Lecture 9 Flashcards
The site of action of NM toxicants/toxins is the ______. At this site _____ is the neurotransmitter and it acts on ________ receptors on the
motor endplate.
However, impact of some toxicants/toxins in the CNS can lead to ______
muscle dysfunction via impulses transmitted via the somatic motor nerves.
NMJ, ACh, nicotinic, skeletal
Upon the arrival of an action potential at the axon terminal, _______ ions flow from the _____ into the motor neuron’s ______ and bind to particular intracellular proteins. These _____-bound proteins cause neurotransmitter-containing vesicles to attach to the motor neuron’s cell
membrane and thus release _________ into the synaptic cleft which then binds to the ________ _______ receptors on the motor end plate. These receptors are ion channels and, when bound by ____, allow _____ and ______ ions to flow in and out of the cytosol of muscle cells, respectively. What is produced as a result?
calcium, ECF, cytosol, calcium, acetylcholine, nicotinic acetylcholine, ACh, sodium, potassium
Because of the differences in electrochemical gradients across the plasma membrane, more sodium moves in than potassium out, producing a local depolarization of the motor
end plate. This depolarization spreads across the surface of the muscle
fiber into transverse tubules, eliciting the release of calcium from the sarcoplasmic reticulum, thus initiating muscle contraction. The acetylcholine is thereafter degraded by acetylcholinesterase to
terminate its effect and stop the contraction.
General Mechanisms of Neuromuscular Toxicosis
* Functional: Impairment of neuromuscular ______
* Structural: peripheral motor ?
What is axonal dieback?
transmission, neuronopathy, axonopathy, and myelinopathy
Axonal die back: This is when, after (toxic) injury of a nerve, the tip of the
proximal axon retracts or moves away from the site of injury towards the cell
body. It is basically the degeneration/death of the axon from the distal end that
progresses to the proximal end (towards the nerve cell body/nucleus).
Clinical Signs of Neuromuscular
Toxicosis
- Atony
- Tetany
- Tremors
- Myotonia
- Paresis/paralysis
- Myasthenia
- Cramps, spasms, twitching
- Convulsions, seizures, ataxia
- Respiratory signs & recumbency
Name the categories of Neuromusuclar Toxicants
Neuromuscular Toxicants
* Biotoxins
* Food-related
* Plants
* Pesticides
* Mycotoxins
- What arachnid is pictured below?
- Where in the world can it be found?
- Females are __________, males are ______. What do females do following mating?
- Where in the environment can they be found?
- What is a distinct physical feature unique to Black Widows?
- Black Widow Spider (Lactrodectus Spp.)
- Found in continental US
- Females are offensive, males are not
- Often found on woodpiles and garages
- Why toxin do Black Widows possess?
- What is this toxin’s MOT?
- Explain the MOA of the Ca-independent and dependent mechanism.
- Toxic principle : alpha-latrotoxin (120-130kD protein)
- MOT: alpha-latrotoxin binds to two neuronal receptors, neurexins and CIRL causing release of neurotransmitters via two mechanisms:
i. Ca-independent: ACh, GABA, glutamate
ii. Ca-dependent: catecholamines
* Inhibits presynaptic neurotransmitter reuptake
- Which species are most susceptible to Black Widow spiders? What other species are affected? Prevalence is?
- Clinical signs of toxicity? What is specifically seen in cats?
- Local tissue changes are typically?
- Susceptible species: cats (very sensitive),
dogs, horses, camels. Prevalence is unknown.
* Toxicity: LD50 ranges from 0.43-1.39mg/kg - Clinical signs: CNS & muscular
– Muscle fasciculation and rigidity, abdominal pain (–>howling in cats), paresthesia, ataxia, cramps,
seizures, flaccid paralysis –> ascending paralysis
– Involvement of respiratory muscles causes dyspnea
– Local tissue changes are typically absent
- How would you best describe treating Black Widow Spider toxicosis?
- – __________ and ___________ support
– Pain management: give an _______, such as?
– Control muscle ___________/__________ with what drugs?
* Administer _________ (Lyovac Antivenin)
– For high-risk patients (?) or those not responding to symptomatic treatment
– Be prepared to respond to _________ reaction
- Supportive and symptomatic
– Respiratory and cardiovascular support
– Pain management: give an opioid
* Morphine, meperidine, butorphanol or fentanyl
– Control muscle cramping/seizures
* Benzodiazepines (diazepam) or methocarbamol
* Administer antivenin (Lyovac Antivenin) for…
– For high-risk patients (neonatal/geriatric) or those not responding to symptomatic treatment
– Be prepared to respond to anaphylactic reaction
Botulinum Neurotoxin (BoNT) toxicosis is also called?
(Botulism, limberneck, shaker foal syndrome, sausage poisoning)
This is the most potent toxin known to mankind.
BoNT is produced under _______ conditions by?
– There are _____ toxin serotypes, A to G
– Types _____ are the most important in animals. ____: cattle; ____: horses; _____: avian.
Produced under anaerobic conditions by
Clostridium botulinum
– There are seven toxin serotypes, A to G
– Types ABCD are the most important in animals.
BCD: cattle; ABC: horses; ABCE: avian.
How does an individual expose themselves/get exposed to the Botulinum toxin?
- – Oral: ingestion of _______, ________ preserved food,
__________ vegetation and _________ (waterfowl) - Via _________ and _____ wounds
carrion, poorly, decaying, invertebrates, inhalation, deep
Which species are susceptible to the Botulinum neurotoxin? Which are the most commonly affected?
Which species are relatively resistant to Botulinum neurotoxin?
Susceptible species: all but most commonly wild birds, poultry, cattle and horses. Pigs and dogs are relatively resistant
These birds commonly died from what toxin? Explain the pathogensis
Active more in summer and fall
Botulinum Neurotoxin (BoNT)
Ontario Oct 2011: Thousands of dead birds litter L.
Huron, Georgian Bay shore
Toxicosis associated with mass fatality of waterfowl.
Carcass-maggot cycle: eat maggots containing BoNT –> dies –> flies deposit eggs in duck –> hatch into maggots –> accumulate with BoNt –> eaten by other ducks which die –> carcass maggot cycle is born and propagates itself.
BoNT may have led to extinction of some avian species.
- Zinc metalloprotease is composed of?
- BoNT consists of?
- What is the mechanism of toxicity of the BoNT?
- Zinc metalloprotease with a heavy chain (100kD) & light chain (50kD)
- BoNT consists of a 150 kDa di-chain
- It enters presynaptic nerve endings by endocytosis –> 100kD chain binds to synaptotagmin. Then, blocks ACh release at the NMJ —> flaccid paralysis
– Inhibits exocytosis of ACh by cleaving proteins essential for fusion of the membrane of synaptic vesicles containing acetylcholine with the neuronal cell membrane
Release of ACh at the nm junction is mediated by?
The release of ACh at the NMJ is mediated by a set of SNARE proteins. SNARE proteins are synaptic fusion complexes that allow the membrane of the synaptic vesicle containing ACh to fuse with neuronal cell membrane.
The set of SNARE proteins includes synaptobrevin, SNAP-25, and syntaxin.
After membrane fusion, ACh is released into the synaptic cleft and then binds to receptors on the muscle cell.
How does BoNT inhibit the release of ACh?
Which toxins play what role in this process?
What happens as a result of no ACh release?
Once BoNT enters the neuron by endocytosis, the LIGHT chain cleaves sites on the SNARE proteins, preventing the set to form a complex —> blocks ACh release.
BoNT toxins type B, D, F, G cleave synaptobrevin
BoNT toxins type A, C, E cleave SNAP-25
BoNT toxins type C cleave syntaxin
Without ACH release –> msucle uncable to contract –> flaccid paralysis
Of all the SNARE proteins in the SNARE synaptic complex, which are Synaptosome-associated proteins (SNAPs), which are Vesicle-associated proteins (VAMPs), and which are Synaptic-associated proteins?
Synaptobrevin - VAMP
SNARE-25 = SNAP
Syntaxin = SNAP
- What are the clinical signs of BoNT toxicosis?
- Why is BoNT the most potent toxin known to humans?
- How would you describe the reflexes of the eyes and throat?
- What are the ANS signs?
- What results due to respiratory paralysis?
Toxic dose: LD50 = 0.1-40ng/kg (IV or IP).
Oral LD50 is 500-700× the IP/IV LD50 dose
1. Sudden death may be the only sign, otherwise it is a
progressive neuromuscular dysfunction. Progressive flaccid paralysis with muscle weakness —> Starts in the rear quarters and ascends to the forequarters then to neck and head. Animals exhibit, ataxia, depression, weakness of
muscles of the tail and tongue [loose (falling)
tongue is common]
- Because it requires the smallest amount to cause toxicity.
- Poor reflexes of eyes and throat: mydriasis, slow pupillary light response, decreased palpebral and gag reflexes, weak
vocalization - ANS signs: bradycardia, vomiting, inability to swallow, ileus, constipation or ruminal atony, frequent attempts to urinate (horses)
- Recumbency and death from respiratory paralysis
The gag reflex is a reflex contraction of the ______ of the throat and can be evoked by touching the _____ palate. The afferent limb of the reflex is supplied by the ___________ nerve (cranial nerve ____) and the efferent limb is supplied by the ______ nerve (cranial nerve ___). Therefore, depression of the gag reflex may indicate damage to the __________ nerve, or the ________ nerve.
The pupillary light reflex is done by shinning a light on the pupil and a normal reflex is ___________ of the pupil to keep the light _____. The afferent limb is supplied by the ____ nerve (cranial nerve __) and the efferent limb is supplied by the ___________ nerve (cranial nerve ___). Therefore, depression of the pupillary light reflex may indicate damage to the these nerves.
The palpebral (?) reflex is performed by touching/tapping the _________ _______ (skin at the medial corner of the eye) with a finger or a pen and a normal reflex is a _____. The afferent limb is supplied by the __________ nerve (cranial nerve __) and the efferent limb is supplied by the ________ nerve (cranial nerve ____). Therefore, depression of the palpebral reflex may indicate damage to these nerves.
back, soft, glossopharyngeal, IX, vagus, X, glossopharyngeal, vagus
constriction, out, optic, II, oculomotor, III
corneal/blink, medial canthus, blink, trigeminal, V, facial, VII
- What are the unique signs of BoNt toxicity in foals?
- How old are the foals that are typically affected?
- Why are foals susceptible to BoNt toxicity?
– Foals: tremors (shaker foal syndrome- Toxico-infection, Common in Kentucky and the mid-Atlantic region) in
2-5 weeks old foals
immature GI tract in foals –> more prone to growth of clostridium; different from ingestion of preformed BoNT from feedstuff, contaminated carcasses, rotten veggies.
Foals that succumb to toxicosis suffer from GI ulcers and liver abscesses.
What are the unique signs of BoNt in waterfowl? How do they die?
Waterfowl: progressive paralysis of the legs, wings and neck (limber neck) –> death by drowning
How do you dx BoNT? What do you analyze?
- Analysis of serum, GI contents, vomitus, ruminal fluids and feedstuff for toxins
- Mouse bioassay
How do you treat BoNT?
- Decontaminate: __________, _______ lavage, activated ________
- Supportive and symptomatic treatment
– __________, ________ for muscle function, _______ for muscarinic signs, and IV _______
* Remove the ________ causing the toxicosis
* Provide __________ support
– ________ feeding and watering
* Administer antitoxin if Dx is made _______; Polyvalent (anti- ____ and anti- _____) and monovalent (anti-___) antitoxins are
available for adult horses and foals & should be given ASAP
- Administer an antibiotic
– Such as? - ________ wound for animals suffering from wound botulism
- Decontaminate: emesis, gastric lavage, activated charcoal
- Supportive and symptomatic treatment
– Ventilation, physostigmine for muscle function, atropine for muscarinic signs, and IV fluids - Remove the feedstuff causing the toxicosis
- Provide nutritional support
– Hand feeding and watering - Administer antitoxin if Dx is made early; Polyvalent (anti-B and anti-C) and monovalent (anti-B) antitoxins are
available for adult horses and foals & should be given ASAP - Administer an antibiotic
– Penicillin, metronidazole or amoxicillin - Debride wound for animals suffering from
wound botulism
Name the sources of tick paralysis in the U.S.? Austrailia?
Does toxicity occur year-round?
- Sources
– Female ticks especially Dermacentor andersoni and D. variabilis {USA}
– Ixodes and Amblyomma sp. (Australia)
– Toxicity is seasonal = seasonal activity of ticks
- What toxin can be seen in this image?
- What is the source of this toxin?
- The ADME of this toxin is the same as?
- What is the MOT of this toxin?
- What are the clinical signs of Anatoxin-a toxicity?
- Anatoxin-a
- Sources: blue-green algae (Anabaena sp.)
- ADME: same as anatoxin-a(s)
- MOT: nicotinic agonist
- Clinical signs: nicotinic (similar to succinylcholine overdose). Rapid onset of muscle rigidity and tremors, cyanosis, convulsions, then paralysis and respiratory distress leading to death
What fish are pictured below?
What toxin do they possess?
Tetrodotoxin source
Sources: Puffer fish, frogs, newts
- What plant is pictured below?
- What is an alternative name for this plant?
- Where can it be found?
Larkspur – Delphinium
(Poison Weed, Stagger Weed)
- it is a Perennial, erect herbs (3-6 ft)
- Mostly found in western USA
What plant is pictured below?
What is the significance of this plant?
Where is this plant found?
Locoweeds – Astragalus & Oxytropis (vetches, milk-vetches)
Probably “the most economically significant” toxic plant
in the US
* Habitat: all of North America
* Most poisonings occur in Pacific Northwest
Family: Leguminosae (Pea family)
Why is the main clinical sign of Tremorgenic toxicity?
Opisthotonus
- Restlessness, irritability, panting, tremors leading to spastic ataxia, hypermetria, opisthotonus, seizures, tetany, muscle
fasciculation, tachycardia, hyperexcitation, vocalization, hyperthermia, exhaustion and recumbency in severe cases - Livestock appear normal at rest. When incited to move they exhibit stiff spastic gait, muscle spasms and tetanic seizures
