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

Abstract

The neuroprotective effect of neuropeptide Y (NPY) receptor activation was investigated in organotypic mouse hippocampal slice cultures exposed to the glutamate receptor agonist alpha-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 microm 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 Y(2) receptor agonist [NPY(13-36), 300 nm]. This effect was sensitive to the presence of the selective Y(2) receptor antagonist (BIIE0246, 1 microm), but was not affected by addition of TrkB-Fc or by a neutralizing antibody against brain-derived neurotrophic factor (BDNF). Moreover, addition of a Y(1) receptor antagonist (BIBP3226, 1 microm) or a NPY-neutralizing antibody helped to disclose a neuroprotective role of endogenous NPY in CA1 region. Cultures exposed to 8 microm 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 (Y(1) and Y(2)), which can be affected by BDNF released by microglia and neurons.

Neuropeptide Y Receptors Y1and Y2are Present in Neurons and Glial Cells in Rat Retinal Cells in Culture

“…3,4 NPY actions are mediated by G protein-coupled receptors, which have been named NPY Y 1 , Y 2 , Y 4 , Y 5 , and y 6 . 3,5 NPY is expressed in the retina of mammals and nonmammals.…”

“…3,5 NPY is expressed in the retina of mammals and nonmammals. [6][7][8][9][10][11][12] In rodent retinas, NPY-immunoreactivity (NPY-ir) is present in the inner retina, it is localized in cell bodies at both inner nuclear layer (INL) and ganglion cell layer (GCL), and is also present in processes located in the inner plexiform layer (IPL).…”

The Neuropeptide Y (NPY)-ergic System is Associated with Behavioral Resilience to Stress Exposure in an Animal Model of Post-Traumatic Stress Disorder

“…BDNF, administered in vitro (Nawa et al, 1993) or in vivo (Nawa et al, 1994), induces an increase in NPY mRNA and peptide content. Xapelli et al (2008) reported that the expression of NPY in the hippocampus is under the control of BDNF receptor activity. Neurotrophins, and particularly BDNF, are known to modulate many aspects of neuronal plasticity (Shieh and Ghosh, 1999;Thoenen, 2000) and the selection of functional neuronal connections in the CNS (Huang and Reichardt, 2001;Mamounas et al, 2000;Poo, 2001).…”

Neuroprotective Effects of Neuropeptide Y and Y2 and Y5 Receptor Agonists In Vitro and In Vivo

“…Many studies have shown that BDNF enhanced an expression of NPY in the striatum, cortex and the hippocampus (Barnea & Roberts, 2001;Barnea et al, 2004;Nawa et al, 1994;Reibel et al, 2000;Takei et al, 1996;Wirth et al, 2005;Yoshimura et al, 2009). In the mouse organotypic hippocampal slice cultures exposed to glutamate receptor agonist, degeneration of CA1 and CA3 pyramidal neurons was diminished by Y2 receptor agonist and such protection strongly inhibited the stimulating effect of AMPA on the BDNF level (Xapelli et al, 2008). It was also found that NPY treatment decreased BDNF and increased nerve growth factor production in the rat hypothalamus (Gelfo et al, 2011).…”

“…The activation of Y1 receptors produced neuroprotective effects in kainate excitotoxicity model of rat organotypic hippocampal slice cultures (Xapelli et al, 2007) and in methamphetamine neurotoxicity model in the mouse striatum (Thieriet et al, 2005), but in both models Y1R had a little weaker effect than Y2R agonists. Excitotoxicity induced by AMPA in organotypic mouse hippocampal slice cultures showed that AMPA-induced degenerations of CA1 and CA3 pyramidal neurons were strongly inhibited by Y2 but not Y1 or Y5 receptor agonists (Xapelli et al, 2008). More detailed studies in hippocampal slices have shown that neuroprotective properties of a particular Y receptor may depend on the region where the receptor is located.…”