Lecture 11 - CNS Toxicants Flashcards
Neurons are the _______ cell type in the nervous system and are responsible for _______ of impulses. They are adapted for _____ signal transmission which predispose CNS to _________.
primary, propagation, rapid, xenobiotics
The CNS depends on what form of metabolism to function?
What supports this high metabolism?
High dependence on aerobic metabolism for function (e.g., maintenance of ion gradients; membrane depolarization).
20-25% of cardiac output goes to the brain to support the high metabolism
Why does the CNS have extended axons?
Extended length of axons: maintenance of large volumes, transport of material
over long distances
Can neurons regenerate after injury?
What is the exception?
Neurons do not regenerate upon injury (except granule cells of the
hippocampus).
How does the CNS compensate for being so vulnerable?
Brain has specialized barriers; BBB and blood-cerebrospinal fluid barrier.
These barriers are effective for many compounds except those that are
nonpolar or actively transported.
What does the BBB consist of? Describe how it maintains its structural integrity.
BBB consists of structural and biochemical barriers that restricts passage of solutes between blood and brain and therefore protects the brain from potentially harmful substances. The structural/ morphological component consists of tight junctions between adjacent capillary endothelial cells, astrocyte end-feet, and pericytes in the capillary basement membrane.
Where is the BBB mainly loocalized?
The barrier is mainly localized in the endothelium.
Where are the primary and secondary components of the anatomical barrier located?
However the main component of the barrier is within the capillary
endothelium. The second component of the anatomical barrier is the tight junctions between
the epithelial cells of the choroid plexus
What molecules can pass through the BBB?
Large molecules (proteins and large peptides) do not usually pass through and polar molecules are generally physically restricted because the BBB is highly lipophilic. It is selectively permeable to some small molecules and there are specialized transport systems for ions and metabolites such as glucose and amino acids that are essential for the function of nerve cells.
What are the biochemical components of the BBB?
Biochemical component:
P-glycoproteins and enzyme metabolism
The biochemical component comprises of P-glycoproteins that eject toxicants as they try to enter the cells and enzymes that metabolize toxicants before they enter the nerve
cells
The transport system in the brain can be hijacked by?
These transport systems can be hijacked by toxicants and facilitate their entrance into
the brain and toxicants may disrupt the BBB
The BBB is weaker in?
neonates and embryonic organisms
Define functional toxicosis.
Impairment of neurotransmission
E.g.: NT synthesis, Storage,
Release, Binding, Degradation/reuptake,
Axonal propagation, etc
What is structural toxicosis?
neuronopathies, myelinopathies
and axanopathies
How do CNS toxicants/toxins act on NT?
CNS toxicants/toxins stimulate or inhibit the release of these
neurotransmitters.
What are some examples of indirect CNS toxicosis?
Impaired metabolism, ion homeostasis, blood supply
Which NT are commonly affected by Toxicants/Toxins?
The main neurotransmitters that are affected by toxicants and toxins of the
CNS are small molecules belonging to all the three classes, I to III.
– Class I: acetylcholine
– Class II (the amines): norepinephrine, epinephrine,
dopamine, serotonin (5-HT), histamine
– Class III (amino acids): GABA, glycine, glutamate, aspartate
– Class IV (gases): nitric oxide
Others:
* Neuropeptides: opioid peptides, tachykinins, etc.
* Purine-based: adenosine, ATP, AMP, ADP
There is one major group of toxins, the ___________ (found in chocolate,
coffee, and tea), that affect _____-based neurotransmitters, specifically _______.
methylxanthines, purine, adenosine
What do NT mediate?
Neurotransmitters mediate excitatory or
inhibitory responses when they are released after exposure to relevant
toxicants/toxins
How are CNS toxicants classified?
Therefore,
CNS toxicants will be classified as:
I. Toxicants causing CNS stimulation and/or
seizures
II. Toxicants causing CNS depression
III. Toxicants causing mixed CNS signs
What are the sources of Tetanus neurotoxin (TeNT)?
A neurotoxin, tetanospamin, produced by Clostridium tetani under anaerobic conditions
* C. tetani spores are commonly present in feces of domestic animals especially those of the horse. Spores are resistant to many standard disinfection processes and can survive in soil for many years
How do you get exposed to the Tetanus neurotoxin (TeNT)?
deep puncture wounds
List the risk factors of exposure to TeNT?
field surgery, castration, docking,
retained placenta, shearing, umbilical infections
Which species are susceptible to TeNT?
all, most toxicoses
occur in horses and ruminants
Tetanus toxin is a ______ _________ and has _____ and ______ chain.
zinc metalloprotease, heavy, light
The ________ and the _______ of the TeNT are mediated by the heavy-
chain (HC), whereas the ______ activity is located in the light-chain (LC) of
the molecule.
targeting, translocation, catalytic
How does the light chain of the TeNT mediate catalytic activity?
Light chain cleave SNARE proteins (VAMP), thereby interfering with the
fusion of synaptic vesicles and the plasma membrane and ultimately blocking neurotransmitter release from pre-synaptic nerve cells.
– Blocks the release of the neurotransmitter glycine in CNS → loss of inhibitory input
* Minor effect: inhibition of release of
GABA as well as ACh at NMJs
What are the clinical signs of TeNT toxiccosis?
- Hyperesthesia, tetany, convulsions, severe rigidity of musculature (sawhorse stance), protrusion of third eyelid, sardonic grin
- Locked jaw, elevated tail, flared nostrils
- Sympathetic effects: sweating, cardiac arrhythmias, vasoconstriction, diminished urination and defecation, colic
- Eventually rigidity of muscles of
respiration asphyxiation and death
Tetanus
Sawhorse stance
The more classic presentation of tetanus includes saw horse stance and rictus sardonicus (“sardonic grin”).
Excessive contraction of the facial muscles causes wrinkled forehead and erect ears,
The ears are pulled tightly back, as are the lips. The eyes bulge, and the animal appears to be grinning.
Tetanus
Fixed stare, sardonic grin
How do you Dx TeNT toxicosis?
Identification of C. tetani in a culture of the
wounD.
How do you treat TeNT toxicosis?
Wound debridement
* Antibiotic therapy (penicillin)
* Administer antitoxin
* Keep animal in a quiet, dark area to minimize
convulsions
* Tranquilizers may be used for convulsions
What is Strychnine?
Strychnine is Gopher bait. It is an a lkaloid derived from seeds/bark of Indian tree,
Strychnos nux vomica and ignatii
Which species are most at risk for Strychnine toxicosis?
All, especially dogs.
List the sources of Strychnine.
– Found in pesticides for control of gophers,
moles, rats, prairie dogs, squirrels, etc. For
below ground use. Bait dyed red or green
– Accidental and malicious poisonings
Describe the ADME of Strychnine toxicosis?
– Absorbed ______ in GI tract, _____ distribution
– Metabolized in ____ and excreted in ____
– Absorbed rapidly in GI tract, wide distribution
– Metabolized in liver and excreted in urine
What is the MOT for Strychnine?
- __________ and __________ __________ the inhibitory neurotransmitter glycine in the
_______ ______ and __________
− Leads to _________ reflex stimulation with extensor rigidity (powerful ________ muscle groups predominate)
- Competitively and reversibly antagonizes the inhibitory neurotransmitter glycine in the
spinal cord and medulla
− Leads to uncontrolled reflex stimulation with extensor rigidity (powerful extensor muscle groups predominate) - Toxicity: Oral LD50 (mg/kg bw) = 0.5-1.2
(dogs); 2 (cats); 0.5-1 (pigs); 0.5 (horses); 0.5
(cows)
What are the clinical signs of Strychnine Toxicosis?
- Poisoning is common in _____ _________
- Onset of toxicosis is fast: ___-__ min After oral exposure, clinical signs may appear within ___-____ min. The Presence of food in the stomach can ____ onset.
- Early signs: apprehension, nervousness,
tenseness, stiffness and excessive salivation - Severe tetanic seizures with _______ stance
– Seizures initiated by touch, sound or bright light - Apnea, cyanosis, hyperthermia, mydriasis and strained facial expression
- No loss of consciousness
- Death from medullary _________ and ________ with rapid onset of rigor mortis
Clinical Signs
* Poisoning is common in Pacific Northwest
* Onset of toxicosis is fast: 10–60 min After oral exposure, clinical signs
may appear within 30-60 min. The Presence of food in the stomach can delay onset.
- Early signs: apprehension, nervousness,
tenseness, stiffness and excessive salivation - Severe tetanic seizures with sawhorse stance
– Seizures initiated by touch, sound or bright light - Apnea, cyanosis, hyperthermia, mydriasis and
strained facial expression - No loss of consciousness
- Death from medullary paralysis and exhaustion
with rapid onset of rigor mortis
What is the MOT of Metaldehyde toxicosis?
What are the clinical signs of Metaldehyde toxicosis?
How do you Dx Metaldehyde toxicosis?
How do you treat Metaldehyde toxicosis?
List the ways in which you would provide symptomatic and supportive Tx for Metaldehyde toxicosis?
Describe how Fluoroacetate spreads between species in the environment
What is the MOA of Fluoroacetate toxicosis?
What are the Consequences of Aconitase Inhibition?
How do you treat Fluoroacetate toxicosis?
- Tx is difficult due to rapid onset of toxicosis
– Often animals die before getting veterinary attention - Decontamination with activated charcoal and
cathartic
*See image for further details
What is the MOT of sodium toxicosis?
- GI mucosal irritation anorexia, vomiting, diarrhea, dehydration, electrolyte imbalance
- Na+ is rapidly absorbed from the GI tract and distributed throughout the body
– Plasma [Na+] increases above normal (>135- 155mEq/l) Na+ passively diffuses into CSF
but requires active transport to be removed.
See photo for more info
In summary, when there is high sodium intake or low water intake, the
concentration of sodium in the ECF increases. This results in the passive entry of sodium (down the concentration gradient) into the CSF/brain, but the removal of sodium from CSF requires active transport, that is, it requires energy in the form of ATP. The problem is that the high sodium concentration inhibits aerobic glycolysis which is the main mechanism of ATP synthesis in
the brain. Therefore, without sufficient ATP sodium cannot be removed and it accumulates in the brain where it can cause dehydration and rupture of blood vessels resulting in hemorrhage. This however is not the main problem. The main problem arises if this sodium accumulation is followed by rapid re-hydration which together with the loss of sodium in urine reduces the ECF sodium concentration to normal or below normal. When the sodium
concentration is lower in the ECF than in the CSF, the high sodium in the CSF
exerts osmotic pressure that draws water from the ECF resulting in cerebral edema and the clinical signs of sodium ion toxicosis.
How do you treat sodium toxicosis?
- Hypertonic saline is recommended to reduce incidence of iatrogenic cerebral edema
– Na+ levels of parenteral and oral fluids should closely match serum Na+ levels - Na+ levels in fluids should be gradually decreased as clinical signs subside
- Give furosemide (loop diuretic) to augment NaCl elimination
- Relieve cerebral edema and brain swelling
– Mannitol
– Glycerin (orally diluted 50/50 with water)
– Dexamethasone
– Dimethyl sulfoxide - Administer diazepam for seizures
