title: Vasopressin Impairment During Sepsis Is Associated with Hypothalamic Intrinsic Apoptotic Pathway and Microglial Activation.
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.
authors.affiliation: Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Luis Henrique Angenendt
authors.initials: LHA
authors.lastname: da Costa
authors.affiliation: Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Nilton Nascimento Dos Santos
authors.initials: NNDS
authors.lastname: Júnior
authors.affiliation: Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Carlos Henrique Rocha
authors.initials: CHR
authors.lastname: Catalão
authors.affiliation: Infection and Epidemiology Department, Institut Pasteur Human Histopathology and Animal Models Unit, Paris, France.
authors.forename: Tarek
authors.initials: T
authors.lastname: Sharshar
authors.affiliation: Infection and Epidemiology Department, Institut Pasteur Human Histopathology and Animal Models Unit, Paris, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Chrétien
authors.affiliation: 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. mjrocha@forp.usp.br.
authors.forename: Maria José Alves
authors.initials: MJA
authors.lastname: da Rocha
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001127:Arginine Vasopressin / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D017208:Rats, Wistar; D018805:Sepsis / Q000378:metabolism*
chemical_list: D001127:Arginine Vasopressin; D009569:Nitric Oxide
keywords: Blood-brain barrier; Cell death; Neuroendocrine dysfunction; Neuroinflammation