Neurotoxicity Flashcards
What is the brain’s environment?
The brain is a lipid-rich environment.
What are the highly lipophilic cells in the PNS and CNS?
Oligodendrocytes and Schwann cells (myelinated which increases transmission speed).
Why are the CNS and PNS susceptible to disturbances?
They involve complex development and can be affected by disturbances that last a lifetime.
Is regeneration possible in the PNS and CNS?
Regeneration is possible in the PNS, not in the CNS.
What are the lobes of the brain?
Frontal, parietal, occipital, temporal.
What is the frontal lobe involved with?
Cognition.
What is the parietal lobe involved with?
Sensory feelings.
What is the occipital lobe involved with?
Sight.
What is the temporal lobe involved with?
Auditory.
What do each part of the brain involve that are specific to function?
Nerve clusters (regions).
What are the systems of the brain?
Basal ganglia, limbic system, motor efferent, sensory afferent.
What are the regions of the brain?
Amygdala, hippocampus, cerebellum.
What is the cerebellum involved with?
Movements; damage can lead to dyskinesia and uncoordinated movement.
What do multiple cell types maintain?
Nervous system health and access via blood.
What do specialized endothelial cells in the brain, spinal cord, retina, and PNS not allow?
Molecules to pass between; they must cross endothelial cell membranes to access the CNS/PNS = blood-brain barrier.
What can happen to molecules that cross into cells?
They can be dumped back into the blood by transporters (mdr).
What are the cells of the CNS?
Neurons, microglia, astrocytes, ependymal cells, oligodendrocytes.
What do neurons do?
Excitable, receive, process, and transmit information.
What are microglia?
Resident macrophages that provide innate immunity.
What do astrocytes do?
Maintain blood-brain barrier integrity and participate in synapses.
What do ependymal cells do?
Build barriers between compartments, produce cerebrospinal fluid (CSF) to wash away metabolite waste.
What do oligodendrocytes produce?
Myelin sheaths.
What are the cells of the PNS?
Neurons, satellite cells, Schwann cells.
What do satellite cells do?
Support other cell bodies.
What do Schwann cells produce?
Myelin sheath around axons.
What do nerves do?
Conduct action potentials (APs) and innervate tissues (highly demanding work).
What are nerves?
Post-mitotic and must maintain gradients for AP conduction, transport down axons, synthesis of neurotransmitters (NTs), and plasticity.
What do nerves use to meet demands?
Aerobic glycolysis and are extremely sensitive to brief disruptions of oxygen and glucose supply.
What can cause neurotoxicity?
Chemicals that cause ATP depletion or hypoxia.
What is Nissl substance?
Highly concentrated clusters of ribosomal complexes in soma that facilitate translation and protein formation.
What are neurofilaments?
Type IV intermediate fibers critical for transport.
What are the two types of transport in neurons?
Anterograde (towards terminals) and retrograde (towards soma).
What is kinesin?
A transport motor for anterograde transport.
What is dynein?
A transport motor for retrograde transport.
What are the most abundant neurotransmitters?
GABA and glutamate (set threshold of CNS).
What does neurotransmission across extracellular space require?
Calcium and tightly regulated membrane fusion events = exocytosis.
Why is transport in a neuron critical?
For maintaining energy and axonal health.
What is slow component A (SCa)?
Made up of neurofilaments and microtubules, moves at 1mm/day by disassembly and reassembly of filaments using nucleoside triphosphates, kinases, phosphatases.
What is slow component B (SCb)?
Made up of actin microfilaments and associated proteins (M2 protein, fodrin) and clathrin, moves at 2-4mm/day.
What is the fast component in neuron transport?
Microtubule and motor protein dependent, reaching up to 400mm/day.
At what speed are organelles (mitochondria) transported?
50mm/day.
What is neuronopathy?
Damage to the cell body (soma) and terminals, lack of axon.
What is axonopathy?
Affected axon dies; cell body shows chromatolysis (build-up of material in the soma that interrupts transport); margination of Nissl substance and nucleus to the cell periphery; lack of terminals.
What is myelinopathy?
Damage to myelin.
What is interrupted neurotransmission?
Damage to synapses leads to a lack of information transmission.
What receptor is responsible for inducing excitotoxicity?
Excessive NMDA receptor-mediated currents.
What is the NMDA receptor?
An ionotropic glutamate receptor superfamily receptor.
What is the subunit composition of NMDA receptors?
Heterotetrameric receptors that contain 2 NR1 subunits + either 2 NR2 or 2 NR3 subunits.
What do NMDA receptors conduct?
Positive depolarizing currents.
What results from overactivity of NMDA receptors?
Prolonged intracellular calcium elevation, leading to activation of multiple signaling cascades (second messenger cascades).
What is the result of elevated nitric oxide synthase activity?
Nitric oxide is produced, which can react with superoxide anion to form reactive peroxynitrite, activating cell death.
What do NO mediated cell death pathways cause?
Neurodegenerative diseases like Huntington’s (damage to basal ganglia).
What amino acids are found on NMDA receptors?
L-Glutamate/NMDA and D-Serine/Glycine.
What does trimethyltin chloride cause?
Irreversible limbic-cerebellar syndrome in humans.
What are the signs of limbic-cerebellar syndrome?
Disorientation, amnesia, self-mutilation, aggressive behavior, seizures, nystagmus, ataxia, mild sensory neuropathy.
What is the mechanism of limbic-cerebellar syndrome caused by trimethyltin chloride?
Cell death within 72 hours via apoptosis; reactive oxygen species/reactive nitrogen species play a role.
Why is trimethyltin chloride limbic selective?
Not entirely clear, but a small protein in membranes contains a metal-binding domain allowing for interaction with tin known as stannin.
Why do longer nerves act as a sink for toxic effects?
They contain higher numbers of targets for poisons and act as sinks.
What is the stocking glove pattern?
Pinpricks, temperature, vibration (sensory impairment).
What is electrophysiological testing of axonopathy?
Slowed nerve conduction velocity, decreased amplitude of muscle and sensory nerve action potentials.
What molecules can cross-link neurofilaments and cause axonopathies?
Hexane and CS2.
What do hexane and CS2 target?
Sulfhydryl and amine groups in distal axons, cross-linking proteins and causing axonopathy and neuropathy.
What is hexane converted to?
Reactive diketone by mixed function oxidases.
What does CS2 conjugate proteins forming?
Dithiocarbamate then isothiocyanate, which cross-links forming dithiocarbamate ester or thiourea end products; thiourea product is irreversible.
What are the signs and markers for CS2 toxicity?
Axonal swelling, demyelination, distal axonopathy.
What can blood tests detect?
Cross-linking of RBC proteins as proxies for neuronal cross-linking, including globin valine-lysine-thiourea or spectrin lysine-lysine-thiourea.
What is one of the first signs of neuronal stress?
Swelling.
How can protein cross-linking be detected?
By Western blot.
How do Western blots work?
They use antibodies to detect protein in a sample, separating samples by size using electrophoresis, then transferring to a membrane for blotting.
How can you tell if a protein has cross-linked on a Western blot?
Detected bands would be shifted higher up, indicating they did not migrate as far = larger.
What is acrylamide?
A chemical suspected of causing cancer in people, used in the gel of Western blot.
What are acrylamide and glycidamide?
Ultimate poisons.
How are acrylamide and glycidamide similar to 4-HNE?
They have similar toxic mechanisms.
What CYP enzyme generates most reactive species glycidamide?
CYP2E1.
What are the toxic mechanisms of acrylamide and glycidamide?
They target sulfhydryl groups and form adducts.
What are the hypotheses for acrylamide/glycidamide toxicity?
- Defective kinesin-mediated anterograde transport leads to fewer mitochondria and vesicles in terminals. 2. Mitochondrial dysfunction or reduced transport to terminals leads to ATP depletion. 3. Adducts with excitotoxic machinery lead to decreased NT levels.
Where can domoic acid accumulate?
In seafood.
What is domoic acid?
A tricarboxylic acid similar to kainic acid (an endogenous glutamate receptor agonist) that is heat stable and bioaccumulates in shellfish.
What is the mechanism of action (MOA) of domoic acid?
Kainate receptor agonist; prolonged cellular depolarization because kainate receptor does not desensitize, leading to excitotoxicity and neuronal apoptosis or necrosis, with enhanced effect in the hippocampus.
What are the symptoms of domoic acid toxicity?
Gastroenteritis, vomiting, abdominal cramps, diarrhea within 24 hours; dizziness, headache, seizures, coma within 48 hours; permanent short-term memory loss and/or death.
What state does ethanol induce?
A hyper-excitable state.
What are the main metabolites of ethanol?
Acetaldehyde and acetate.
What is acetaldehyde?
Highly reactive and oncogenic (cancer-causing).
Why are alcoholic brains prone to excitotoxicity?
Due to cellular tolerance (hyperexcitability).
Why can withdrawal from ethanol be lethal?
Alcoholics require medical supervision to quit.
What is observable in alcoholics?
A long-term decrease in brain volume due to cell death.
