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Interleukin-1 Receptor Antagonist Decreases Hypothalamic Oxidative Stress During Experimental Sepsis

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Abstract

In our previous work, we demonstrated that the intracerebroventricular (i.c.v.) injection of an interleukin-1 receptor antagonist (IL-1ra) prevented the impairment in vasopressin secretion and increased survival rate in septic rats. Additionally, we saw a reduction in nitric oxide (NO) levels in cerebroventricular spinal fluid (CSF), suggesting that the IL-1ra prevents apoptosis that seems to occur in vasopressinergic neurons. Here, we investigated the effect of IL-1ra pre-treatment on the sepsis-induced increase in oxidative stress markers in the hypothalamus of rats. The animals were pre-treated by an i.c.v. injection of IL-1ra (9 nmol) or vehicle (0.01 M PBS) before being subjected to cecal ligation and puncture (CLP) or left as control (sham-operation or naive). After 4, 6, and 24 h, the animals were decapitated (n = 9/group) and the brain removed for hypothalamic tissue collection. Transcript and protein levels of IL-1, inducible nitric oxide synthase (iNOS), caspase-3, and hypoxia-inducible factor 1-alpha (HIF-1α) were measured by quantitative polymerase chain reaction (qPCR) and western blot, respectively. Hypothalamic mRNA levels of all these genes were significantly (P < 0.005) increased at 4, 6, and 24 h CLP, as compared to sham-operated animals. IL-1ra pre-treatment in these CLP animals significantly decreased IL-1 gene expression at all time points and also of iNOS, caspase-3, and HIF-1α at 24 h when compared to vehicle-treated CLP animals. The effect of the pre-treatment on protein expression was most clearly seen for IL-1β and iNOS at 24 h. Our results showed that blocking the IL-1-IL-1r signaling pathway by central administration of an IL-1ra decreases hypothalamic oxidative stress markers during sepsis.

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Acknowledgments

We thank Nadir Martins for the technical assistant and Klaus Hartfelder for providing the infrastructure for the qPCR analysis and reviewing a prior version of the manuscript.

Funding

Financial support from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) is gratefully acknowledged. Fazal Wahab was a recipient of a FAPESP post-doctoral scholarship.

Conflict of Interest

The authors declare that they have no competing interests.

Compliance with Ethical Standards

This study involves the use of rats. All animal experiments in this study were carried out according to an Institutional Ethics Committee-approved protocol (CEUA protocol number: 12.1.1205.53.0).

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Authors and Affiliations

  1. Departmento de Morfologia Fisiologia e Patologia Básica, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Avenida do Café, s/n, Ribeirão Preto, 14040-904, SP, Brazil

    Fazal Wahab, Rodrigo Pereira de Almeida Rodrigues & Maria Jose A. Rocha

  2. Departamento de Neurociências e Ciências Comportamentais, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Avenida dos Bandeirantes, 3900, CEP 14040-900, Ribeirão Preto, SP, Brazil

    Nilton N. Santos-Junior, Luis Henrique A. Costa, Carlos Henrique R. Catalão & Maria Jose A. Rocha

Authors
  1. Fazal Wahab
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  2. Nilton N. Santos-Junior
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  3. Rodrigo Pereira de Almeida Rodrigues
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  4. Luis Henrique A. Costa
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  5. Carlos Henrique R. Catalão
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  6. Maria Jose A. Rocha
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Correspondence to Maria Jose A. Rocha.

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Wahab, F., Santos-Junior, N.N., de Almeida Rodrigues, R.P. et al. Interleukin-1 Receptor Antagonist Decreases Hypothalamic Oxidative Stress During Experimental Sepsis. Mol Neurobiol 53, 3992–3998 (2016). https://doi.org/10.1007/s12035-015-9338-4

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  • DOI: https://doi.org/10.1007/s12035-015-9338-4

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