PNS Neurotoxicity Flashcards
Biomarkers
Electromyography (EMG) to detect neuromuscular abnormalities
Neurofilament light chain - could also indicate CNS toxicity
Beta-endorphins, C-reactive peptide (CRP) and other inflammatory cytokines produced as a result of increased pain signals
Endocannabinoids: 2-AG and anandamide (AEA)
Peripheral neuropathy
Peripheral neuropathy that arises from excess glucose in diabetes can manifest as:
- Loss of balance, poor coordination or poor reflexes
- Muscle weakness
- Poor nerve conduction velocity and EMG tests
- Paresthesia
- Lack of sensation (numbness), often in extremities
- Skin ulceration (with high risk of infection) - occurs when sensory nerve supply to the skin is lost
Glucose is therefore a good model toxin.
Common side effect of chemotherapeutics like cisplatin and paclitaxel. Sensory nerves are the most affected and toxicity includes microtubule disruption, mitochondrial damage and myelin sheath damage (motor/autonomic nerves).
Thalidomide, a treatment of ankylosing spondylitis and rheumatoid arthritis, mostly affects sensory nerves, reversible after drug suspension
Isoniazid, used to treat tuberculosis, interferes with Vitamin B6 synthesis and causes neuropathy, principally affecting motor nerves. Effects reversed by pyridoxine.
Other peripheral neuropathy inducing agents include metronidazole, statins and amiodarone.
Neuroprotective agents
Alpha-lipoic acid and Amifostine - used to treat cisplatin-induced neuropathy. However, there is a concern, particularly with amifostine, that it is protecting the cancer cells from toxicity too, undoing the effects of cisplatin.
Acetyl carnitine, especially post chemotherapy, with possible utility post stroke. It raises ATP levels, protecting against mitochondrial damage.
Pyridoxine, useful in isoniazid neuropathy and also the CNS to diminish glutamate excitotoxicity.
Ciguatoxins - Na+ channel toxins
Ciguatoxins are produced by dinoflagellate algae species (Gambierdiscus toxicus) and cause ciguatera fish poisoning (CFP).
Act as voltage-dependent Na+ channel openers, leading to opening of VGCCs and excess nerve activation.
Ciguatoxin is lethal at 0.45 μg/kg intraperitoneal.
Symptoms involve nausea, vomiting, diarrhoea, convulsions, breathing difficulties, asphyxia and death
Calcium channel blockers, such as gabapentin, are used as treatment
Saxitoxin - Na+ channel toxin
Saxitoxin (STX) is a potent neurotoxin from the blooms of dinoflagellate algae (Alexandrium/Gymnodinium) causing paralytic shellfish poisoning (PST).
Ingestion in humans occurs through consumption of shellfish contaminated by algae.
Effects include: tingling sensation to lips, gastrointestinal problems (nausea, vomiting, diarrhoea) breathing difficulties, leading to complete paralysis, respiratory arrest and death
STX inhibits NA+ channels to cause respiratory and general paralysis.
PSP toxins are the most well-known potent neurotoxins that bind sodium channels.
Classified as a weapon of mass destruction (WMD).
Mouse LD50 (IP) is 3-10 ug/kg and oral is 263 ug/kg.
Tetrodotoxin - Na+ channel toxin
Tetrodotoxin (TTX) is a Na+ channel blocker found in the liver, skin and ovaries of the puffer fish.
TTX is water soluble, heat stable and 1000x more toxic than cyanide.
Initial symptoms include tingling (paresthesia) of the tongue and lips, followed by or concurrent with headache and vomiting, which may progress to muscle weakness and ataxia. In severe cases death may occur due to respiratory and/or heart failure.
TTX is selective for Na+ channel on nerves, not muscles, so it’s a useful pharmacological agent, as it helps identify if a response is a neurological or muscle effect.
TTX can be synthetically made from glucose.
Strychnine
Strychnine is a highly toxic alkaloid derived from rhubarb. Rhubarb also contains the nephrotoxic oxalic acid.
Allegedly used in small quantities as an athletic performance enhancer and also used as an arrow poison and a pesticide.
It inhibits glycine receptors, which are Cl- channels. Inhibition in the spinal cord leads to increased neuronal activity and muscle spasms, which eventually leads to respiratory failure.
Lethal dose of 30-120 mg orally and 5-10 mg intravenously.
Treatment is achieved by anticonvulsants, such as phenobarbitone and diazepam, as these enhance inhibitory GABA neurotransmission.
α-Latrotoxin - ACh toxin
α-Latrotoxin is found in the venom of the black widow spider.
It causes massive presynaptic release of ACh by exocytosis. Potent toxin targeting the molecular machinery of exocytosis, which has a high affinity for receptors that are expressed specifically on neuronal and endocrine cells.
cramps and muscle spasms occur within an hour.
Only in the most serious cases do we get latrodectism, a syndrome consisting of generalised muscle pain, abdominal cramps, profuse sweating, a rise in blood pressure and tachycardia, with death encountered only on very rare occasions
Bungarotoxins - ACh toxins
Bungarotoxins like α-BuTx are produced by the Banded Krait snake.
These bind postsynaptic nACh receptors at the NMJ, which makes them useful for isolating nicotinic receptors.
α-BuTx binds to the α1 nAChR subunit, a mechanism that qualifies it as a curare-mimetic.
Causes skeletal muscle paralysis.
α-BuTx is also capable of blocking neuronal cholinergic receptors in the central nervous system, but to a lesser extent.
Botulinum toxin - ACh toxin
Botulinum toxin (BOTOX) comes from Clostridium botulinum spore-forming anaerobic bacteria found in the soil, river water and the intestines of animals.
The toxin enters the general circulation and binds presynaptic membranes of motor neuron nerve terminals, enters the cytosol and blocks the release of ACh, causing neuromuscular blockade - opposite mechanism to α-latrotoxin.
Canning processes can allow the bacteria to grow if not followed correctly, as anaerobic conditions are favourable to these bacteria. John West Salmon killed 2 people and put another 2 on artificial ventilation in 1978.
LD50 of 10 ng/kg.
Botulism is a food-borne illness caused by this bacteria.
Infection of wounds can occur from bacterial contamination from the soil, allowing spore germination.
Symptoms include: inhibition of skeletal muscle innervation, flaccid muscular paralysis, blurred vision, difficulty swallowing and respiratory paralysis which may cause death.
An antitoxin is available
Medical uses of the toxin were introduced in 1983. Very small amounts of this toxin are used both as a cosmetic treatment and to treat painful muscle spasms, such as in the oesophagus. It is sold under the brand names Botox and Dyspot, respectively.
Organophosphates - ACh toxins
Originally developed as warfare agents, now used as insecticides: Parathion, Malathion (used to treat head lice), Diazinon and Chlorpyrifos.
Nerve agents include sarin, malathion, VX nerve agent, and novichok 5 and 7.
Inhibit acetylcholinesterase, causing increased ACh in the synapse.
This leads to cholinergic syndrome, which has widespread manifestations, affecting the nervous, respiratory, cardiovascular and gastrointestinal systems - cause lacrimation, blurred vision, abdominal cramps, vomiting, diarrhoea, incontinence, bronchoconstriction, bradycardia, hypotension, muscle twiching and cramps, dizziness, fatigue, respiratory depression, etc.
Supportive measures in acute organophosphate poisoning include: decontamination, airway stabilisation and active charcoal for internal decontamination.
Antidotes include atropine, a muscarinic antagonist, and Pralidoxime, a chemical antagonist used to regenerate active cholinesterase after organophosphate inhibition → only useful if you get it in quickly.
