the 2 Non-NMDA receptors?
AMPA receptor
Kainate receptor
How does AMPA receptor work?
can bind AMPA, glutamate, aspartate
usually leads to Na+ influx
modulation site for benzodiazipines leads to inhibition of ion influx
How does the kainate receptor work?
can bind kainate, glutamate, aspartate
leads to some Ca2+ influx but primarily Na+ influx
general mode of action of metabotropic receptors
some decrease cAMP
some increase IP & DAG
1 causes increase in cAMP
Rasmussen’s encephalopathy
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
Process of removal of EAA @ synapse by astrocytes & neurons
3 different transport systems for removal @ synapse
Na+ dependent secondary active transport
high affinity systems
loss of Na+ gradient will slow uptake down considerably
Glutamate-glutamine cycle
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)
EAA @ non-NMDA receptors
most of primary afferents in spinal cord
general excitatory synaptic transmission
EAA @ NMDA receptors
found thru CNS but mostly @ hippocampus
produces long-term changes in synaptic strength
memory
learning
EAA @ metabotropic receptors
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
Where does NO come from?
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
actions of Nitric Oxide
increases activation of guanylyl cyclase=increase cGMP
increases Ca2+ dependent K+ channel
effects from increased cGMP
effects of cGMP (from NO)
smooth muscle=relaxation
made by endothelial cells=acts on smooth muscle for relaxation
major inhibitory NT in gut causing relaxation
effects of NO in CNS
respiratory control
cardiovascular control
memory/learning
major non-neural effect of NO
NO is mechanism for dilation in cerebral vasculature
increase in neuronal activity leads to increased blood flow as vasculature dilates
Removal of NO from synapse
NO UPTAKE b/c is lipid soluble
half life is 5 sec & then degrades
what is excitotoxicity?
direct consequence of activation of EAA system following insult to brain
proposed to explain neuronal death/damage following ischemic events in brain
what are strong examples for evidence implicating excitotoxicity?
cerebral ischemia
hypoxia or anoxia
mechanical trauma to CNS
hypoglycemia
in what cases does excitotoxicity have some involvement?
substantial evidence in epileptic seizures
good evidence:
Huntington’s disease
AIDS dementia complex
neuropathic pain syndromes
what is the 1st step with ischemic event?
increase in intracellular calcium
what is the 2nd step with ischemic event?
activation of enzymes by excess Ca2+ in cell
what is the 3rd step with ischemic event?
deranged cellular metabolism following enzyme activation
what is the 4th step with ischemic event?
induction of apoptotic pathways
what happens during reperfusion?
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
What contributes to reperfusion injury?
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
what is a specific effect to alterations in blood flow/vasc permeability?
reactive hyperemia due to O2 deprivation leads to vasodilation
what is a non-specific effect to alter blood flow/vasc permeability?
lots of NO from neurons w/ activated NMDA receptors & from WBC which cauess smooth muscle relaxation & vasodilation
what causes increase in vascular permeability?
direct effect of high conc of NO & indirect damage due to free radical production
what is the main result of influx of fluid into damage areas?
EDEMA
what is the problem with edema?
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
What might protect a brain from edema?
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
Why was the swelling of Billy’s brain so severe?
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
What was the cause of Billy’s initial symptoms?
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
Why would systemic hypothermia & drug induced comas possibly help people who suffered brain injury?
both treatments decrease metabolism by neurons which should improve neuron’s chances for survival
