BB30044: Excitotoxicity (RW)
Excitotoxicity = an over-excitation of neurons involving:
Glutamate
Ca2+-dependent mechanisms
Free radicals – oxidative stress
Inflammation
Glutamate-mediated excitotoxic damage: 2 types:-
Rapidly-developing excitotoxic damage (mins, hours & days following brain
insult/trauma) following:
- Head trauma, alcohol withdrawal (latter: over-activation of NMDARs)
- Cerebral ischaemia (Stroke), Foetal ischaemia
Slowly-developing excitotoxic damage associated with:
- Neurodegenerative conditions: AD, PD, HD, Motor neuron disease (ALS)
- Age-related cognitive decline
Experimental evidence that Glutamate is an excitotoxin:
In vitro: administration of high doses of glutamate induced degeneration of retinal
neurons
In vivo: injection of glutamate/ glutamate analogues (NMDA, domoate, kainate)
into brain caused cell loss particularly at postsynaptic dendrites and somas in
glutamatergic-rich brain regions
Prolonged electrical stimulation of preforant path fibres damages hippocampal
neurons
All of the above can be diminished by glutamate receptor antagonists: these show
some protection in models of cerebral ischaemia (stroke)
Epidemiological (& controversial) evidence that Glutamate is an excitotoxin:
Number of syndromes are associated with ingestion of dietary excitotoxins:
- Domoate: from
seaweed
contaminated
with algal toxins, not
limited to humans (seals, seabirds). Domoate is an analogue of kainate (3 times
the potency) so over-activates kainate receptors
- BOAA: agonist at AMPA receptor, causes syndrome similar to motor neuron
disease (degeneration of motor neurons)
- BMAA: agonist at AMPA and NMDA receptors
Mechanisms of glutamate-mediated
excitotoxicity:
E.g. Excitotoxicity in Ischaemia:
Ischaemia = loss of oxygen and glucose supply
to the brain, due to stroke or other reasons
, Leads to depletion of the brain’s energy supply: this is vulnerable since the brain
has limited endogenous metabolic stores (glycogen) and a limited capacity to
utilise fatty acid stores.
Reduction in aerobic metabolism leads to loss of ATPase pump activity – lack of
ATP-dependent active transport across neuronal membranes
Loss of ionic homeostasis leads to neuronal depolarisation
This deregulates control of synaptic signalling – triggers glutamate release
unlinked to action potential arrival
Glutamate activates postsynaptic NMDA and AMPA receptors and opens ion
channels, leading to a huge increase in intracellular calcium ion levels
This drives subsequent neuronal injury
Another pathway to neuronal injury involves acidosis, free radicals & lipases
1. Reversal of glutamate
transporters:
Extracellular
glutamate is usually
dealt with by sodium-dependent transporters on
glial cells and neurons
However, these glutamate transporters depend
on a sodium gradient for their functionality. This
is normally maintained by sodium-potassium
pumps.
Under ischaemic conditions, these sodium-
potassium pumps fail (lack of ATP) and
intracellular sodium levels rise.
Sodium gradient required to pump glutamate
out of the synapse is lost.
Sodium eventually rises to a threshold level that results in failure of glutamate
transport back into cells but also causes transporter reversal – glutamate is
pumped back out into the synapse.
This is the cycle of excitotoxicity: failure of glutamate clearance contributes
further to extracellular concentration of glutamate.
2. Rise in postsynaptic calcium ions:
Excessive synaptic glutamate binds to
postsynaptic AMPARs, causing a sodium ion influx.
This triggers NMDAR channel opening and calcium
ion influx.
In addition, sodium-calcium antiporter activity is
lost (lack of ATP) – usually pumps Na+ out of
neuron and Ca2+ into neuron. Leads to further
rise in intracellular calcium.
Also a loss of calcium-buffering into key
organelles – in neurons, mitochondria have a key
calcium-buffering role, and failure of
Excitotoxicity = an over-excitation of neurons involving:
Glutamate
Ca2+-dependent mechanisms
Free radicals – oxidative stress
Inflammation
Glutamate-mediated excitotoxic damage: 2 types:-
Rapidly-developing excitotoxic damage (mins, hours & days following brain
insult/trauma) following:
- Head trauma, alcohol withdrawal (latter: over-activation of NMDARs)
- Cerebral ischaemia (Stroke), Foetal ischaemia
Slowly-developing excitotoxic damage associated with:
- Neurodegenerative conditions: AD, PD, HD, Motor neuron disease (ALS)
- Age-related cognitive decline
Experimental evidence that Glutamate is an excitotoxin:
In vitro: administration of high doses of glutamate induced degeneration of retinal
neurons
In vivo: injection of glutamate/ glutamate analogues (NMDA, domoate, kainate)
into brain caused cell loss particularly at postsynaptic dendrites and somas in
glutamatergic-rich brain regions
Prolonged electrical stimulation of preforant path fibres damages hippocampal
neurons
All of the above can be diminished by glutamate receptor antagonists: these show
some protection in models of cerebral ischaemia (stroke)
Epidemiological (& controversial) evidence that Glutamate is an excitotoxin:
Number of syndromes are associated with ingestion of dietary excitotoxins:
- Domoate: from
seaweed
contaminated
with algal toxins, not
limited to humans (seals, seabirds). Domoate is an analogue of kainate (3 times
the potency) so over-activates kainate receptors
- BOAA: agonist at AMPA receptor, causes syndrome similar to motor neuron
disease (degeneration of motor neurons)
- BMAA: agonist at AMPA and NMDA receptors
Mechanisms of glutamate-mediated
excitotoxicity:
E.g. Excitotoxicity in Ischaemia:
Ischaemia = loss of oxygen and glucose supply
to the brain, due to stroke or other reasons
, Leads to depletion of the brain’s energy supply: this is vulnerable since the brain
has limited endogenous metabolic stores (glycogen) and a limited capacity to
utilise fatty acid stores.
Reduction in aerobic metabolism leads to loss of ATPase pump activity – lack of
ATP-dependent active transport across neuronal membranes
Loss of ionic homeostasis leads to neuronal depolarisation
This deregulates control of synaptic signalling – triggers glutamate release
unlinked to action potential arrival
Glutamate activates postsynaptic NMDA and AMPA receptors and opens ion
channels, leading to a huge increase in intracellular calcium ion levels
This drives subsequent neuronal injury
Another pathway to neuronal injury involves acidosis, free radicals & lipases
1. Reversal of glutamate
transporters:
Extracellular
glutamate is usually
dealt with by sodium-dependent transporters on
glial cells and neurons
However, these glutamate transporters depend
on a sodium gradient for their functionality. This
is normally maintained by sodium-potassium
pumps.
Under ischaemic conditions, these sodium-
potassium pumps fail (lack of ATP) and
intracellular sodium levels rise.
Sodium gradient required to pump glutamate
out of the synapse is lost.
Sodium eventually rises to a threshold level that results in failure of glutamate
transport back into cells but also causes transporter reversal – glutamate is
pumped back out into the synapse.
This is the cycle of excitotoxicity: failure of glutamate clearance contributes
further to extracellular concentration of glutamate.
2. Rise in postsynaptic calcium ions:
Excessive synaptic glutamate binds to
postsynaptic AMPARs, causing a sodium ion influx.
This triggers NMDAR channel opening and calcium
ion influx.
In addition, sodium-calcium antiporter activity is
lost (lack of ATP) – usually pumps Na+ out of
neuron and Ca2+ into neuron. Leads to further
rise in intracellular calcium.
Also a loss of calcium-buffering into key
organelles – in neurons, mitochondria have a key
calcium-buffering role, and failure of
