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New insight into the molecular etiopathogenesis of konzo: Cyanate could be a plausible neurotoxin contributing to konzo, contrary to thiocyanate

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Title: New insight into the molecular etiopathogenesis of konzo: Cyanate could be a plausible neurotoxin contributing to konzo, contrary to thiocyanate
Authors: BAGUMA, Marius, KESSELS, Sofie, BITO, Virginie, BRONE, Bert, Triller, Antoine, Maynard, Stephanie, Legendre, Pascal, RIGO, Jean-Michel, Le Corronc, Herve, Chabwine, Joelle Nsimire
Contributors: BAGUMA, Marius, KESSELS, Sofie, BITO, Virginie, BRONE, Bert, Triller, Antoine, Maynard, Stephanie, Legendre, Pascal, RIGO, Jean-Michel, Le Corronc, Herve, Chabwine, Joelle Nsimire
Source: NeuroToxicology. 105:323-333
Publisher Information: Elsevier BV, 2024.
Publication Year: 2024
Subject Terms: Neurons, Manihot, Dose-Response Relationship, Drug, Cell Survival, Neurotoxins, Cyanide poisoning, Rats, Rats, Sprague-Dawley, Mice, Spinal Cord, Thiocyanate, Konzo, Cell Line, Tumor, Caspases, Neurotoxicity, Animals, Humans, Cell culture, Reactive Oxygen Species, Cyanate, Thiocyanates, Cyanates
Description: Chronic cassava-derived cyanide poisoning is associated with the appearance of konzo, a tropical spastic paraparesis due to selective upper motor neuron damage. Whether the disease is caused by a direct action of cyanide or its metabolites is still an open question. This preliminary study assessed the neurotoxic effects of thiocyanate (SCN) and cyanate (OCN), two cyanide metabolites hypothesized to be plausible toxic agents in konzo.Cultured mouse neuroblastoma (Neuro-2A) and human neuroblastoma (SH-SY5Y) cell lines were incubated (24, 48, and 72 hours) in sodium OCN or sodium SCN in a disease-relevant concentration range. Cell viability, caspase (3, 8, and 9) activities, and reactive oxygen species (ROS) generation were evaluated using appropriate assay kits. Additionally, electrophysiological responses induced by OCN and SCN in primary spinal cord neurons (from Sprague Dawley rats) were assessed by whole-cell patch-clamp techniques.Both OCN and SCN were toxic in a dose-dependent way, even if SCN toxicity appeared at very high concentrations (30 mM, corresponding to more than 100-fold higher than normal plasmatic levels), contrary to OCN (0.3-3 mM). OCN was markedly more toxic in a poor culture medium (MEM; IC50 = 3.2 mM) compared to a glucose- and amino acid-rich medium (DMEM; IC50=7.6 mM). OCN treatment increased the ROS generation by 8.9 folds, as well as the Caspase-3, Caspase-8, and Caspase-9 activities by 3.2, 2.5, and 2.6 folds, respectively. Finally, OCN (and SCN to a lesser extent) induced depolarizing currents in primary spinal cord neurons, through an activation of ionotropic glutamate receptors.Our results suggest OCN as the most plausible neurotoxic agent involved in konzo, while SCN toxicity could be questioned at such high concentrations. Also, they support apoptosis, oxidative stress, and excitotoxicity as probable mechanisms of OCN neurotoxicity.
Document Type: Article
File Description: application/pdf
Language: English
ISSN: 0161-813X
DOI: 10.1016/j.neuro.2024.11.004
Access URL: https://pubmed.ncbi.nlm.nih.gov/39608576
http://hdl.handle.net/1942/45042
Rights: Elsevier TDM
Accession Number: edsair.doi.dedup.....dee32ce70d42b454e8f64fa6ba3942db
Database: OpenAIRE
Description
Abstract:Chronic cassava-derived cyanide poisoning is associated with the appearance of konzo, a tropical spastic paraparesis due to selective upper motor neuron damage. Whether the disease is caused by a direct action of cyanide or its metabolites is still an open question. This preliminary study assessed the neurotoxic effects of thiocyanate (SCN) and cyanate (OCN), two cyanide metabolites hypothesized to be plausible toxic agents in konzo.Cultured mouse neuroblastoma (Neuro-2A) and human neuroblastoma (SH-SY5Y) cell lines were incubated (24, 48, and 72 hours) in sodium OCN or sodium SCN in a disease-relevant concentration range. Cell viability, caspase (3, 8, and 9) activities, and reactive oxygen species (ROS) generation were evaluated using appropriate assay kits. Additionally, electrophysiological responses induced by OCN and SCN in primary spinal cord neurons (from Sprague Dawley rats) were assessed by whole-cell patch-clamp techniques.Both OCN and SCN were toxic in a dose-dependent way, even if SCN toxicity appeared at very high concentrations (30 mM, corresponding to more than 100-fold higher than normal plasmatic levels), contrary to OCN (0.3-3 mM). OCN was markedly more toxic in a poor culture medium (MEM; IC50 = 3.2 mM) compared to a glucose- and amino acid-rich medium (DMEM; IC50=7.6 mM). OCN treatment increased the ROS generation by 8.9 folds, as well as the Caspase-3, Caspase-8, and Caspase-9 activities by 3.2, 2.5, and 2.6 folds, respectively. Finally, OCN (and SCN to a lesser extent) induced depolarizing currents in primary spinal cord neurons, through an activation of ionotropic glutamate receptors.Our results suggest OCN as the most plausible neurotoxic agent involved in konzo, while SCN toxicity could be questioned at such high concentrations. Also, they support apoptosis, oxidative stress, and excitotoxicity as probable mechanisms of OCN neurotoxicity.
ISSN:0161813X
DOI:10.1016/j.neuro.2024.11.004