Bezafibrate prevents mitochondrial dysfunction, antioxidant system disturbance, glial reactivity and neuronal damage induced by sulfite administration in striatum of rats: Implications for a possible therapeutic strategy for sulfite oxidase deficiency
| Autor: | Guilhian Leipnitz, Belisa Parmeggiani, Pauline Maciel August, Julia Tauana Pletsch, Angela T. S. Wyse, Cristiane Matté, Gabriela Miranda Fernandez Cardoso, Moacir Wajner, Mateus Grings, Alana Pimentel Moura |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Glutathione reductase Pharmacology Antioxidants 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Sulfite Sulfite oxidase medicine Animals Sulfites Rats Wistar Amino Acid Metabolism Inborn Errors Molecular Biology Sulfite oxidase deficiency Neurons chemistry.chemical_classification Bezafibrate Sulfite Oxidase Glutathione peroxidase Neurotoxicity Glutathione medicine.disease Corpus Striatum Mitochondria Rats 030104 developmental biology chemistry Biochemistry Molecular Medicine Neuroglia 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1863:2135-2148 |
| ISSN: | 0925-4439 |
| DOI: | 10.1016/j.bbadis.2017.05.019 |
| Popis: | Sulfite accumulates in tissues of patients affected by sulfite oxidase (SO) deficiency, a neurometabolic disease characterized by seizures and progressive encephalopathy, often resulting in early death. We investigated the effects of sulfite on mitochondrial function, antioxidant system, glial reactivity and neuronal damage in rat striatum, as well as the potential protective effects of bezafibrate on sulfite-induced toxicity. Thirty-day-old rats were intrastriatally administered with sulfite (2μmol) or NaCl (2μmol; control) and euthanized 30min after injection for evaluation of biochemical parameters and western blotting, or 7days after injection for analysis of glial reactivity and neuronal damage. Treatment with bezafibrate (30 or 100mg/kg/day) was performed by gavage during 7days before (pre-treatment) or after sulfite administration. Sulfite decreased creatine kinase and citrate synthase activities, mitochondrial mass, and PGC-1α nuclear content whereas bezafibrate pre-treatment prevented these alterations. Sulfite also diminished cytochrome c oxidase (COX) IV-1 content, glutathione levels and the activities of glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST) and glucose-6-phosphate dehydrogenase (G6PDH). On the other hand, catalase activity was increased by sulfite. Bezafibrate pre-treatment prevented the reduction of GPx, GR, GST and G6PDH activities. Finally, sulfite induced glial reactivity and neuronal damage, which were prevented by bezafibrate when administered before or after sulfite administration. Our findings provide strong evidence that sulfite induces neurotoxicity that leads to glial reactivity and neuronal damage. Since bezafibrate exerts neuroprotective effects against sulfite toxicity, it may be an attractive agent for the development of novel therapeutic strategies for SO-deficient patients. |
| Databáze: | OpenAIRE |
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