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Bezafibrate Prevents Glycine-Induced Increase of Antioxidant Enzyme Activities in Rat Striatum

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Abstract

Non-ketotic hyperglycinemia (NKH) is a severe neurological disorder caused by defects in glycine (GLY) catabolism and characterized by a high cerebrospinal fluid/plasma GLY ratio. Treatment is often ineffective and limited to the control of symptoms and detoxification of GLY. In the present work, we investigated the in vivo effects of GLY intracerebroventricular administration on oxidative stress parameters in rat striatum, cerebral cortex, and hippocampus. In vitro effects of GLY were also evaluated in striatum. The effects of bezafibrate (BEZ), a potential neuroprotective agent, on the possible alterations caused by GLY administration were further evaluated. Our in vivo results showed that GLY increased the activities of the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G6PDH) in striatum. Furthermore, GLY decreased the concentrations of total glutathione and reduced glutathione (GSH), as well as GSH/oxidized glutathione ratio in vivo in hippocampus. In vitro data also showed that GLY induced lipid peroxidation and decreased GSH in striatum. Regarding the effects of BEZ, we found that GLY-induced increase of GPx, SOD, and GR activities was attenuated or prevented by this compound. However, BEZ did not alter GLY-induced decrease of GSH in hippocampus. We hypothesize that GLY-induced increase of the activities of antioxidant enzymes in striatum occurs as a mechanism to avoid accumulation of reactive oxygen species and consequent oxidative damage. Furthermore, since BEZ prevented GLY-induced alterations, it might be considered as an adjuvant therapy for NKH.

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Funding

This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Programa de Apoio a Núcleos de Excelência (PRONEX II), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Pró-Reitoria de Pesquisa/Universidade Federal do Rio Grande do Sul (PROPESQ/UFRGS), Financiadora de estudos e projetos (FINEP), Rede Instituto Brasileiro de Neurociência (IBN-Net) # 01.06.0842-00, and Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção (INCT-EN).

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Authors and Affiliations

  1. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Belisa Parmeggiani, Mateus Grings, Nevton Teixeira da Rosa-Junior & Renata Britto

  2. Serviço de Genética Médica do Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

    Moacir Wajner

  3. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos No. 2600 – Attached, Porto Alegre, RS, 90035-003, Brazil

    Moacir Wajner & Guilhian Leipnitz

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  1. Belisa Parmeggiani
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Correspondence to Guilhian Leipnitz.

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Supplementary figure

Effect of intracerebroventricular administration of glycine (GLY, 5 μmol) on total (GS) (a), reduced (GSH) (b) and oxidized glutathione (GSSG) (c) concentrations, GSH/GSSG ratio (d) and γ-glutamate-cysteine ligase (GCL) activity (e) in rat hippocampus 15 min after the administration. Results are presented as mean ± standard deviation for three to five independent experiments (animals). Statistical analysis was performed using Student’s t test for unpaired samples. *P < 0.05, **P < 0.01, compared to controls. (GIF 45 kb)

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Parmeggiani, B., Grings, M., da Rosa-Junior, N.T. et al. Bezafibrate Prevents Glycine-Induced Increase of Antioxidant Enzyme Activities in Rat Striatum. Mol Neurobiol 56, 29–38 (2019). https://doi.org/10.1007/s12035-018-1074-0

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