Excitatory amino acids - Excitotoxicity

Anna mph
Flashcards by Anna mph, updated more than 1 year ago
Anna mph
Created by Anna mph over 5 years ago


Degree Neuropharmacology Flashcards on Excitatory amino acids - Excitotoxicity, created by Anna mph on 12/19/2015.

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Question Answer
What are the diseases that are in which glutamate-induced neuronal death can be seen? Stoke Epilepsy Traumatic Head injuries Epilepsy Alzheimer's Parkinson's Schizophrenia Amyotrophic Lateral Sclerosis (Motor neuron disease)
Define necrosis Swelling due to osmosis (ions enter the cell i.e. through a ligand gated ion channel) leading to vacuolisation and cell lysis.
Define apoptosis. What is it used for? Programmed cell death. Cell cycle regulation - embryogenesis, maturation and aging.
What are the characteristics of apotosis? Condensation of chromatin in nucleus, reduction in cell volume, withering and shedding of cell membrane.
What can cause apoptosis to occur in healthy cells? Too much glutamate
What do elevated levels of extracellular glutamate cause? Persistent neuronal depolarisation
What are the three key elements in the cascade of cell death? 1) Increased Na+ influx 2) Increased Ca2+ influx 3) Exocytosis of glutamate
Why is increased influx of Na+ bad? Upsets the osmotic balance - causes necrosis (cell swell and dies)
Why is increased Ca2+ influx bad? Responsible for delayed neurodegeneration
Why is increased glutamate exocytosis bad? Spread and amplification of neurodegeneration.
What happens in slow excitotoxicity? 1) Mitochondrial energy production impaired 2) Reduction of ATP 3) Na+/K+ exchange impaired 4) Membrane resting potential becomes more depolarised 5) Cell is more excitable >> Increased glutamate release
What are the two components excitotoxicity? Necrosis and apoptosis
What are the two things that happen as a result of Ca2+ overload in a cell? 1) Mitochondrial impairment > decreased ATP > Cell death 2) Increase in Ca2+ dependent enzymes such as PLA2 > Increases arachadonic acid> inhibited glutamate re-uptake
What are the three pathways through receptors which mediate excitotoxicity? Starting from head injury etc. to Calcium overload. 1) i) Increased Glutamate ii) Increases NMDAR activation iii) Ca2+ overload
2/3) i) Increased glutamate ii) Increased KAR/AMPAR activation iii) Irreversible removal of Mg2+ (NMDAR pathway) iv)Increased Na2+ entrance, cell swells (reversible) > cell death
What is oxidative stress? Production of free radicals which leads to cell death.
What are the two different pathways that can cause oxidative stress? 1) Mitochondrial 2) PLA2
What happens when mitochondria 'mop up' intracellular calcium? Uncoupling of ATP production from mitochondria and production of free radicals.
Name a free radial Superoxide
What effect does the ATP deficiency have on extracellular glutamate concentrations? Failure ATP-dependent 3Na+/2K+ pump leads to reversal of glutamate transporters. Glutamate transported out of cell >> Increase in extracellular glutamate concentration.
What effect to free radicals have on neurons and what else does superoxide do? Free radicals kill neurons - superoxide is highly reactive and creates more free radicals
Which enzyme is responsible for destroying superoxide? Why doesn't it do so during oxidative stress? Superoxide dismutase (SOD). During oxidative stress it is over loaded (there is too much superoxide).
What is thought to occur in Huntington's disease in terms of free radicals? Misfolded/mutated a superoxide dismutase. Free radicals likely cause of neurodegeneration.
Which enzymes are activated by calcium influx? PLA2 - Phospholipase A2 nNOS - Nitric oxide synthase Proteases Lipases Endonucleases
What effect does the activation of PLA2 have? Increases arachadonic acid which inhibits glutamate uptake and leads to the production of free radicals.
What effect does the activation of nNOS have? Produces excessive amounts of NO" free radical.
What does the NO" react with? What does this produce and what damage does this cause, how can it cause this damage? NO" reacts with superoxide (O2"-) Forms peroxynitrite (ONOOH) Spreads neuronal damage to neighbouring regions Is membrane permeable
What is activated in response to inflammation and what does this cause? Inducible Nitric Oxide Synthase (iNOS) which leads to more NO" than nNOS.
What damage do lipases, proteases and endonucleases cause? 1) Damage lipid 2) Damage protein 3) Damage DNA
What are the two causes of stroke? Ischaemia Haemorrhage
What three major processes occur in an ischaemic stroke? 1) Inflammation 2) Production of free radicals 3) Increase in extracellular Glutamate
What is inflammation caused by? How does this effect extracellular glutamate levels? Necrotic cell death leads to release of inflammatory mediators. Glial cells transport glutamate >> cell death leads to increased glutamate release.
What can be used to treat a patient within three hours of having a stroke? How does it work? Tissue plasminogen activator (tPA) Disperses the blood clot.
Why can't treatment with tPA be used for a prolonged duration? tPA is an NMDAR PAM >> exacerbates excitotoxicity by enhancing the effect of glutamate.
Which type of stroke is treatment with a tPA limited to and what is required for diagnosis? Ischaemic CT scan
After blood supply has been restored after a stroke what can continue to cause damage? How long do you have to give treatment and what is this called? Free radicals 2-3h - therapeutic windown
What does ischaemia create in terms of neurons and what is it surround by? A core of neurons undergo irreversible ischaemic cell death - surround by a penumbra of tissue which is susceptible to cell death over the next 2-3h.
What effect should an ionotropic GluR antagonist or Glu release inhibitor have on neurons? Protect neurons from damage.
Why is there an anti-excitotoxic hypothesis? NMDAR antagonist, channel blocker, glycine site antagonists + AMPAR antagonist (NBQX) failed to live up to potential.
What have been the problems with treatments that try to decrease the effect of increased glutamate? Cause ataxia, memory loss and hallucinations.
What are the two underlying problems with targeting glutamatergic receptors? 1) Hard to separate effect on abnormal glutamatergic transmission and normal physiological transmission. 2) Stroke is multifactorial disorder - more than just glutamate receptors involved.
What characterises ALS (amyotrophic lateral sclerosis), symptoms and histology. 1) Muscle weakness>paralysis>death 2) Loss of upper and lower motoneurons.
When is ALS usually diagnosed and how long do people usually survive post diagnosis? 50s, 2-5 years.
What happens in terms of glutamate levels? How does this happen? Which receptor type is effected and what does this lead to? 1) Increase 2) Glu glial transporters selectively lost 3) Increase Ca2+ through AMPAR, cell death.
What is Riluzole? Glutamate release inhibitor and Na channel blocker - Treat ALS, modest increase in survival after taking drug for 1 year.
What is domoic acid/domoate? Where is it found? Potent AMPAR/KAR agonist - found in contaminated shellfish of West coast of USA and Canada.
What happens in amnesic shellfish poisoning? Why? 1) loss of short term memory 2) motor weakness 3) seizures 4) death Domoate can cross the BBB
What would expect to see in the hippocampus of an animal which ingested domoic acid? Atrophy - loss of neurons, vacuolisation and band of damaged tissue (white scarring).
What is the kindling response? Experimental form of epilepsy. Repeated low intensity stimulation of amygdala conditions it to further low intensity stimulation which leads to seizures.
What effect to NMDAR antagonists have on seizures? Prevent them.
How do repeated seizures lead to excitotoxicity? Increase Glu concentration
What is Rasmussen's enchephalitis? A very rare and severe form of human epilepsy - AMPAR antibodies created causing them to activate creating an epileptic focus.
What is PERAMPANEL? Negative Allosteric Modulator of AMPARs - treats partial seizures
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