Interaction between neuropeptide Y (NPY) and brain-derived neurotrophic factor in NPY-mediated neuroprotection against excitotoxicity: a role for microglia

Authors

  • S. Xapelli,

    1. Center for Neuroscience and Cell Biology of Coimbra and Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
    Search for more papers by this author
  • L. Bernardino,

    1. Center for Neuroscience and Cell Biology of Coimbra and Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
    Search for more papers by this author
  • R. Ferreira,

    1. Center for Neuroscience and Cell Biology of Coimbra and Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
    Search for more papers by this author
  • S. Grade,

    1. Center for Neuroscience and Cell Biology of Coimbra and Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
    Search for more papers by this author
  • A. P. Silva,

    1. Center for Neuroscience and Cell Biology of Coimbra and Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
    2. Institute of Pharmacology and Therapeutics, Faculty of Medicine, University of Coimbra, 3004–504 Coimbra, Portugal
    Search for more papers by this author
  • J. R. Salgado,

    1. Center for Neuroscience and Cell Biology of Coimbra and Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
    Search for more papers by this author
  • C. Cavadas,

    1. Center for Neuroscience and Cell Biology of Coimbra and Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
    2. Faculty of Pharmacy, University of Coimbra, 3004-123 Coimbra, Portugal
    Search for more papers by this author
  • E. Grouzmann,

    1. Centre Hospitalier Universitaire Vaudois, Division de Pharmacologie et Toxicologie Clinique, 1011-Lausanne, Switzerland
    Search for more papers by this author
  • F. R. Poulsen,

    1. Department of Anatomy and Neurobiology, Institute of Medical Biology, University of Southern Denmark, DK-5000 Odense C, Denmark
    Search for more papers by this author
  • B. Jakobsen,

    1. Department of Anatomy and Neurobiology, Institute of Medical Biology, University of Southern Denmark, DK-5000 Odense C, Denmark
    Search for more papers by this author
  • C. R. Oliveira,

    1. Center for Neuroscience and Cell Biology of Coimbra and Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
    Search for more papers by this author
  • J. Zimmer,

    1. Department of Anatomy and Neurobiology, Institute of Medical Biology, University of Southern Denmark, DK-5000 Odense C, Denmark
    Search for more papers by this author
  • J. O. Malva

    1. Center for Neuroscience and Cell Biology of Coimbra and Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
    Search for more papers by this author

Dr J. O. Malva, as above.
E-mail: jomalva@fmed.uc.pt

Abstract

The neuroprotective effect of neuropeptide Y (NPY) receptor activation was investigated in organotypic mouse hippocampal slice cultures exposed to the glutamate receptor agonist α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Exposure of 2-week-old slice cultures, derived from 7-day-old C57BL/6 mice, to 8 µm AMPA, for 24 h, induced degeneration of CA1 and CA3 pyramidal cells, as measured by cellular uptake of propidium iodide (PI). A significant neuroprotection, with a reduction of PI uptake in CA1 and CA3 pyramidal cell layers, was observed after incubation with a Y2 receptor agonist [NPY(13-36), 300 nm]. This effect was sensitive to the presence of the selective Y2 receptor antagonist (BIIE0246, 1 µm), but was not affected by addition of TrkB-Fc or by a neutralizing antibody against brain-derived neurotrophic factor (BDNF). Moreover, addition of a Y1 receptor antagonist (BIBP3226, 1 µm) or a NPY-neutralizing antibody helped to disclose a neuroprotective role of endogenous NPY in CA1 region. Cultures exposed to 8 µm AMPA for 24 h, displayed, as measured by an enzyme-linked immunosorbent assay, a significant increase in BDNF. In such cultures there was an up-regulation of neuronal TrkB immunoreactivity, as well as the presence of BDNF-immunoreactive microglial cells at sites of injury. Thus, an increase of AMPA-receptor mediated neurodegeneration, in the mouse hippocampus, was prevented by neuroprotective pathways activated by NPY receptors (Y1 and Y2), which can be affected by BDNF released by microglia and neurons.

Ancillary