Neurotoxicity

define neurotoxicity

any adverse effect on the structure or function of the central and/or peripheral nervous system by a biological, chemical, or physical agent

• cam be permanent or reversible, direct or indirect

• involves any aspect of neuronal function e.g. myelin sheath, axonal transport and synaptic neurotransmission

why is irreversible damage to neurons more severe

• neurons are post mitotic (cannot divide)

• are not quickly replaced so present for long duration

• cannot afford to lose any

describe the effects of neurotoxicity

• Functional adverse effects on receptor-mediated responses

• Adaptive changes- altered gene expression, epigenetic changes, receptor up/down-regulation, altered neurochemistry

• Structural changes- changes in synaptic plasticity, demyelination, dendritic shrinkage

• Neurodegeneration- loss of neurons and/or glia

state common types of drug-induced FUNCTIONAL neurotoxicity and give an example of drugs that cause this

functional- fatigue, cognitive impairment, tremor, anorexia, depression

• Jimson weed- contains muscarinic antagonists atropine, hyoscyamine and scopolamine

• can get into the brain. Ingestion causes delirium, hallucinations and amnesia

state 5 types of drug-induced STRUCTURAL neurotoxicity and for each give 2 examples of drugs that causes it

• CNS neurotoxicity- heroin, cocaine

• peripheral neuropathy- antimicrobials e.g. chloroquine, chemotherapy drugs e.g. cisplatin

• retinal degeneration- gentamicin, quinine

• optic nerve degeneration- ibuprofen, cisplatin

• ototoxicity- streptomycin, amoxicillin

describe the CNS neurotoxicity caused by COCAINE

• MOA- blocks reuptake transporters for DA, NA, 5HT which means they accumulate in the synaptic cleft

• result is excessive stimulation of their post synaptic receptors, prolonged neuronal firing

• mechanism of cocaine neurotoxicity: high DA

  • cocaine causes high cytoplasmic DA which undergoes auto-oxidation and MOA-mediated enzymatic metabolism to produce ROS

    • auto-oxidation produces superoxide anion and hydrogen peroxide

    • MOA metabolism produces hydrogen peroxide

  • these damage DNA and proteins leading to OS, synaptic dysfunction, neuronal degeneration

where is the predominant site for acute adverse functional effects and why

synapse- these are specialised junctions where neurons communicate with each other

• this is the main site where neurons communicate rapidly and effectively

• therefore small disruptions can lead to large changes in brain function and structure

state direct and indirect mechanisms of drug-induced neurotoxicity

DIRECT

• Disruption of mitochondrial function

• Oxygen free radical formation

• Release of excitatory amino acids

• Ion channel inhibition

• Apoptosis

INDIRECT

• Hypoglycaemia

• Hypoxia

• Ischaemia

• Disruption of BBB

• Hepatotoxicity

give an example of a neurotoxicant that causes DIRECT drug-induced neurotoxicity

MK-801 (dizocilpine)

• this is a noncompetitive NMDAR antagonist that blocks inside the NMDAR channel and prevents ion flux

• used to treat ischaemia and reduce stroke phenotype

• therapeutic use limited as it was neurotoxic

• blocked NMDAR that were essential for normal neuronal communication, Ca2+ signalling

• although MK801 blocks excitatory receptors it paradoxically causes abnormal excitation

• it blocks NMDAR on inhibitory interneurons leading to overexcitability and dysregulated Glu release

• result is cortical hyperexcitability, excitotoxic stress and increased ROS production

explain why the brain is highly susceptible to oxidative stress

• has high content of polyunsaturated fatty acids

• Low levels of anti-oxidants

• Presence of transition metals

• High levels of oxygen consumption

describe 2 examples of CNS cell types that are highly susceptible to oxidative stress

• state their role, consequence of degeneration and the reason for their susceptibility

substantia nigra dopamine neurons

• Role- motor function

• Effects of degeneration- Parkinson

• Reason for higher risk- dopamine metabolism produces ROS

retinal pigment epithelial cells

• Role- nutritional support to photoreceptors

• Effects of degeneration- loss of vision

• Reason for higher risk- exposure to high levels of UV light and oxygen from high blood supply

describe in silico and post-mortem approaches to assessing drug-induced neurotoxicity preclinically

IN SILICO

• Machine learning (QSTR)

• Uses the molecular structure to predict whether the drug will cause peripheral neuropathy

POST MORTEM

• neurohistopathology

describe in vitro approaches used to assess drug-induced neurotoxicity preclinically

• knock down studies- investigate MOA of drug-induced neurotoxicity

• functional readouts- in vitro electrophysiology, live cell Ca2+ imaging

• morphological readouts

  • Dendritic spine morphology and density

    • studied using rat primary hippocampal neurons using MAP2 a dendrite specific marker and Actin a microfilament protein

• 3D brain organoids

  • self assembled 3D constructs generated from neural subtypes that resemble human brain

  • able to replicate gene expression in vitro

  • brain region specific using guided differentiation

  • used to look at morphological, neurochemical and electrophysiological responses to neurotoxic drug in different brain regions

  • e.g. organoids on a chip, retinal organoids

• hippocampal slice preparation used to investigate seizure liability- anatomy of HIP is well defined; CA1 neurons used

describe in vivo approaches to assessing drug-induced neurotoxicity preclinically

Behavioural

• 24/7 home cage monitoring in group/housed rates

  • standard home cage, groups, nocturnal

  • systems tracks individual animals using radio frequency ID reader inserted under ventral abdomen of rat

  • measure locomotion, social interaction, feeding, aggression

• test for nociception

  • assess hyperalgesia, allodynia

  • tail flick test, paw withdrawal threshold,

Neurophysiological e.g EEG, ERG

• EEG devise implanted under anaesthesia and used to detect seizures

  • convulsant agents make spike and wave changes

• ERG measure retinal dysfunction- measure electrical response of retinal cells to light stimulation

  • uses long evan rats- retinas closer to humans

neurochemical e.g. soluble biomarkers

• GFAP for astrocyte, myeline basic protein, NFL for axons, MAP2 for dendrities

neuroimaging e.g. MRI, MRS (detects neurochemical changes)