Neurotoxicity

Question 1

Patterns of injury neurotox

Answer 1

Neuropathy: irreversible death-apop or necrosis
Axonopathy: repaired in PNS but not CNS
Myelinopathy: some regen in PNS, not in CNS = slow conduction
Transmission toxicity: alternation of NT(too much or too little)
Nissl substance: clusters of ribosomal complex

Question 2

Trimethyltin Chloride(TMtin)

Answer 2

Cause NEURONOPATHY
PVC plastic and silicone, pesticide and antifungal product
Irreversible limbic-cerebellar syndrome in humans
Specifically target limbic system-hippocampus and amygdala
Cell death acutely within 72hrs apop events-ROS and RNS
Stannin-small protein associated with mito and ER membrane
Distributed in areas most affected by TMtin, contains metal-binding domain
Possibly helps initiate apopo when bound to trimethyltin via CALCIUM FLUX

Question 3

Carbon disulfide

Answer 3

Cause AXONOPATHY
Weakness of muscles in all four limbs and absence of tendon reflex
Sensory impairment
Slowed nerve conduction, decrease amplitude of muscle and sensory nerve action potentials
Crosslink p with amino group
Dithiocarbamate, isothiocyanate, dithiocarbamate, thiourea
Rxn w/ 2 amino = IRREVERSIBLE , Rxn 1 amino and 1 cysteine = reversible
Axon swelling neurofilament proteins: high-molec weight species crosslink

Question 4

Carbon disulfide(CS2) mechanism

Answer 4

See picture
Axon swelling
Demyelination
Degeneration of distal axon(axonopathy)
Markers
Valine-lysine thiourea cross-link erythrocyte globins RBC(V-K)
Lysine-lysine thiourea cross-linking in erythrocyte spectrin RBC(K-K)-irr

Question 5

Acrylamide

Answer 5

Cause AXONOPATHY
Vinyl monomer used in water purification, paper manufacturing, electrophoresis gels
Fries+potato chip and baking, reducing sugars+asparagines
MAILLARD RXN-non enzymatic browning that adds flavor and colour.
N-glycosyl conjugate between sugar and asparagine
Amadori rearrangement to form Amadori compound
Diet levels are below NOAEL, not clear if ave human consumption is dangerous or not
Metabolic scheme: mod P and DNA(covalent mod): CYP2E1 make: glycidamide(GA)-Toxic or glyceramide(non toxic), GSH detox

Question 6

Acrylamide mech of toxicity

Answer 6

Form adduct with protein-sulfhydryl rich proteins
Axonopathy hypothesis:
Defective kinesin-based fast anterograde transport(FEWER organelle in nerve terminal)
Nerve terminal toxicity due to energy deficit
Direct effect on NT release-adducts with sulfhydryl-rich protein in presynaptic protein complex involved in vesicle fusion

Question 7

Domoic acid

Answer 7

Cause TRANSMITTER-ASSOCIATED NEUROTOXICITY
Amnesic shellfish poisoning(ASP)
Contaminated mussel, fish and crab
Toxigenic organism: Pseudo-nitzschia spp.(diatom)
Domoic acid tricarboxylic acid; strucural anal of kainic acid(glut receptor)
Heat stable
Bioconcentrated by shellfish
Domic acid mechanism
Stimulate kainate glutamate receptors
Massive, prolong Ca2+ influx-excitotoxicity
Doesn’t cause receptor desensitization
Cause neuronal DEATH(apop or necrosis)
Hippocampus seems preferentially damaged
Symptoms:
Within 24hr: gastroenteritis: vomiting, abdominal cramps, diarrhea
48hrs- neurological effect: dizziness, headache, seizure, coma
Permanent neurological effects or death