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

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. •Thiocyanate neurotoxicity is questionable as it needs extremely high concentrations.•Cyanate could be a plausible neurotoxin contributing to the occurrence of konzo.•Cyanate induces excitotoxicity, oxidative stress, and apoptosis in neuronal cells.•New insights on the etiopathogenesis of konzo are raised, but more are still needed.