L15. Neurotoxicology Flashcards
How were neurotoxicants first discovered?
They were discovered by accident because people would eat any plant and then would eventually get sick.
What is Hemlock? What are its other names? What is its mechanism of action?
- Poisonous plant that exists in North America.
- Also called spotted parsley or spotted cowbane
- Major poison in hemlock is Coniine, a derivative of nicotine.
- Also contains nicotine, methylconiine, and coniceine
- The compounds in hemlock stimulate and then block the nicotinic receptors which causes bradycardia (heart rate slows down), ascending paralysis (because blocking nicotinic receptors in the periphery), and coma (once the paralysis extends up) –> death
How can the toxins in living organisms be classified? Why is that so?
Most of the toxins in living organisms are neurotoxins. They evolved over evolution so the creature could protect itself and as a mechanism of attack (harm something to attack and consume it).
What is an example of a synthetic neurotoxin? What can it effect?
Ex: Electronic waste has a lot of neurotoxins. Can affect neurotransmission, neurodevelopment, intellectual development, motor functions, etc.
What is the top 6 priority list of hazardous substances ?
Every 2 years the substances are ranked by official agencies, the top 6 are all neurotoxins:
- Arsenic
- Lead
- Mercury
- Vinyl Chloride
- Polychlorinated biphenyls
- Benzene
- Cadmium
What are neurotoxicants?
- Covers neurotoxins (made by living creatures) and synthetic ones made by humans.
How is neurotoxicology studied?
We use animal models to study them, but they may not be the same as humans:
- It’s difficult to extrapolate more subtle neurotoxic effects on mood etc. when looking at animals.
New systems for studying neurotoxicity in vitro are being developed:
- In cultures, neuron cells can grow out and talk to each other and you can see what happens to them when they’re exposed to something.
- There’s a push to avoid animal models if there are other available methods
Specific methods that you can use to study neurons and their communication with each other:
- You can make specific cultures of motor neurons, cortical neurons, astrocytes, and you can even grow cerebral organoids. (Figure 1)
Nerve outgrowth assay:
- You can watch neurons growing in culture and see if something affects dendrite and axon growth.
There are systems where neurons are growing in culture in the presence of electrodes that can record the firing rate of the neurons. (Figure 2)
- Experiment measuring firing rate of neurons: “Domoic Acid” completely inhibits neuron firing. “Ibuprofen” (the anti-inflammatory) doesn’t affect the neurons compared to the control. The last two compounds observed are convulsants and the firing rate is shown to increase.
Is acute or chronic neurotoxicity easier to study?
- It’s much easier to study acute toxicity in animal models or in vitro than it is to study chronic neurotoxicity.
- Chronic neurotoxicity is very important.
What are potential neurotoxic effects?
- Cognitive: Memory, learning, confusion
- Motor: Weakness, convulsion, paralysis
- Sensory: Vision, hearing, touch, balance
- Mood and personality: Sleep, depression, irritability, excitability
- Very hard to detect in animal models or in vitro - General: loss of appetite, fatigue
What diseases are still not fully understood? What do we know and what are we missing?
Parkinson’s disease, Alzheimer’s disease, and autism spectrum disorders.
We know the regions of the brain that are targeted and the end result, but we don’t know why they happen.
These diseases are not a result of aging. We still don’t know what causes them so there’s a lot of research on whether they are related to neurotoxic exposure early in life or not.
What are some important characteristics of the neuron?
Neurons cover an extensive surface area with their axons (largest cells in the body) and dendritic trees. They therefore have a very high energy requirement:
- Neurons depend on aerobic glycolysis, so they need glucose and oxygen. They’ll die within minutes without the continuous supply via blood flow.
There are very few enzymes in neurons that metabolize xenobiotics. Therefore, exposure is risky.
They have a very high lipid content, 50% of which is in the myelin sheath surrounding the axons.
They must maintain their membrane potential difference with their ion pumps across their cell membranes and they must transport material back and forth from the cell body to the periphery.
- Ex: neuron to move your big toe must send impulses all the way from top of body to bottom.
What is axonal transport?
The neuron moves things back and forth in the neuron along microtubules. It is important, vulnerable, and sophisticated.
What are ways neurons can be injured?
- Neuronopathy: Neuron is destroyed. You can’t replace it.
- Axonopathy: only the axon is injured. You may be able to recover. If you still have Schwann cells in the periphery, the axon can regrow.
- Myelinopathy: if myelin is injured, but the axon is still okay it can recover.
- Destruction of the nerve ending can also occur, where the nerve ending would have to sprout new ones to survive but the cell body can live.
Can neurons regenerate?
No. Once neurons have died, that section of the brain is dead for good.
How much of the brain must be destroyed to kill a person?
In the brain, you don’t have to destroy a large part for a person to die. A small area of damage that hits a vital center can kill a person.
What is neuronal plasticity? What are the consequences of this?
Neuronal plasticity: our brains are designed to be constantly changing. Since neurons are so adaptable, some neurons can die, and other neurons will make up for their loss which can camouflage toxicity for a long time. This can make it difficult to associate problems in individuals with prior exposure years before.
What is the brain protected by? What is the spine protected by? What kind of injuries does this protect them from, what does it not?
- The brain is protected from mechanical damage by the skull and meninges (three layers of membranes that cover and protect your brain and spinal cord).
- Spinal cord is protected by vertebrae.
- The factors above don’t necessarily protect you from chemical injury, they protect from mechanical injuries. Neurotoxins tend to target specific locations. Some can also have more general effects as well such as causing brain atrophy.
What does the peripheral nervous system control? How is it affected by neurotoxicants?
- Peripheral nervous system controls all our muscles
- Sensory neurons in the periphery can be affected by neurotoxicants
What is the role of the nervous system? Can we pinpoint where in the nervous system a toxicant is acting?
- All parts of the NS (central and peripheral) must coordinate for you to properly function. They’re interconnected.
- We can find out the main site where a toxicant is acting in the NS but it will affect pretty much everything in in the NS in consequence due to them being interconnected.
What are the different cell types in the brain?
- Neurons
- Glial cells: microglia, astrocytes, oligodendrocytes
What are astrocytes?
Control microenvironment. Protector cells of neurons.
What are oligodendrocytes (oligodendroglial)?
- the myelinating cells of the central nervous system (CNS).
- Send out branches so that one cell can interact with several axons.
What are microglia?
- Microglia are variant macrophages.
- Have a lot of pattern recognition receptors (PRRS)
- They can be targeted and then they can have the ability to trigger intense inflammatory reactions. Dangerous.
- Can release free radicals, ROS’s, inflammatory cytokines
- Damage to microglial cells or toxins that stimulate them can cause neurotoxicity.
What are Schwann cells? (SCs) Where can damage occur?
- the main glial cells of the peripheral nervous system which wrap around axons of motor and sensory neurons to form the myelin sheath.
- Damage to Schwann cells in the periphery can occur
What are the meninges? Are they a target for neurotoxicants?
-Protective membranes covering the brain. Not a target for neurotoxicants.
What is the blood brain barrier? Can it be targeted by neurotoxicants?
- Can be affected by neurotoxicants.
- It’s a very sophisticated barrier designed to keep things in the periphery out of the brain.
- Made up of endothelial cells with tight junctions between them (whereas in the periphery there are spaces). Also made up of foot processes of the astrocytes that surround it.
