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
