The mitochondrial-targeted reactive species scavengerJP4-039 prevents sulfite-induced alterations in antioxidant defenses, energy transfer, and cell death signaling in striatum of rats

被引：9

作者：

Glanzel, Nicolas Manzke ^{[1
]}

Grings, Mateus ^{[1
]}

da Rosa-Junior, Nevton Teixeira ^{[1
]}

de Carvalho, Leila Maria Cereta ^{[1
]}

Mohsen, Al-Walid ^{[2
,3
]}

Wipf, Peter ^{[4
,5
,6
]}

Wajner, Moacir ^{[1
,7
,8
]}

Vockley, Jerry ^{[2
]}

Leipnitz, Guilhian ^{[1
,7
]}

机构：

[1] Univ Fed Rio Grande do Sul, Programa Posgrad Ciencias Biol Bioquim, Porto Alegre, RS, Brazil

[2] Univ Pittsburgh, Dept Pediat, Div Med Genet, Pittsburgh, PA 15260 USA

[3] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA

[4] Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA

[5] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA USA

[6] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA

[7] Univ Fed Rio Grande do Sul, Inst Ciencias Basicas Saude, Dept Bioquim, Ramiro Barcelos St 2600, BR-90035003 Porto Alegre, RS, Brazil

[8] Hosp Clin Porto Alegre, Serv Genet Med, Porto Alegre, RS, Brazil

来源：

JOURNAL OF INHERITED METABOLIC DISEASE | 2021年 / 44卷 / 02期

关键词：

antioxidant defenses; apoptosis; JP4-039; striatum; sulfite; sulfite oxidase deficiency; ACTIVATED PROTEIN-KINASES; OXIDASE DEFICIENCY; CREATINE-KINASE; INACTIVATION; IDENTIFICATION; HOMEOSTASIS; NITROXIDE; INHIBITOR; FEATURES; JP4-039;

D O I：

10.1002/jimd.12310

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Sulfite oxidase (SO) deficiency is a disorder caused either by isolated deficiency of SO or by defects in the synthesis of its molybdenum cofactor. It is characterized biochemically by tissue sulfite accumulation. Patients present with seizures, progressive neurological damage, and basal ganglia abnormalities, the pathogenesis of which is not fully established. Treatment is supportive and largely ineffective. To address the pathophysiology of sulfite toxicity, we examined the effects of intrastriatal administration of sulfite in rats on antioxidant defenses, energy transfer, and mitogen-activated protein kinases (MAPK) and apoptosis pathways in rat striatum. Sulfite administration decreased glutathione (GSH) concentration and glutathione peroxidase, glucose-6-phosphate dehydrogenase, glutathione S-transferase, and glutathione reductase activities in striatal tissue. Creatine kinase (CK) activity, a crucial enzyme for cell energy transfer, was also decreased by sulfite. Superoxide dismutase-1 (SOD1) and catalase (CAT) proteins were increased, while heme oxygenase-1 (HO-1) was decreased. Additionally, sulfite altered phosphorylation of MAPK by decreasing of p38 and increasing of ERK. Sulfite further augmented the content of GSK-3 beta, Bok, and cleaved caspase-3, indicating increased apoptosis. JP4-039 is a mitochondrial-targeted antioxidant that reaches higher intramitochondrial levels than other traditional antioxidants. Intraperitoneal injection of JP4-039 before sulfite administration preserved activity of antioxidant enzymes and CK. It also prevented or attenuated alterations in SOD1, CAT, and HO-1 protein content, as well as changes in p38, ERK, and apoptosis markers. In sum, oxidative stress and apoptosis induced by sulfite injection are prevented by JP4-039, identifying this molecule as a promising candidate for pharmacological treatment of SO-deficient patients.

引用

页码：481 / 491

页数：11