PHAR 303 Lecture Notes - Lecture 12: Paralytic Shellfish Poisoning, Ciguatera, Botulinum Toxin
11 May 2018
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Lecture 12 (Feb 20th) Neurotoxicology 2
Mechanisms of neurotoxicity
1. Direct agonist or antagonist – receptors
2. Indirect effect : synaptic modulation
3. Prevent transmitter inactivation or reuptake
4. transmitter release
• Domoic acid refers to amnesia shellfish poisoning bc people have amnesia, loss memory. Has an affinity with
hippocampus.
• Harmful Algal Blooms (Toxic or non-toxic) – the non-toxic ones are not directly toxic to humans but they are
harmful for aquatic life. They can be so dense that they interfere with light and seagrass beds die
• Dinoflagellate – causes red tide (red water) marine fauna die. Toxin in the algea gets in the air and people can get
respiratory symptoms if they breathe the air.
Algae Toxins
• Saxitoxin (Dinoflagellate)– blocks Na+ channels & blocks axonal conduction
PSP - Paralytic Shellfish Poisoning (paralyzed) Alexandrium species
Rapid: ataxia, drowsiness, respiratory arrest – with support can recover completely
8-10% Mortality
o Numbness in lips, mouth & tongue & may progress into arms, fingers, legs and toes
o Headaches, dizziness & nausea CNS symptoms
o Numbness in diaphragm leads to paralysis & respiratory failure & death
o It can even kill big whales bc it can eat huge quantities of fish & accumulate SXT
o 3 x 1014 molecules causing death
• Brevetoxin – opens V-gated Na+ channel : ANS transmitter release
• NSP Neurotoxin Shellfish Poisoning Gymnodinium breve
Florida red tide – mild gastroenteritis, but massive kills of fish and birds
• Okadaic Acid – DSP – Diarrhetic Shellfish Poisoning Dinophysis
• A lot of different types of algae that could lead to a variety of poisoning (amnesia, ciguatera fish poisoning)
• Tetrodotoxin – Blocks Na+ channel and alter electrical transmission (same as saxitoxin)
50-80% mortality – the most lethal
• TTX and SXT have the same mechanism of action & similar structure
The lethal part of the molecules is a NH – NH2 – NH that will bind the Na+ channel at site 1 & block it
preventing AP conduction – paralysis & widespread throughout nervous system
TTX can be produced be puffer fish
TTX is also found in the skin of frogs (specific N part)
3 x1014 molecules causing death
• The Na+ channel has 4 subunits & each of them separately crosses the membrane 6 times
• Many biological toxins target the sodium channel : various scorpion toxins ( α-toxin block site 3 and β-toxin
blocks site 4) – some block, some keeps it open.
• Local anesthetics Procaine, Lidocaine also block the Na+ channel. Since they are injected locally (dentist), they
don’t have a systemic effect, thus not paralyzing your body.
Batrachotoxin “poison arrow frogs” – brilliant colorful frogs are toxin (aware other animals). They are so poisonous
that you can just take the arrow and rub it on the frog’s skin, which puts enough poison on the arrow to kill the
creature you target. How can these frogs live with such a poison? How do they make it?
• Poison made by bacteria that leave in beatles, which accumulate the toxin particularly in the skin.
• Batrachotoxin has a steroid skeleton & oxazapane ring.
• Prevents voltage gated Na+ channel to close & cell depolarize – cant conduct AP = paralyzed
• Birds in Australia that can eat beetles that contain this toxin. The toxin gets concentrated in their skin.
• What prevents these birds and frogs from being affected by this toxin? They all have a modification in their Na+
channel that makes them resistant & able to harbor this toxin at very low concentrations, quick.
• 5 x 1013 molecules causing death
Bacterial neurotoxins
• Alter transmitter release
• Botulinum (2 x 107) & Tetanus toxin (8 x 107) – number of molecules causing death is very small.
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Mechanisms of neurotoxicity: direct agonist or antagonist receptors, indirect effect : synaptic modulation, prevent transmitter inactivation or reuptake, (cid:313)(cid:315) transmitter release, domoic acid refers to amnesia shellfish poisoning bc people have amnesia, loss memory. Has an affinity with hippocampus: harmful algal blooms (toxic or non-toxic) the non-toxic ones are not directly toxic to humans but they are harmful for aquatic life. They can be so dense that they interfere with light and seagrass beds die: dinoflagellate causes red tide (red water) marine fauna die. Toxin in the algea gets in the air and people can get respiratory symptoms if they breathe the air. Algae toxins: saxitoxin (dinoflagellate) blocks na+ channels & blocks axonal conduction. Psp - paralytic shellfish poisoning (paralyzed) alexandrium species. Rapid: ataxia, drowsiness, respiratory arrest with support can recover completely. It can even kill big whales bc it can eat huge quantities of fish & accumulate sxt.
