Neurotoxicology

Question 1

True/False? Neurotoxicants aren’t that effective at killing something

Answer 1

FALSE

Question 2

Most toxins from living organisms are ____-toxic?

Answer 2

Neurotoxic

Question 3

True/False? Computers contain neurotoxicants

Answer 3

True

Question 4

What are the limitations to testing neurotoxicity on animals?

Answer 4

Can’t measure eg a mouse’s emoitons/cognitive behaviour

Question 5

Is growing neurons in culture a good way to test in vitro toxicology? What can it measure? (2)

Answer 5

Yes, can measure outgrowth and firing rate

Question 6

What are the four neuoroxic effects?

Answer 6

Cognitive
Motor
Sensory
Mood/personality
General

Question 7

What are examples of Cognitive neurotoxic effects?

Answer 7

Memory, learning, confusion

Question 8

What are examples of Motor neurotoxic effects?

Answer 8

Weakness, convulsion, paralysis

Question 9

What are examples of Sensory neurotoxic effects?

Answer 9

Vision, hearing, touch, balance

Question 10

What are examples of Mood/Personality neurotoxic effects?

Answer 10

Sleep, depression, irritability, excitability

HARD TO TEST

Question 11

What re examples of General neurotoxic effects?

Answer 11

Loos of appetite, fatigue

Question 12

Neurons have a high energy requirement dependent on aerobic glycolysis. What is the consequence of this?

Answer 12

Anything that alters blood/O2 flow will greatly affect neurons

Question 13

What are properties of the brain that affect neurotoxicity? (3)

Answer 13

• Don’t have many enzymes to metabolize xenobiotics (any alien particle that reaches brain is pretty much stuck there)
• High lipid content (50% myelin) so lipophillic toxins can get through BBB and latch onto myelin
• Largest cells in body, High E content

Question 14

Define anterograde and retrograde transport along axonal microtubules

Answer 14

Anterograde: From cell body to axon terminal
Retrograde: reverse, from axon terminal to cell body

Question 15

How can toxins affect neurons? (4)

Answer 15

Can kill the neuron itself
Can cut the axon (through chemical/physical damage)*
Can damage the myelin sheath*
Can damage transmission of AP

*Damage can be temporary if schwann cells/oligodendrocytes are intact

Question 16

True/False? Neurons can regenerate (if a toxin damages a neuron, it can regrow/be replaced)

Answer 16

False, brain damage is permanent

Question 17

How much brain damage is necessary to be fatal?

Answer 17

Depends on where the damage occurs

e.g. breathing center is very small

Question 18

Can you extrapolate data from animals to humans?

Answer 18

Yes but it’s hard

Question 19

What property of the brain can mask toxicity for many years?

Answer 19

Neuronal plasticity - if you’re exposed to low levels of toxin chronically, brain can reconfigure to compensate

Question 20

What happens during fetal exposure of neurotoxins?

Answer 20

Nonreversible tolerand and chemical imprinting

Question 21

What are the 3 components of the Nervous system?

Answer 21

Central nervous system (Brain/Spinal chord)
Peripheral Nervous System
Autonomic Nervous System

Question 22

What is an example of generalized neuronal damage?

Answer 22

Cerebral atrophy

Question 23

What is a critical property of neurons? Why is that a problem?

Answer 23

Extremely specialized functions - vulnerable

If any one step gets disrupted, serious trouble

Question 24

What are the 3 types of cells found in the brain?

Answer 24

Neurons
Glia
Capillaries

Question 25

What are oligodendrocytes?

Answer 25

Provide myelination in CNS | One oligodendrocyte has many projections which wrap around axon

Question 26

What is a Schwann cell?

Answer 26

Provide Myelination in PNS | One schwann cells at a time wraps around axon

Question 27

What are microglia?

Answer 27

Variant of macrophage in CNS, many receptors to detect foreign bodies Can stimulate local inflammation

Question 28

Describe the properties of the Blood Brain Barrier (2)

Answer 28

Designed to keep out foreign compounds Reinforced version of a capillary Has pumps to let vital things through

Question 29

How can a drug get into the CSF?

Answer 29

Has to cross: Endothelial cell wall Astrocyte Pericytes

Question 30

True/False? Most things cannot get through the BBB

Answer 30

True

Question 31

True/False? Water and lipids cross the BBB through the same mechanism

Answer 31

True BUT Water diffuses through tight junctions Lipids/lipid soluble agents diffuse through cell wall

Question 32

How does glucose/amino acids/nucleosides cross BBB?

Answer 32

Active transport

Question 33

How does albumin/other plasma proteins cross BBB?

Answer 33

Adsorptive transcytosis

Question 34

How does a drug get out of the CSF?

Answer 34

Circulates around until it leaves through arachnoid villus

Question 35

Is there a significant barrier between the brain and CSF?

Answer 35

No

Question 36

Can drugs alter the permeability of BBB?

Answer 36

Yes

Question 37

What are 7 mechanisms of Neurotoxicity?

Answer 37

Interfering with aerobic metabolism (eg CO) Interfering with protein synthesis (methyl Hg) Interfering with Intermediate metabolism (MPTP) Alter electrical transmission (tetrodotoxin) Plant neurotoxins (vinka alkaloids) Damage to myelin sheaths (hexachlorophene) Selective Cytotoxicity (...)

Question 38

What are 3 ways for NT transmission that can be affected?

Answer 38

Increase/Decrease NT release (Indirect effect) Synaptic modulation Prevent transmitter reaction/reuptake

Question 39

What happened during the domoic acid epidemic of 1987?

Answer 39

Several cases of the same unusual symptoms (CNS problems but also GIT issues) Many people died/suffered memory loss *Excitation followed by neuronal necrosis Turns out they had all eaten muscles fro PEI that were affected by algae to produce DOMOIC ACID Domoic acid - heat stable, cooking didn't denature it Excites glutamate receptors - agonism followed by inactivation of neurons (prolongs opening of pre/post synaptic Na channels) Na depolarization opens Ca channels, which is cytotoxic in cells "Excitotoxicity"

Question 40

How does Saxitoxin kill you?

Answer 40

Numbs everything (diaphragm numbness, can't breathe)

Question 41

How does Bioaccumulation kill larger animals?

Answer 41

Small amounts of toxin in small eg algae Fish eat lots of algae - lots of toxin in fish People eat lots of fish - LOTS of toxin in people

Question 42

How are some animals immune to tetrodotoxin?

Answer 42

Different Na channels that aren't affected by TDT

Question 43

Is betrachotoxin safe to eat?

Answer 43

Yes, inactivated by stomach/cooking

Question 44

Is betrachotoxin produced by tree frogs?

Answer 44

No, the frogs eat the insec that makes it and concentrates it

Question 45

What is the main mechanism of bacterial neurotoxins?

Answer 45

Affect NT release

Question 46

What are the two most common bacterial neurotoxins?

Answer 46

Botulinum and Tetanus toxin | Both are 2-chain polypeptides

Question 47

When is botulinum toxin a risk?

Answer 47

In low acid home canning

Question 48

Describe the funciton of each polypeptide chain of Botulinum and Tetanus Toxin

Answer 48

Heavy Chain - one side locates cholinergic neurons, other side translocates into cell Light Chain - does the damage: Breaks down SNARE complex (normally incorporates vescicles) Doesn't destroy neuron but breaks that branch (permanent nerve damage)

Question 49

How can botulinum be used therapeutically?

Answer 49

Can treat hypercontractility by targeting specific nerves (botox) Achalasia (contraction of esophageal sphincter

Question 50

True/False? Tetanus toxin funcitons in the same way as botulinum

Answer 50

True

Question 51

True/False? Tetanus toxin functions in the same palce as botulinum

Answer 51

False BT - Brain TT - Spinal Chord, specific to cholinergic receptors

Question 52

What are the symptoms of tetanus toxicity?

Answer 52

Spasm and Paralysis | Different from botulism in that it doesn't effect that specific neuron, but the neuron inhibitory to that neuron

Question 53

How does the Latrotoxin of Black widow Spiders work?

Answer 53

Acts at neuromuscular junction, Creates a Ca Channel on nerve ending, allows NT flooding (LETHAL)

Question 54

How does alpha Bungarotoxin work?

Answer 54

Binds to muscular receptors Irreversibly blocks Nicotinic Cholinergic receptors Paralysis, diaphragmatic shock

Question 55

How does Sarin (an organophosphate) work?

Answer 55

Prevents inactivation of NT Normally: Postsynaptic membrane has receptors that receive and break down ACh (and reuptakes metabolites) Sarin is an "anticholinesterase" AChE is inactivated, you die quickly

Question 56

What i the safest insecticide for mammals?

Answer 56

Malathion

Question 57

How are organophosphate insecticides absorbed?

Answer 57

Through the skin

Question 58

Is there an antidote for Organophosphate toxicity?

Answer 58

Yes! Pralidoxime (reactivates AChE, rips off organophosphates)

Question 59

Describe Lead toxicity

Answer 59

Brain/nerve damage GI damage Stunted Growth Hearing Loss

Question 60

There is a direct relationship between placental concentration of _____ and emotional/behavioural problems

Answer 60

Lead

Question 61

How does lead lead to brain damage?

Answer 61

Interference with synapse function