! Veterinary Neurotoxins II

What are the toxicants causing polioencephalomalacia?

softening (malacia) of the gray matter in the brain (polioencephalon), leading to significant neurological dysfunction by deleting thiamine diphosphate, cerebral edema and disruption of BBB, and neuronal death

What are the clinical signs of toxicants causing polioencephalomalacia?

blindness from swelling of optic disc and head pressing

What are the two mechanisms of toxicants causing polioencephalomalacia?

1. toxicants act as thiaminase → thiamine deficiency

2. toxicants causing neuronal necrosis and cerebral edema

What are the toxicants acting as thiaminase to cause polioencephalomalacia?

plants such as pteridium spp (bracken fern), Equisetum spp (horsetail, scouring rush) or other causes of thiamine deficiency such as an all fish diet

What is bracken fern toxicity?

pteridium aquilinum has both thiminase and ptaquiloside activity. Thiaminase causes thiamine (vitamin B1) deficiency which leads to PEM (horse and pig) while Ptaquiloside causes bone marrow suppression, neurological issues (cattle) and retinal degeneration (sheep)

What is a one health risk of bracken fern toxicity?

accumulates in meat and milk

What are the toxicants causing neuronal necrosis and cerebral edema?

sulfur, lead, mercury, and hypernatremia/water deprivation

What is sulfur toxicity?

excessive S in feed or water (molasses, brassica spp - turnip,canola) causes a decrease in cell respiration leading to a decrease in copper and thiamine bioavailability (decrease absorption in rumen); ruminants most susceptible GI upset and PEM

What is lead (Pb) toxicity?

inorganic forms such as metals and salts (automotive batteries, bullets) and inorganic forms such as petroleum products interferes with numerous enzymatic processes leading to neurological, gastrointestinal, and hematologic effects (compete with calcium ions)

Why are immature animals more susceptible to lead toxicity?

trying to absorb calcium as they develop and since lead replaces it gets rapidly absorbed instead (50-90% GI absorption)

How can diet and health status effect lead toxicity?

greater absorption with high-fat diet and mineral-deficiency

What are the characteristics of lead toxicokinetics?

>90% bound to RBCs and of the 10% left, 90% is stored in bone; crosses placenta and present in milk; multiphasic excretion

What are the neurological symptoms of lead toxicity?

PEM, laryngeal paralysis causing roaring and pneumonia “plumbism”, wing tenting and loss of grip, anemia, GI symptoms

What can be seen on clinical pathology of lead toxicity?

normocytic normochromic anemia with basophilic stippling; on whole blood, serum won’t work

What is hypernatremia/water deprivation?

water deprivation, increased Na+ (feed mixing error, mineral block), secondary dehydration (heat stroke, diabetes insipidus), homemade play dough or paintballs causes an increase in the osmotic gradient leading to cellular dehydration, neurological symptoms and cerebral edema

What are the toxicants causing mixed CNS signals?

block specific enzymes or CNS oxidative phosphorylation inhibitors

What are the toxicants blocking specific enzymes to cause mixed CNS signals?

fumonisin (fusarium spp) inhibits ceramide synthase and swainsonine does competitive inhibition of a-D-mannosidases

What is fumonisin toxicity?

mold corn poisoning in horses causes a decrease in ceramide synthase which disrupts sphingolipid production thats required for cell membrane development and folate metabolism

What is the FDA guideline for fumonisin in corn for horses?

<5 ppm

What are the lesions associated with fumonisin toxicity?

leukoencephalomalacia

What is swainsonine toxicity (locoism)?

locoweeds in western US inhibit alpha-mannosidase causing glycoprotein lysosomal accumulation (mannosidosis) leading to cellular dysfunction

What are the CNS oxidative phosphorylation inhibitors?

oxidative phosphorylation is required for ATP production so failure of Na/K pumps, loss of cellular osmoregulation, and vacuolation of myelin leads to disrupted conductance and cerebral edema; bromethalin

What is bromathalin toxicity?

cats are sensitive to rodenticides for mice and rats, this CNS oxidative phosphorylation inhibitor causes fluid accumulation in myelinated areas of brain leading to cerebral edema (green stool)

What are the two clinical manifestation of bromethalin toxicity?

convulsant and paralytic syndromes

What is convulsant syndrome?

high dose and early onset of hyperexcitability and seizures

What is paralytic syndrome?

low doses and late onset of paralysis, coma, death

What lesion is associated with bromethalin toxicity?

cerebral edema, spongy degeneration of white matter

What are the toxicants causing CNS depression?

specific receptor agonists, serotonergic toxins, and depressants with other/unknown MOA

What are the specific receptor agonists causing CNS depression?

opioid receptors, GABA receptors, and canabinoid receptors

What is ivermectin toxicity?

dogs with the ABCB1/MDR1 (multi-drug resistance) gene mutation are most sensitive (collies, australian shepherds, shetland sheepdogs), stimulate GABA activity in the nervous system so non-function P0glycoprotein increases toxicity

What is cannabis/THC toxicity?

dogs more sensitive than humans, partial agonist of CB1 receptors in the CNS inhibiting neurotransmitter release and neuronal activity

What are serotonergic toxins?

excess serotonin due to increased production, decrease reuptake, decreased breakdown, or combination (more severe signs); serotonin syndrome can cause paradoxical excitation

What are the depressants with other/unknown MOA?

alcohols, terpenoids, phenoxy herbicides

What is alcohol poisoning?

sanitizers cause CNS depression but also hypoglycemia and metabolic acidosis; methanol can cause blindness

What is toxicity of essential oils and terpenoids?

citrus extracts used in shampoos, tea tree oil, used to “natural” ectoparasite control; cats most susceptible

What is toxicity of 2,4-D (2,4-Dichlorophenoxyacetic a.)

herbicide for weed control in lawns acts as synthetic auxin (plant hormone) causing uncontrolled plant growth leading to death but ingestion or dermal exposure causes corroxive and neurotoxic nature

What are the toxicants that cause extreme weakness, paresis, or paralysis?

toxicants acting on the neuromuscular junction, toxicants affecting dopamine, Na+ channel antagonist

What are the toxicants acting on the neuromusclar junction to cause extreme weakness, paresis, or paralysis?

inhibit ACh release (botulism and tick paralysis), ACh receptor inhibitors, release and receptor inhibitors (aminoglycosides + muscle relaxants), unknown (macadamia nuts)

What is botulism toxicity?

carrion incorporated into feed, water contamination, blocks release of acetylcholine at neuromuscular junction (irreversible binding) causes progressive muscular weakness (flaccid paralysis); horses and cattle are extremely susceptible and waterfowl are susceptible to outbreaks

What are the toxicants affecting dopamine?

dopamine inhibition by yellow star-thistle and russian knapweed

What is yellow star-thistle and russian knapweed toxicity?

horses susceptible to these that grow in dry western US, abrupt onset of tongue and lip paralysis that impairs eating and drinking and tongue protrusion; permanent damage, risk of starvation

What lesion is associated with yellow star-thistle and russian knapweed toxicity?

nigropallidal encephalomalacia, substantia nigra and globus pallidus

What are Na+ channel antagonists?

selective Na+ channel antagonist (saxitoxin - paralytic shellfish poisoning) and Na/K ATPase inhibitor (mycotoxin of rice - citreoviridin)