Neurotoxicology Flashcards
what is neurotoxicology
an adverse change in the structure or function of the central nervous system and/or peripheral nervous system following exposure to a chemical
why is neurotoxicology important?
- provides insights into the structure and function of the nervous systems
- allows us to identify which drugs are potentially harmful
- understanding mechanisms allows us to treat and prevent neurotoxicity
what is a-bungarotoxin (a-BTX)
- ## One of the components of the venom of Taiwanese banded krait (Bungarus multicinctus). - It binds to the nicotinic acetylcholine receptor found at the neuromuscular junction, causing paralysis, respiratory failure and death in the victim
why is a-bungartoxin useful in studying the nervous system
conjugated to dye and used to label nicotinic receptors in the nervous system
Why is it particularly important to identify potentially harmful effects of drug
one of the only major systems of which has there is significantly more clinical safety failures however few appeared in pre-clincial
Give examples of how mechanism identified has allowed treatment/prevention of nuerotoxicity
- acute neurotoxocity (poisoning) = e.g hypercholinergic syndrome following sarin exposure
- neurotoxicity from low level, chronic exposure = cognitive deficits in children with leaf exposure
- increase risk/ onset of neurological disorders =evidence that pesticide exposure contributes to neurodegenerative disorders
How does the complexity affect neurotoxicities
Motor = paralysis, tremor, weakness, ataxia
Sensory = auditory, olfactory, pain, touch
Cognitive = memory, speech, language, coma
Mood = anxiety, aggression, sleep, apathy
why are neurones susceptible to toxicity
Receive and transmit information through chemical transmission = multiple proteins = multiple targets
Many neurotoxicants very selective for a target
neurones are excitable membranes, how do these relate to toxic
requires high energy consumption even just to maintain resting membrane potential. This energy level is maintained by aerobic glycolysis which relates to a large O2 requirements
Chemicals which interfers with any part of energy supply will automatically cause damage
why are the long axons suceptible to toxicity
long - needs to transport proteins along
Neurones need support from _
glia = non neuronal cells
Astrocytes
Ependymal cells
Microglia (phagocytic)
Oligodendrocytes
Schwann (myelin)
what are astrocytes
Fill almost all of the space between neurons
Induce and stabilise neuronal connections
Regulate content of extracellular space
Regulate blood flow to areas of neuronal activity
Control CNS regeneration
what are ependymal cells
line ventricles
guide cell migration during development
T/F -The majority of neurons stop reproducing shortly after birth
true
How are the brain and spinal cord protected from toxins
blood brain barrier
blood cerebral spinal fluid barrier
how does the BBB and the BCSFB prevent chemical enter the nervous system
tight junctions + endothelial cells
give the 7 ways that the nervous system is vulnerable
- Complexity
- Multiple protein e.g neurotransmiter receptor (multiple target)
- High energy requirement so deprivation can cause rapid death
- Long cellular processes
- Need support from other cells
- Post mitotic
- Gaps in BBB or incomplete e.g at birth
How is neurotoxicity detected in clinical evaluation in humans
- medical history
- brief assessment
- specialised evaluations
- postmortem - histopathology
how does a brief assessment determine neurotoxicity is clinical evaluation
- metal status (Consciousness, speech, mood)
- motor ability (tremor, gait)
- sensory (touch pain)
how does a specialised evaluation determine neurotoxicity is clinical evaluation
- Neuropsychological tests (Memory, attention)
- Psychiatric (Mood questionnaires)
- Electrophysiological (Nerve conduction velocity)
- Neuroimaging
why is behaviour used to assess neuronal function in animals
Given that behaviour represents the integration and integrity of the nervous system, it is generally considered a sensitive indicator, and perhaps the ultimate assay, of neuronal function” Moser Functional Assays for Neurotoxicity Testing, Moser, Toxicologic Pathology, 39: 36-45, 2011
what are the advantages of using behaviour to evaluate neuronal function in animal models
- Generally quantitative
- Generally non- invasive so animal can be tested repeatedly
- Sensitive to even subtle alteration in NS
- Unique as can be used to assess NS affects which cannot be assessed by alternative methods
what are the disadvantages of using behaviour to evaluate neuronal function in animal model
- Behaviour may not be neural e.g. gut discomfort
- Some tests involve stressful stimuli e.g. footshock, or deprivation
- Can require specialist expertise and equipment
what are all of the observable signs seen in animals when neurotoxicity is evaluated clinically
- Appearance (changes in skin, fur, eyes, mucous membranes)
- Secretions and excretions
- Autonomic activity (e.g. lacrimation, piloerection, pupil size, unusual respiratory pattern, urination)
- Activity level
- Changes in gait (e.g., waddling, ataxia)/posture (e.g., hunched-back)
- Convulsions
- Stereotypies (e.g., excessive grooming, unusual head movements) or bizarre behaviour (e.g. biting or excessive licking, self-mutilation
- Aggression
What are the basic functional test when test neurotoxicity in animals
-sensory reactivity (auditory, visual or proprioceptive stimuli)
- limb grip straight
- motor activity
What are the end-point test to evaluate motor behaviour when test neurotoxicity in animals
Gait analysis (Inexpensive, habituation free)
Motor activity (Home cage [stress free, 24h], computerised video/photobeam monitoring)
what are specialised functional test and give examples
More specialized tests of sensory and motor function = learning and memory. Anxiety-like and depressive behaviour, social interaction
- Cognition = Spatial memory in Morris Water Maze/ Barnes Maze
= Memory and attention in serial reaction time talk
- Social interactions
what are the supplementary assessment in neurotoxicity detection
Neurochemcial
electrophysiological
tissue for histophathology
why must a combination of test be used in detecting neurotoxicity
interpreting result of a single test may be problematic
how is neurophysiology used in neurotoxicity detection
- brain slices are taken
- detailed quantification of neuronal function
- In vitro assessments allow direct action of toxicant to be studies
- firing rate can, for example, be recording for a 5-HT neurone
how is neuroimaging used in neurotoxicity detection
do to it being relatively invasive, mutiple repeat measures can be taken form the same specimen.
Multiple test can be done - structural (MRI) & functional (fMRI, PET)
what is the gold standard of neurotoxicity assessments
Neuropathology
- Assess gross structural changes in tissue
= brain region specific
= cell type specific
= activation, degeneration, loss of cells
what is the negative of neuropathology
does not detect subtle changes or functional capacity of organism
what are the five neurotoxicity mechanisms
Neuronopathies = neuronal loss
Axonpathies = axonal injury
Myelinopathies = myelin injury
Neurotransmission- associated neurotoxicity
Developmental neurotoxicity
What occurs during neuronopathies
if cell body is damaged, it degenerates and losses the axon and synpase. Nueronal loss & gliosis causes changes in glial cells (increase in astrocytes)
what occurs after axon injury
- can be transection
- distal axon and synapse will degenarte and cause axonal stump.
Schwann cells in the PNS can regernate and faciliate the regeneration of axons. However in the CNS there is no regeneration
why might cell bodies be swollen in myelinopathies
chromatolysis - chromatin pushed to periphery of cell body
True/False disruption of neurotransmission always causes cell death
false = not necessarily
Neuronopathies - neurone loss is _
irreversible
Nueronopathies is initial _ followed by /
injuy
apoptosis
necrosis
what is MPTP
designer drug which presents with parkinson-like symptoms
= slowed movements, gait problems, frozen features
During MPTP treatment, autopsy released extensive cell death only in _
dopeminergic neurones of substantia migra (involved in movement)
what is the mechanism of action of MPTP
- metabolsied by MAO-B to MPP+
- taken up by dopamine transporter
- inhibits respiration at mitocondrial complex (interupts energy supply)
- apoptosis
what is the actual toxin of MPTP
MPP+
What is axonopathies
Axon degeneration but cell body is intact, often due to chenical transection of axon. Axon transport is often target
Can be reversible
Longer axons are vulnerable such as sensory and motor = peripheral neuropathy
what toxins can cause axonopathies
Acrylamide, n-Hexane, organophosphates (TCE)
what is the symptomatology of axonopathies
sensation impairment
loss of motor strength e.g foot drop
what are the uses of n-Hexane
organic solvent
glue, solevent to extract oil form seeds.
Cleaner in texile, furniture, and leather industries
- cheap, non-polar. Easily evaporated
what is the mechanism of action for n-Hexane
1 - oxidation by mixed function
2 - link with protein to form pyrole adducts
3 - Pyrole adduct oxidised and react with adjacent neurofilaments = cross linking
When used, what was discovered in the 1960s when hexane was used
chronic high exposures in industry led to progressive sensiorimotor distal axonopathies
what happens to the neurones during axanopathies
- Distal axonopathy distal degeneration,
- Accumulation of neurofilaments
- Swelling
- Axonal atrophy
what is intramyelinic oedema
separation of myelin which insulates axons - causes vacuoles ‘spongiosis’
Remyelination can occur but more successful in PNS
What is demyelination
loss of myelin, less likely to be reversible
what has been linked to myelinopathies
lead, disulfiram Hexachlorophene
what occurs if myelinopathy is diffuse in NS =
what occurs if it limited to PNS =
- global neurological deficits = brain swelling
- peripheral neuropathy
how does myelinopathy effect conduction/neurones
slows/stops conduction along neuronal processes
aberrant conduction between adjacent neuronal processes
What was the use of hexachlorophene
newborns were bathed in this t stop staphylococcal skin infection
however it caused seizures and brain swelling
What is hexachlorophene mechanism of toxicity in the cell
- bind to memebrane and stops ions being excluded form between yelin layers
- leads to water and ion entry = seperation
-> intramyelinic oedema
what changes in neurotransmitters are seen during adverse alteration due to neurotransmission-associated neurotoxicity.
metabolising enzymes
receptors
ion-channels
often natural toxins and psychoactive drugs come into what catagory of neurotoxicity
neurotransmission-associated neurotoxicity
what are some examples of compound/drugs which cause neurotransmission-associated neurotoxicity
Domoic acid, Amphetamine, Cocaine, Nicotine, Organophosphate pesticides and nerve agents e.g. sarin
what are the outbreaks of domoic acids and what were the symptoms
California 1961 - Shearwaters banged into building and streetlights, ‘cried-like babies’ and bit residents
Canada’s PE island - outbreak of amnesic shelfish poising (permanent short term memory loss paralysis and death, >100 permeanently effected)
California 2002 - thousands of sea mammials were disoriented, experiencing seizures, paralysis + death
what is domoic acid
psuedo-nitzchia species of algea produce the toxin domoic acid
- ingested and accumulated by shellfish e.g mussels, razor clams (+ anchiovies)
what is domoic aid mechanism of action
excites neurones possessing gluatamate receptors (Kainate and AMPA receptor)
Xs releases of endogenous gluatmate = excessive NMDA receptor activation
=== excitotoxicity -> neuronal death
where does domoic acid effect in the brain
- shown in sea lions to effect DA receptor in the hippocampus
Vacuolation and necrosis in the hippocampus causes amnesia
why are embroyo/foetuses/children normally more sensitive to developmental neurotoxicity
Not just because a decrease in body weight means increase dose/bodyweight ratio
- developing NS more vulnerable to disruption
what neurological deficits are seen in developmental neurotoxicity
- generalised deficits
= developmental disability
= cognitive deficits
what happens in the nervous system during developmental neurotoxicity
Disruption of replication, migration, differentiation, myelination and synapse formation in NS
what may cause development neurotoxicity
- Teratogens
= Psychoactive drugs e.g Ethanol, Valproate
= Enviromental chemicals e.g lead
what are the sources of lead
leaded petrol, paint and soil
what was the effects of Blood level levels being elevated
decreased IQ
According to the Avon longitudinal study (chandramouli et al , 2009) how did the blood lead levels relate to 7-8 year old SAT results/ performance in school
Blood lead level 2-5 ug/dl = no effect on outcome
>5ug/dl = decrease SATs scores for reading and writing
>10ug/dl = increased antisocial activities and hyperactivity scores
what is the 2012 blood lead level
<5ug/dl
what is a hypothesised mechanism for Ca disruption involving Pb
Ca2++ is substituted for Pb
how is mitocondrial dysfuction initiated
opening of the mitochondrial transition pore leads to mitochondrial depolarization, release of cytochrome C, activation of a variety of caspases and cleavage of downstream death effector proteins, and ultimately results in apoptotic cell death
What can Ca2+ substitution/disruption effect or cause
- Uptake,
- Mitocondrial dysfunctional
- Disruptional of Ca2+ second messenger
- Disrupts Ca2+-dependent neurotransmitters release
why does Ca2+ substitution/disrupts cause mitocondrial dysfunction
dirsupts Ca2+ homeostatsis, Ca2+ accumulated and triggers apoptosis
what is Ca2+ disruption
initially activate but then repeated low level exposure or high level leads to reduction in function
how is uptake of Calcium effected by its own disruption/substitution
- Blood brain barrier = Uptake into endothelial cells if Ca2+ depletion
- Neurones and glia = Uptake through voltage-gated Calcium channels
Which of calciums second messengers are effected by its own disruption/substitution
Calmodulin which activates kinases, regulates Ca2+ homeostasis
Protein Kinase C involved in proliferation and differentiation
