In vitro evidence that sulfite impairs glutamatergic neurotransmission and inhibits glutathione metabolism‐related enzymes in rat cerebral cortex

Abstract

Sulfite oxidase (SOX) deficiency is an inherited neurometabolic disorder biochemically characterized by tissue accumulation and high urinary excretion of sulfite and thiosulfate. Affected patients present severe neurological dysfunction accompanied by seizures, whose pathophysiology is poorly known. In the present study we evaluated the in vitro effects of sulfite and thiosulfate on important parameters of glutamatergic neurotransmission and redox homeostasis in rat cerebral cortex slices. We verified that sulfite, but not thiosulfate, significantly decreased glutamate uptake when cerebral cortex slices were exposed during 1h to these metabolites. We also observed that thiosulfate inhibited glutamine synthetase (GS) activity. A pronounced trend toward GS inhibition induced by sulfite was also found. Regarding redox homeostasis, sulfite, at the concentration of 10 μM, increased thiobarbituric acid-reactive substances and decreased glutathione concentrations after 1h of exposure. In contrast, thiosulfate did not alter these parameters. We also found that 500 μM sulfite increased sulfhydryl group content in rat cerebral cortex slices and increased GSH levels in a medium containing oxidized GSH (GSSG) and devoid of cortical slices, suggesting that sulfite reacts with disulfide bonds to generate sulfhydryl groups. Moreover, sulfite and thiosulfate did not alter the activities of glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST) and glucose-6-phosphate dehydrogenase (G6PDH) after 1h of incubation. However, sulfite inhibited the activities of GPx, GST and G6PDH when cortical slices were exposed for 3h to sulfite. We finally verified that sulfite did not induce cell death after 1h of incubation. Our data show that sulfite impairs glutamatergic neurotransmission and redox homeostasis in cerebral cortex. Therefore, it may be presumed that these pathomechanisms contribute, at least in part, to the seizures observed in patients affected by SOX deficiency.

The mitochondrial‐targeted reactive species scavenger JP4‐039 prevents sulfite‐induced alterations in antioxidant defenses, energy transfer, and cell death signaling in striatum of rats

“…However, it has been shown that sulfite, the main accumulating metabolite in both disorders, is neurotoxic. Sulfite undergoes auto‐oxidation in vitro and in vivo in rat brain, leading to the formation of reactive species 9 and impairing redox homeostasis and antioxidant defenses 9‐14 . Moreover, sulfite disrupts mitochondrial bioenergetics and biogenesis and induces mitochondrial permeability transition, 11,15 as well as glial reactivity and neuronal loss in rat striatum 11 …”

The sulfite oxidase Shopper controls neuronal activity by regulating glutamate homeostasis in Drosophila ensheathing glia

“…In shopper mutants sulfite accumulates (Fig. 4d ) which is reported to inhibit glutamate dehydrogenase (Gdh) or Glutamine synthetase in mammalian cells (Gs) 28 , 29 . Thus, shopper might influence glutamate homeostasis in the ensheathing glia.…”

“…Sulfite oxidase oxidizes neurotoxic sulfite that originates from the catabolic metabolism of sulfur containing amino acids. Thus, impaired sulfite oxidase activity results in accumulation of sulfite which suppresses the activity of glutamate dehydrogenase, glutamate transporters, and glutamine synthetase 28 , 29 . Here, we identified Shopper due to its specific function in ensheathing glial cells.…”

Metabolomic study of the mechanism of Dai medicine <italic>Orthosiphon stamineus</italic> on “Jiajie”

“…酰化起到抗衰老作用 [41] . 谷胱甘肽代谢能够促进机体 对毒素的排泄, 能够有效清除体内自由基, 可预防帕 金森疾病 [42,43] , 提高机体免疫力. 嘌呤代谢参与阿尔茨 海默病 [44,45] 、帕金森 [46] 、痛风等疾病 [47] , 能够有效降…”