Abstract
We sought to elucidate the protein carbamoylation patterns associated with cyanate neuropathy relative to cyanide poisoning. We hypothesized that under a diet deficient in sulfur amino acids (SAA), the carbamoylation pattern associated with cyanide poisoning is similar to that of cyanate neuropathy. Male rats (6–8 weeks old) were fed a diet with all amino acids (AAA) or 75%-deficiency in SAA and treated with 2.5 mg/kg/body weight (bw) NaCN, or 50 mg/kg/bw NaOCN, or 1 μl/g/bw saline, for up to 6 weeks. Albumin and spinal cord proteins were analyzed using liquid chromatography mass spectrometry (LC-MS/MS). Only NaOCN induced motor deficits with significant levels of carbamoylation. At Day 14, we found a diet-treatment interaction effect on albumin carbamoylation (p = 0.07). At Day 28, no effect was attributed to diet (p = 0.71). Mean number of NaCN-carbamoylated sites on albumin was 47.4% higher relative to vehicle (95% CI:16.7-86.4%). Only NaOCN carbamoylated spinal cord proteins, prominently, under SAA-restricted diet. Proteins targets included myelin basic and proteolipid proteins, neurofilament light and glial fibrillary acidic proteins, and 2', 3' cyclic-nucleotide 3'-phosphodiesterase. Under SAA deficiency, chronic but not acute cyanide toxicity may share biomarkers and pathogenetic similarities with cyanate neuropathy. Prevention of carbamoylation may protect against the neuropathic effects of cyanate.
Highlights
Dietary dependency on cyanogenic cassava and low intake in sulfur amino acid (SAA) have been implicated in outbreaks of a central motor neuron disease known as konzo
We hypothesized that under a diet deficient in sulfur amino acids (SAA), the carbamoylation pattern associated with cyanide poisoning is similar to that of cyanate neuropathy
On the assumption that these findings would hold true for additional experimental time points and time dependent correlations between levels of carbamoylation and NaOCN-induced deficits in a large sample of rats, our results suggest that cyanate neuropathy may be mediated through carbamoylation
Summary
Dietary dependency on cyanogenic cassava and low intake in sulfur amino acid (SAA) have been implicated in outbreaks of a central motor neuron disease known as konzo. Cassava is a carbohydrate-enriched and cyanogenic crop with a very low content in proteins and only 1-2% content in SAA, which are needed for humans to detoxify cyanide (Diasolua Ngudi et al 2002, Kassa et al 2011, Nunn et al 2011). It contains linamarin, a cyanogenic compound that is metabolically converted to cyanohydrins and hydrogen cyanide, a well-known mitochondrial toxin. Limited progress has been made partially due to the lack of experimental models
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