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Vasopressin Impairment During Sepsis Is Associated with Hypothalamic Intrinsic Apoptotic Pathway and Microglial Activation

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Abstract

Previous studies have shown that in the early phase of sepsis, the plasma concentration of arginine vasopressin (AVP) is increased, but in the late phase, its levels remain inadequately low, despite of persistent hypotension. One hypothesis suggested for this relative deficiency is apoptosis of vasopressinergic neurons. Here, we investigated apoptosis pathways in the hypothalamus during sepsis, as well as mechanisms underlying this process. Male Wistar rats were submitted to sepsis by cecal ligation and puncture (CLP) or nonmanipulated (naive) as control. After 6 and 24 h, the animals were decapitated and brain and blood were collected to assess hypothalamic apoptotic markers, IFN-γ plasma levels, and evidence for breakdown of the blood-brain barrier (BBB). Sepsis caused a decrease in mitochondrial antiapoptotic proteins (Bcl-2, Bcl-xL) in the hypothalamus, but had no effect on markers of cell death mediated by death receptors or immune cells. In the supraoptic nuclei of these animals, microglia morphology was consistent with activation, associated with an increase in plasma IFN-γ. A transitory breakdown of BBB in the hypothalamus was seen at 6 h following CLP. The results indicate that the intrinsic but not extrinsic apoptosis pathway is involved in the cell death observed in vasopressinergic neurons, and that this condition is temporally associated with microglial activation and BBB leaking.

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Acknowledgments

We thank Nadir Martins for general technical assistance and Elizabete Rosa Milani for help with laser confocal microscopy. Financial support from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) is gratefully acknowledged (grant 2012/22246-9). LHAC has received a FAPESP scholarship (grant 2013/03723-3).

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Authors and Affiliations

  1. Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil

    Luis Henrique Angenendt da Costa, Nilton Nascimento dos Santos Júnior & Carlos Henrique Rocha Catalão

  2. Infection and Epidemiology Department, Institut Pasteur Human Histopathology and Animal Models Unit, Paris, France

    Tarek Sharshar & Fabrice Chrétien

  3. Department of Morphology, Physiology and Basic Pathology, School of Dentistry of Ribeirão Preto, University of São Paulo, Avenida do Café s/n, CEP, Ribeirão Preto, 14040-904, Brazil

    Maria José Alves da Rocha

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  1. Luis Henrique Angenendt da Costa
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Correspondence to Maria José Alves da Rocha.

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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 13.1.337.53.0).

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da Costa, L.H.A., Júnior, N.N.d.S., Catalão, C.H.R. et al. Vasopressin Impairment During Sepsis Is Associated with Hypothalamic Intrinsic Apoptotic Pathway and Microglial Activation. Mol Neurobiol 54, 5526–5533 (2017). https://doi.org/10.1007/s12035-016-0094-x

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  • DOI: https://doi.org/10.1007/s12035-016-0094-x

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