Increased ROS levels, antioxidant defense disturbances and bioenergetic disruption induced by thiosulfate...

Sulfite oxidase deficiencies, either caused by deficiency of the apoenzyme or the molybdenum cofactor, and ethylmalonic encephalopathy are inherited disorders that impact sulfur metabolism. These patients present with severe neurodeterioration accompanied by cerebral cortex and cerebellum abnormalities, and high thiosulfate levels in plasma and tissues, including the brain. We aimed to clarify the mechanisms of such abnormalities, so we assessed the ex vivo effects of thiosulfate administration on energetic status and oxidative stress markers in cortical and cerebellar tissues of newborn rats. Thiosulfate (0.5 µmol/g) or PBS (vehicle) was injected into the fourth ventricle of rat pups. Thirty minutes after the injection, animals were euthanized and the brain structures were utilized for the experiments. Our data showed that thiosulfate decreased the reduced glutathione (GSH) concentrations, and superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST) activities in the cortical structure. Thiosulfate also increased DCFH oxidation, hydrogen peroxide generation and glutathione reductase activity. In the cerebellum, thiosulfate reduced SOD and glutathione peroxidase activities but increased GST and CAT activities as well as DCFH oxidation. Regarding energy metabolism, thiosulfate specifically decreased complex IV activity in the cortex, whereas it increased cerebellar complex I and creatine kinase activities, indicating bioenergetic disturbances. The results suggest that the accumulation of thiosulfate causing redox disruption and bioenergetic alterations has a prominent role in the pathogenesis of sulfur metabolism deficiencies.