Neuronal and muscle toxins Flashcards
Where does tetrodotoxin come from?
It is produced by marine bacteria- animals have the bacteria living inside them which produce the toxin- symbiosis
Some animals which have TTX
Puffer fish- chef has to remove the part of the fish which causes the effects
Blue ringed octopus- toxin is in the bite
What are the symptoms of TTX ingestion
Numbness of lips and tongue Facial tingling Headache Nausea Dizziness Vomiting Increased bodily paralysis- it spreads Respiratory paralysis which leads to death 20 mins-8 hours to death depending on how much is ingested
What are the symptoms of being bitten?
Same as ingested but no facial effects
Numbness in the place where you were bitten
Faster time to death because toxin goes straight to the blood
Treatment of TTX
Mechanical ventilation because it is the respiratory failure which kills you
No anti-venom as TTX binds too strongly
What is the mechanism of TTX action?
Blocks Nav channels which means no neuronal APs and no ACh release- no contraction of muscle- causes respiratory paralysis
Why are sensory neurons implicated first?
In the neuronal bundles- the sensory neurons tend to be on the outside meaning that the toxin doesn’t have to diffuse into the fibre to have effect. This is why you get sensory effects first.
Paralysis comes second because the toxin needs time to reach the motor neurons.
What happens to the Na conductance across the neuronal cells in the presence of TTX
Decreases due to much less activation of the Na channels
Some channels are insensitive to TTX- why?
There are very small changes in the channel structure meaning that the TTX cannot bind
Which channel is impacted by TTX
Nav1.2
What is the effect of mutating the channels impacted by TTX
Mutating the channel in the pore region meant that the channel is insensitive to TTX. Only 1 AA was changed so the sensitivity is conferred by one single AA
What did the snake study on TTX determine?
Small and subtle changes can lead to different channel properties.
Two geographically separated populations of the same snake had different sensitivities to the TTX
Due to differences in prey choice one population developed an insensitivity to the toxin
Where do dendrotoxins come from
Sneks- mambas
How to DDXs work
inhibit repolarisation- different DDX work on different channels so there are a variety of effects.
What are the symptoms of DDX?
Early numbness is place of bite Systemic responses in 30 mins-1 hour Ptosis- drooping eyelids Paralysis of eye muscles difficulty swallowing mild paralysis respiratory failure
What is the effect of DDX on the K channels
Smaller currents- not a complete block and the effects are reversible.
Inhibition prevents repolarisation
Excess ACh release from pre-synaptic membrane
ACh depletion
Thus there is subsequent failure in neurotransmission due to lack of ACh
Problem in muscle control and respiratory paralysis
Treatment of DDX
Antitoxins work- need to know the species of mamba to give right one
Where do conotoxins come from
Cone snails- there are over 8000 toxins which have varying lethality
Could potentially be used in pain therapy
What are some targets of CTX
nAChR Nav Kv Cav Serotonin receptors Depends on which type has shanked you
General symptoms of CTX
Burning pain Swelling at site of injection Numbness Cardiac and respiratory stress Muscle weakness Loss of co-ordination Ptosis Headache Nausea Stomach cramps
Lethal symptoms of CTX
Lips become stiff
Blurred vision
Paralysis
Coma
What are some uses of conotoxins?
Different ion channels are being investigated for use in conotoxin pain treatment
In nociceptive neurons, the AP generates the feeling of pain
Loss of ion channels in the nerve endings an t the post-synaptic membrane in the spinal cord have been investigated to be targets for conotoxin therapies for chronic pain
How is Cav2.2. being targeted for pain treatment?
Found in nociceptive neurons- release of NT and the propogation of pain
Transmits the signal from the sensory neuron to the relay neuron in the spinal cord
In the presence of EU1.6 which is a CTX- Ca currents across the membrane were decreased at the same voltage as the control experiment so it is blocking the channel- less NT release- less likely to fire an AP
The response is dosage dependent
What were the results of the in vivo study of the CTX in rats?
In the DRG cells- use barium to prevent Ca feedback- currents stull decreased (not complete lack of function) in the presence of EU1.6
How are pain models in animals set up?
Partial nerve ligation-
Sciatic nerve in rats exposed- tied off 1/3 of the nerve which generates a sensation of pain in the animals
How are pain models in animals used?
Application of pressure to the hind paw- sciatic nerve innervation- and measure how much pressure it takes for the paw for the rat to withdraw it.
This is done with 3 sets of rats- saline, positive control (known pain medication) and EU1.6
What were the results of the EU1.6 experiments in the rat paws?
In the presence of EU1.6, the rats took longer to withdraw their paws- they could withstand higher pressures- these effects wore off over time.
It blocks Cav2.2
What is the target of the peruvian green velvet tarantula toxin (Tp1a)
Nav1.7-
What is the effect of Tp1a on Nav1.7?
smaller inward current of Na- inhibition of the channel which affects the AP in sensory neurons- blocks the pain signal
The synthtic and native toxin have this ability
What does the scorpion OD1 toxin do?
Activates Nav1.7/1.6
Increases AP- mimicks the pain response- channels stay open for longer
