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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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