L20 & 21 Neurotoxicity Flashcards
Exposure to a teratogen in the pre-embryonic phase probably has an ‘all or nothing’ effect – what does this mean?
Damage to all or most cells causes death of the blastocyst - hence either you die or you live. Injury to only a few undifferentiated cells probably allows compensation and normal development.
Medications taken during the _ - _ weeks phase have the greatest potential to cause gross malformations by affecting _________ e.g. Thalidomide – inhibits _____ factors involved in limb differentiation. The type of malformation depends on which organs are most susceptible at the time of exposure.
3-8, organogenesis, homeobox
Folate deficiency is associated with _____ _____ defects (closure). What type of medications are folate antagonists?
Neural tube, anti-seizure meds - methotrexate, valproic acid, 5-florouracil, sulfasalazine, oral contraceptives, diphenylhydantoin, trimethoprim, and pyrimethamine.
Folates function as carbon donors in the synthesis of a.cid to a.acid? Directly in the synthesis of ___- and ____ bases? Indirectly in the synthesis of? ______ donor in remethylation of homocysteine to methionine?
Glycine to serine, purines and pyrimidine bases, transfer RNA, methyl donor
Tobacco Smoke - pre-natal and early postnatal exposure possibly the leading cause of environmentally induced developmental disease and morbidity. Increased risk of SIDS, increased learning, behavioral & attention disorders. Nicotine - a known neuroteratogen.
Tobacco Smoke - pre-natal and early postnatal exposure possibly the leading cause of environmentally induced developmental disease and morbidity. Increased risk of SIDS, increased learning, behavioral & attention disorders. Nicotine - a known neuroteratogen.
In utero exposure to ethanol causes fetal alcohol syndrome (FAS) – what is FAS?
Resulting in craniofacial dysmorphism, intrauterine & postnatal growth retardation, retarded psychomotor & intellectual development etc.
The only way drugs and toxins can get into the brian is via?
Blood vessels
Most drugs that have toxic effects on CNS function gain access by?
either being transported in OR lipid soluble
(+ able to avoid pgp-mediated efflux)
*P-glycoprotein pumps many foreign substances out of cells. More formally, it is an ATP-dependent efflux pump with broad substrate specificity
Byproduct of manufacturing ATP from mitochondria?
ROS (reactive O2 species) can react with Fe3+ transition metal to create toxic byproducts
T/F - Adult CNS neurons have no neuronal stem cells
F- have a few
What hypothesis is suggested about people that get Parkinson’s?
ROS hypothesis = Production of DA generates Fe3+ which reacts with ROS to switch on pathway that activates apoptosis
Dynein and kinesin are? Which moves towards - end?
Cytoskeletal motor proteins involved in axonal transport on microtubles
Dynein moves towards - end (cell body) - retrograde
Kinesin moves towards + end (nerve terminal) - anterograde
What neurotoxins affect axonal transport?
Mercury -Binds to Beta subunit of tubulin (on the GTP binding site and since GTP provides energy for tubulin proteins to link, without it - disrupts MT formation, transport and disrupts neurite growth cones so that you no longer have tubulin and see the actin instead (actin is what the tubulin is wrapped around)
Taxol - MT stabilized in polymerized state, blocks transport (requires switching between polymerized & depolymerized states)
Colchicine, Vincristine -MT polymerization inhibitor, prevents MT formation and blocks transport
Imino-dipropionitrile - Blocks neurofilament, slows anterograde transport down the axon
All metals are potentially toxic yet essential for life - how?
Metals frequently bound to proteins for transport, storage and to limit their redox reactivity
Lead toxicity
a) Symptoms
b) Pathology
c) Recovery is accompanied by
d) Affects ____ and ___ transmission
a) Symptoms - lethargy, vomiting, irritability, “foot drop” or “wrist drop” due to demyelination and axonal degen with Schwann cell degen
b) Pathology - edema of brain due to extravasation of fluid from capillaries, loss of neuronal cells and gliosis
c) Recovery - accompanied by epilepsy, mental retardation optic neuropathy and blindness
d) Glutamergic and dopaminergic
In children, absorption of Pb from ____ is greater
GIT - Pb crosses intestinal cells via Ca uptake systems that are upregulated in children to support bone growth
Why can’t lead be removed by chemical chelating agents in the brain?
These chelating agents cannot cross BBB
Effects of acute exposure (common to almost all solvents e.g. alcohol) are primarily CNS. What are the effects of CHRONIC exposure?
Impairment of memory and learning skills, increased irritability, tiredness, sleeping problems, changes in personality
*These are seen in a chronic alcoholic as well as chronic abuse of n-hexane and nitrous oxide
n-Hexane toxicity leads to?
Damages to neurofilaments and cross-linked cytoskeletal proteins, which aggregate in distal axon proximal to the nodes of Ranvier HENCE signal transmission disrupted
Methanal metabolised by __ into ____? Most critical effect of methanol consuption is?
ADH (Alcoholic dehydrogenase) into formic acid
*ADH also metabolises ethanol into acetaldehyde
Blindness caused by formic acid metabolite
MPTP - how is it neurotoxic?
- Lipid-soluble, crosses BBB
- Enters astrocytes, converted to toxic MPP+ by MAO-B (blocked by MAO-B inhibitors pargyline and selegiline)
- MPP+ depletes DA channel by being actively uptaken by DA transporter (blocked by DAT inhibitors e.g. maxindol)
- MPP+ blocks the mitochondrial resp chain (inactivates NADH dehydrogenase) results in energy depletion and neuronal death
- It causes Parkinson-like symptoms and selective degeneration of substantia nigra (s.n. pars compacta)
- PARP-1 knockout mice have reduced sensitivity to MPTP+, suggesting that PARP inhibitors may be of use in the treatment of Parkinson’s disease
T/F - MDMA also block 5-HT uptake
True - also leads to 5-HT depletion and loss of 5-HT neurons
