CNS Neurotoxicity Flashcards
Biomarkers
Animals: consciousness, sleep patterns, motor activity, behaviour, eating habits, aggressiveness, cognitive function, seizure threshold, etc.
Exclusive to humans: headache and nausea
Electroencephalographs (EEGs)
Functional magnetic resonance imaging (fMRI)
Neuron specific enolase - glycolytic enzyme in the brain
Neurofilament light chain
Tau protein - indicates PD
Beta amyloid - indicates AD
Inflammatory markers like IL-1, IL-6 and C-reactive proteins may be elevated after brain injury, but also have origins outside the CNS.
Glial fibrillary acidic protein (GFAP) and the neuronal protein ubiquitin C-terminal hydrolase L1 (UCHL1) are elevated following stroke and traumatic brain injury
Endogenous ammonia and toxicity
Ammonia may be generated in the liver through transamination, where it is then converted to urea.
Plasma ammonia may rise following liver failure. A raise from the normal <50uM to >200uM causes neurotoxicity and convulsions.
In astrocytes, glutamine synthase converts ammonia and glutamate to glutamine, which is osmotically active, causing cerebral oedema.
Glutamine is transported in the mitochondria and converted back to ammonia.
Ammonia also activates NMDA receptors, causing excitotoxicity.
Can disrupt pH balance, interfering with lysosomes and Golgi. In mitochondria, the proton gradient is disrupted.
Can cause oxidative and nitrosative stress.
Can result in neuropsychiatric disorders and hepatic encelopathy.
In children it can cause mental retardation and learning difficulties.
Linked with Alzheimer’s - elevated levels observed in patients.
Can trigger neuroinflammation, causing cytokine release and upregulation of iNOS and COX-2.
Ammonia role in the toxicity of METH
Ammonia is involved in the toxicity of methamphetamine (METH).
METH exposure leads to elevated brain ammonia, which disrupts the function of EAATs on astrocytes. These normally remove glutamate from the synapse, but ammonia interferes with pH gradients and can reverse transport.
Excitotoxicity occurs.
Treatments for ammonia toxicity
Glutamine synthase inhibitors like methionine sulfoximine (MSO)
Lactulose - acidifies the gut so that ammonia is retained as the non-transportable NH4+ ion and less penetrates the BBB.
NMDA antagonists: MK-801, phencyclidine and ketamine
β-Methylamino-L-alanine (BMAA) toxicity
Cycad seeds and cyanobacteria may produce BMAA, which can cross the BBB and agonise glutamate to cause exicitotoxicity.
BMAA can be incorporated in proteins in place of serine, causing protein misfolding - possible link to AD.
Linked to amyotrophic lateral sclerosis (ALS) by causing neurodegeneration, muscle atrophy and behavioural dysfunctions.
NMDA antagonists can be used as treatment.
NMDA antagonists
MK-801and Ketamine have hypnotic and anaesthetic properties.
Ketamine is unusual as it seems to be a respiratory stimulant - abolishes the coupling between loss of consciousness and upper airway dilator muscle dysfunction. Can be considered a safer anaesthetic due to this.
However, there have been cases where anaesthesia has been very difficult to reverse, leading to a prolonged coma - exaggerated pharmacology.
MK-801 and phencyclidine can induce a schizophrenia-like state in humans and are drugs of abuse
Chloroform
Was used as an anaesthetic as acute exposure causes unconsciousness, but it can cause sudden death - exaggerated pharmacology.
Causes respiratory depression.
GABA receptor agonist, and sodium channel inhibitor in glutamatergic neurons.
Also affects glycine and nACh receptors.
Chloroform also causes hepatotoxicity and nephrotoxicity through the metabolite phosgene, which covalently binds macromolecules.
Respiratory depressants
Depressants include solvents, anaesthetics, benzodiazepines, opioids, and barbiturates.
Effects are characterised by amnesia, sedation, loss of consciousness, respiratory depression and death in some cases.
In rodent models loss of righting reflex is a model to assess consciousness levels.
These facilitate inhibitory neurotransmitters by activation of chloride channels via GABA release and/or activation of GABA-A receptors.
Individual depressants may function through additional mechanisms.
Alcohol (Ethanol) inhibits glutamate transmission via a multitude of mechanisms alongside activation GABA-A receptors
Gamma-hydroxyl-butyric acid (GHB) is a drug of abuse that acts as a GABA agonist, with risk of death through respiratory depression.
Barbiturates depress ventilator drive in response to inhaled carbon dioxide via GABA-A agonism within the medulla. They also antagonise glutamate release and receptors.
In overdose, ingestion of pentobarbital rapidly leads to sedation and depression of medullary centres leading to respiratory and cardiovascular depression, which progresses to coma, apnoea, and death.
Opioid-induced respiratory depression can occur through the suppression of respiratory drive by interacting with neurons in the pons and medulla by activating mu receptors and inhibiting NMDA receptors.
Opioid effects can be reversed with Naloxone, an antagonist
There is a major problem with newer fentanyl derivatives that act as ultra-potent opioid agonists.
MPTP and 6-hydroxydopamine
MPTP and 6-hydroxydopamine produce Parkinson-like toxicity.
MPTP was produced as a contaminant of synthetic heroin, MPPP.
MPTP produces Parkinson’s-like symptoms including tremor and bradykinesia, and there is immediate improvement with L-dopa administration.
MPTP itself is not toxic, but it’s lipophilic and can enter astrocytes, where MAO-B converts it to MPP+.
MPP+ is a substrate for DAT transporters, so it selectively accumulates in dopaminergic neurons in the substantia nigra.
MPP+ concentrates in the mitochondria and inhibits complex 1, decreasing ATP production and causing oxidative stress.
Vesicular dopamine is displaced into the cytoplasm, causing more ROS generation.
Treated with MAO-B inhibitors: selegiline, safinamide, pargyline.
MPTP used in PD models.
6-hydroxydopamine is a synthetic toxin also used as an experimental model, acting via DAT uptake to cause oxidative stress and neurodegeneration.
Lead (Pb)
Heavy metal and environmental toxin.
Soft and malleable, used for roofing material and historically in pipes and children’s toys - children particularly susceptible to toxicity as the BBB is not fully formed.
Affects neuronal migration, differentiation and development.
Pb can substitute Ca2+ in biochemical reactions, which is responsible for toxicity. Interferes with mitochondrial calcium release, promoting mitochondrial pore transition and apoptotic neuronal cell death.
Also antagonises NMDA and can bind sulfhydryl, amine, phosphate and carboxyl groups.
Inhibits sodium-potassium ATPase.
High lead concentrations cause lead-encephalopathy. Symptoms include irritability, headache, mental dullness, memory loss and hallucinations.
A blood lead concentration of 10 ug/dl leads to reduced cognitive functions and cerebral cortex necrosis.
Lead poisoning treated with: Ca-diNa-EDTA, Dimercaprol (BAL = British anti-Lewisite), Penicillamine (originally used for gold toxicity).
Aluminium
Light metal toxicity.
20 tonnes of aluminium sulphate were accidentally added to the water supply in Cornwall, raising the concentration to 3000x the admissible level. This coloured the water black.
Consumption causes stomach cramps, skin rashes, diarrhoea, mouth ulcers and aching joints, and even one death.
Human intake of up to 30 mg day can occur from cooking utensils, saucepans, drinking water, and cosmetics - up to 0.1% is absorbed
Aluminium has no known physiological role, but may disrupt action of Ca, Mg and Fe, leading to neurodegeneration, iron accumulation and oxidative stress.
Aluminium accumulates in the hippocampus and frontal cortex and is a contributing factor in pathogenesis of neurodegenerative disease, encephalopathy and seizures.
Aluminium has a biphasic effect on cholinesterase, causing an increase early on and a decrease later on.
Aluminium increases glutamate, causing excitotoxicity.
There is a suggested link between aluminium and Alzheimer’s disease, but this is controversial - has been shown to promote the aggregation of amyloid-β.
