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Differential Age-Dependent Mitochondrial Dysfunction, Oxidative Stress, and Apoptosis Induced by Neonatal Hypoxia-Ischemia in the Immature Rat Brain

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Abstract

Neonatal hypoxia-ischemia (HI) is among the main causes of mortality and morbidity in newborns. Experimental studies show that the immature rat brain is less susceptible to HI injury, suggesting that changes that occur during the first days of life drastically alter its susceptibility. Among the main developmental changes observed is the mitochondrial function, namely, the tricarboxylic acid (TCA) cycle and respiratory complex (RC) activities. Therefore, in the present study, we investigated the influence of neonatal HI on mitochondrial functions, redox homeostasis, and cell damage at different postnatal ages in the hippocampus of neonate rats. For this purpose, animals were divided into four groups: sham postnatal day 3 (ShP3), HIP3, ShP11, and HIP11. We initially observed increased apoptosis in the HIP11 group only, indicating a higher susceptibility of these animals to brain injury. Mitochondrial damage, as determined by flow cytometry showing mitochondrial swelling and loss of mitochondrial membrane potential, was also demonstrated only in the HIP11 group. This was consistent with the decreased mitochondrial oxygen consumption, reduced TCA cycle enzymes, and RC activities and induction of oxidative stress in this group of animals. Considering that HIP3 and the sham animals showed no alteration of mitochondrial functions, redox homeostasis, and showed no apoptosis, our data suggest an age-dependent vulnerability of the hippocampus to hypoxia-ischemia. The present results highlight age-dependent metabolic differences in the brain of neonate rats submitted to HI indicating that different treatments might be needed for HI newborns with different gestational ages.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This study was supported by research grants from the Conselho Nacional de Desenvolvimento Científico e Tecnologico (CNPq), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

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Authors and Affiliations

  1. Graduate Program in Physiology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil

    Felipe Kawa Odorcyk, L. E. Duran-Carabali & C. A. Netto

  2. Graduate Program in Neuroscience, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil

    R. T. Ribeiro, A. C. Roginski, N. S. Couto-Pereira, C. Dalmaz, M. Wajner & C. A. Netto

  3. Department of Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil

    C. A. Netto

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  1. Felipe Kawa Odorcyk
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  3. A. C. Roginski
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  4. L. E. Duran-Carabali
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Contributions

FKO conceived and directed the project, analyzed data, interpreted results, and wrote the manuscript. RTR, ACR, and MW performed respirometry and oxidative stress analysis. NSCP and CD aided in the Western blot techniques. LEDC assisted with all experiments. CAN directed the project and co-wrote the manuscript. All authors reviewed and edited the manuscript.

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Correspondence to Felipe Kawa Odorcyk.

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Odorcyk, F.K., Ribeiro, R.T., Roginski, A.C. et al. Differential Age-Dependent Mitochondrial Dysfunction, Oxidative Stress, and Apoptosis Induced by Neonatal Hypoxia-Ischemia in the Immature Rat Brain. Mol Neurobiol 58, 2297–2308 (2021). https://doi.org/10.1007/s12035-020-02261-1

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