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Creatine plus pyruvate supplementation prevents oxidative stress and phosphotransfer network disturbances in the brain of rats subjected to chemically-induced phenylketonuria

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Abstract

Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism. Usually diagnosed within the first month of birth, it is essential that the patient strictly follow the dietary restriction of natural protein intake. Otherwise, PKU impacts the development of the brain severely and may result in microcephaly, epilepsy, motor deficits, intellectual disability, and psychiatric and behavioral disorders. The neuropathology associated with PKU includes defects of myelination, insufficient synthesis of monoamine neurotransmitters, amino acid imbalance across the blood-brain barrier, and involves intermediary metabolic pathways supporting energy homeostasis and antioxidant defenses in the brain. Considering that the production of reactive oxygen species (ROS) is inherent to energy metabolism, we investigated the association of creatine+pyruvate (Cr + Pyr), both energy substrates with antioxidants properties, as a possible treatment to mitigate oxidative stress and phosphotransfer network impairment elicited in the brain of young Wistar rats by chemically-induced PKU. We induced PKU through the administration of α-methyl-L-phenylalanine and phenylalanine for 7 days, with and without Cr + Pyr supplementation, until postpartum day 14. The cotreatment with Cr + Pyr administered concurrently with PKU induction prevented ROS formation and part of the alterations observed in antioxidants defenses and phosphotransfer network enzymes in the cerebral cortex, hippocampus, and cerebellum. If such prevention also occurs in PKU patients, supplementing the phenylalanine-restricted diet with antioxidants and energetic substrates might be beneficial to these patients.

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Abbreviations

PKU:

Phenylketonuria

IEM:

Inborn error of metabolism

PAH:

Phenylalanine hydroxylase

Phe:

Phenylalanine

HPA:

Hyperphenylalaninemia

ROS:

Reactive oxygen species

Cr:

Creatine

Pyr:

Pyruvate

αMePhe:

α-methyl-L-phenylalanine

DCFH:

2′,7′-dihydrodichlorofluorescein

SH:

Sulfhydryl groups

GSH:

Reduced glutathione

CAT:

Catalase

SOD:

Superoxide dismutase

GPx:

Glutathione peroxidase

CytCK:

Cytosolic creatine kinase

MtCK:

Mitochondrial creatine kinase

PCr:

Phosphocreatine

PK:

Pyruvate kinase

HK:

Hexokinase

AK:

Adenylate kinase

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

OXPHOS:

Oxidative phosphorylation

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Acknowledgements

The authors express their gratitude to the Department of Biochemistry, and the Basic Health Sciences Institute of the Federal University of Rio Grande do Sul, especially to the people responsible for animal care. We also thank the funding agencies that supported the present study – Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Financiadora de Estudos e Projetos (FINEP) Rede Instituto Brasileiro de Neurociência.

Funding

This study was funded by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Financiadora de Estudos e Projetos (FINEP) Rede Instituto Brasileiro de Neurociência.

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  1. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600-Anexo, Porto Alegre, RS, CEP 90.035-003, Brazil

    Vanessa Trindade Bortoluzzi, Letícia Brust, Thales Preissler, Itiane Diehl de Franceschi & Clovis Milton Duval Wannmacher

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  1. Vanessa Trindade Bortoluzzi
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Correspondence to Vanessa Trindade Bortoluzzi.

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Bortoluzzi, V.T., Brust, L., Preissler, T. et al. Creatine plus pyruvate supplementation prevents oxidative stress and phosphotransfer network disturbances in the brain of rats subjected to chemically-induced phenylketonuria. Metab Brain Dis 34, 1649–1660 (2019). https://doi.org/10.1007/s11011-019-00472-7

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