"Methods for Assessing Cytochrome c Oxidase Inhibitors and Potential Antidotes"
Date: Tuesday, August 6, 2019
Time: 1:30 pm
Location: Room 1149
Jim Peterson, PhD
Linda Pearce, PhD
Aaron Barchowsky, PhD
Joel Haight, PhD
Mitochondrial toxicants (sulfide, cyanide and/or azide) and their putative antidotes (NaNO2 and/or CoN4[11.3.1]) were examined in two models (BPAEC and Galleria mellonella) and compared to a mouse model. Bovine pulmonary artery endothelial cells (BPAEC) responded in a dose-dependent manner to millimolar (0-10) concentrations of sodium hydrosulfide (NaHS) and when treated five minutes before the NaHS with a sodium nitrite (NaNO2) solution there was a marked reversal in the mitochondrial-linked toxicity of sulfide. This was similar to the results observed in male Swiss-Webster mice administered NaNO2 prophylactically (24 mg/kg ip), five minutes before an LD40 dose of NaHS. In G. mellonella both nitrite and the Busch compound reduced the recovery time of cyanide, azide and sulfide poisoning, demonstrating the usefulness of this invertebrate organism for examining cytochrome c oxidase inhibitors and testing putative antidotes. Inoculation of the three toxicants by intra-haemocoel injection (ih) through the larval proleg, resulted in a dose-dependent unconscious or “knockdown” state and subsequent recovery, similar to the righting recovery observed in our animal studies. The time from knockdown until recovery was measurable in the larvae (<1 to ~40 min). Effectiveness of the antidotes was assessed by measuring the length of righting recovery in larvae treated with antidotes versus larvae receiving only the toxicant. These putative antidotes were shown to be helpful in ameliorating the toxicity of all three toxicants in cells, mice and G. mellonella larvae, especially in the case of sulfide and azide toxicity, since there are no effective antidotes available. Most importantly, NaNO2 ameliorated cyanide toxicity in the larvae. The larvae do not have hemoglobin, demonstrating that the antidotal action of nitrites does not require involvement of methemoglobin, verifying that NaNO2 acts as a NO donor and not a methemoglobin former.
Last Updated On Tuesday, July 23, 2019 by Snyder, Bryanna M
Created On Tuesday, July 23, 2019
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