Neuro Flashcards
Agents known to delay repolarization
Due to prolongation of opening of Na channels
DDT (organochlorine insecticide)
Pyrethroid insecticides
Toluene
paints, lacquers, thinners, cleaning agents, glues, gasoline
Inhalation is the primary route of exposure, though skin contact occurs frequently. Toluene is a favorite of solvent abusers, who intentionally inhale high concentrations of the VOC.
well absorbed from the lungs and GI tract. It rapidly accumulates in the brain, and subsequently, is deposited in other tissues according to their lipid content,
The CNS is the primary target organ
Klaassen, Curtis D.; Watkins, John B.. Casarett & Doull’s Essentials of Toxicology, Third Edition (Lange) . McGraw-Hill Education. Kindle Edition.
metronidazole
peripheral neuropathy characterized by paraesthesias, dysesthesias, headaches, glossitis, urticaria, and pruritus in addition to other somatosensory disorders.
an irreversible sensorimotor deficit in the lower extremities of humans
reduced to the highly reactive and toxic hydroxylamine intermediate and binds to cellular macromolecules including proteins and DNA
neurons and glia appear to be equally susceptible
Klaassen, Curtis D.. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition (p. 857). McGraw-Hill Education. Kindle Edition.
Myelin Toxicants
Hexachlorophene • Used in antimicrobial soaps (e.g., Phisohex ™) Myelin damage when used on very young children
Triethyl • tin Used in marine paints to prevent algal growth
Amiodarone, perhexilene • Inclusions (phospholipidosis ) in Schwann cells
Associated with slowed nerve conduction velocity • E.g. topical DMSO treatment
n-Hexane; 2, 5-HD, carbon disulfide
crosslinking agents - impair axonal transport
MPTP
street drug contaminant that caused Parkinson’s
very lipophilic; taken up by astrocytes and converted to MPP+ (toxic metabolite) by MAO-B enzyme
MPP+ taken up by dopamine receptors -> inhibits mitochondrial complex 1 (no ATP synthesis)
Carbon monoxide
cortical neurons, necrosis of globus pallidus
Methanol
toxic to retina
primates > rats due to abundant folate in rodents
Triorthocresyl Phosphate (TOCP)
Used as fire retardant, in manufacturing for lacquers and varnishes as a plasticizer
During the Prohibition Era in the U.S., TOCP was component of some bootleg liquor
Individuals who ingested the adulterated beverages developed a spastic gait called “ginger jake ” walk
Neuropathy was unrelated to acetylcholinesterase inhibition (note structure)
Occurred days to weeks after exposure — “ o rgano p hosphorousi nduced delayed, hence the description d elayed n europathy” (OPIDN)
Neuropathy involved peripheral nerves “dying back” neuropathy plus degeneration of ascending and descending spinal cord tracks • Hence another acronym “OPinduced delayed polyneuropathy” (OPIDP)
Organic solvents
ethyl benzene, trichloroethylene (ototoxic)
isoniazid
peripheral nerve damage
most pronounced in people who are slow acetylators (NAT2 polymorphism)
tardive dyskinesia
patient is left with a permanent disability that includes prominent facial grimaces
phenothiazines, which have been used to treat chronic schizophrenia for long periods of time,
Klaassen, Curtis D.. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition (p. 843). McGraw-Hill Education. Kindle Edition.
Cocaine
blocks the reuptake of dopamine (DA), norepinephrine, and serotonin at nerve terminals in the CNS, and causes release of DA from storage vesicles.
Klaassen, Curtis D.. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition (p. 859). McGraw-Hill Education. Kindle Edition.
Zinc
intranasal -> olfactory neurons
botulinum toxin
Zn-protease that hydrolyzes the fusion proteins required for exocytosis of the neurotransmitter acetylcholine preventing its release and leading to paralysis.
Klaassen, Curtis D.. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition (p. 75). McGraw-Hill Education. Kindle Edition.
Glutamate receptor agonists
domoic acid (shellfish; hippocampus), kainate
excitotoxins - binding to glutamate receptor results in opening of calcium ion channels -> nerve cells swell and die
Glutamate is the main excitatory neurotransmitter of the brain, and its effects are mediated by several subtypes of receptors called excitatory amino acid receptors
Toxic Events at the Synapse
Most common cause: failure to properly terminate neurotransmission
Cocaine and amphetamine block reuptake of dopamine and serotonin in the synapse (e.g. inhibition of dopamine transporter [DAT]) • Results in serotonin syndrome, writhing, and abnormal muscle movements (choreiform movements)
Organophosphorous (OP) insecticides inhibit acetylcholinesterase ( activity, thereby preventing degradation of acetylcholine ( • ACh ) AChE Dysregulation of secretion by glands, muscle twitching, diarrhea………… SLUD
Glutamate receptor agonists — ) prolonged stimulation due to poor degradation of nonphysiological ligands (e.g., domoic acid, • kainate ) Causes death to target cell due to influx of calcium ions + water; activation of calcium activated proteases
Agents that block opening of sodium channels
tetrodotoxin; saxitoxin
Methyl mercury
Prenatal exposure can impair brain development
Manganese
neurons of substantia nigra -> Parkinsonism
welders
Organophosphorous and carbamate insecticides
inhibit acetylcholinesterase
SLUD; muscle twitching; pinpoint pupils
Treatment - atropine (ACh antagonist) and 2-PAM (reactivates AChE)
OP degraded via Paraoxonases (PONs)
OPs: chlorpyrifos, malathion
carbamates: carbaryl, aldicarb (Temik)
Aminoglycoside antibiotics
streptomycin, gentamicin, kanamycin, etc (ototoxic)
strychnine
antagonizes the effect of the inhibitory neurotransmitter glycine, and is thus a potent convulsant.
Klaassen, Curtis D.. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition (p. 1093). McGraw-Hill Education. Kindle Edition.
curare
interference in the conduction of nerve impulses from the motor nerve to skeletal muscle. sensory nerves were left intact.
high affinity for the acetylcholine receptor at the neuromuscular junction. Reversibly inhibits nAChR.
Klaassen, Curtis D.. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition (p. 1286). McGraw-Hill Education. Kindle Edition.
dimethlaminopropionitrile
affects nerves innervating bladder
Rotenone (botanical)
insecticide; piscicide
Taxol and colchicine
affect microtubules
taxol - stabilizes microtubules
colchicine - prevents tubulin polymerization
batrachotoxin
beetles, frogs; poison darts
irreversibly opens, the sodium channels of nerve cells and prevents them from closing, resulting in paralysis and death. No antidote is known.
Carbon disulfide
most significant exposures of humans to CS2 have occurred in the vulcan rubber and viscose rayon industries. High-level exposures of humans to CS2 cause a distal axonopathy that is identical pathologically to that caused by hexane.
ultimate toxicant
also cross-linking of neurofilaments
Klaassen, Curtis D.; Watkins, John B.. Casarett & Doull’s Essentials of Toxicology, Third Edition (Lange) . McGraw-Hill Education. Kindle Edition.
acrylamide
peripheral neuropathies in factory workers exposed to high doses.
Klaassen, Curtis D.; Watkins, John B.. Casarett & Doull’s Essentials of Toxicology, Third Edition (Lange) . McGraw-Hill Education. Kindle Edition.
HIV-associated dementia (HAD)
is a neurological disorder afflicting many AIDS patients. Exposure to cocaine and amphetamines in AIDS patients results in a synergistic neurotoxicity, which is attenuated by β-estradiol
Klaassen, Curtis D.. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition (p. 859). McGraw-Hill Education. Kindle Edition
trimethyltin
Organotins are used industrially as plasticizers, antifungal agents, or pesticides. Intoxication with trimethyltin has been associated with a potentially irreversible limbic-cerebellar syndrome
triggers selective apoptosis in specific subregions of the mammalian CNS and specific subsets of immune system cells
hippocampus is particularly vulnerable
Klaassen, Curtis D.. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition (p. 847). McGraw-Hill Education. Kindle Edition.
methyl n-butyl ketone
axonal degeneration w/ neurofilament swelling
hexachlorophene
spongiosis
