RANTES release contributes to the protective action of PACAP38 against sodium nitroprusside in cortical neurons

Abstract

Pituitary adenylate cyclase activating polypeptide (PACAP), a promising neuroprotective peptide, plays an important role during development of the nervous system and in regeneration after injury. PACAP directly promotes survival via multiple signaling systems in neurons. This neuropeptide also has immuno-modulatory properties and can regulate the expression of various inflammatory mediators such as chemokines in nonneuronal cells. Chemokines and their G protein-coupled receptors are widely distributed in the brain, suggesting important functions for these inflammatory proteins in the CNS. The ability of brain endothelial cells and glia to release chemokines has been well documented, whether neurons are also a source for these mediators is unclear. The objective of this study is to determine whether PACAP38 affects expression of regulated on activation normal T expressed and secreted (RANTES) and macrophage inflammatory protein 1-alpha (MIP-1α) in cultured neurons and if these chemokines contribute to the neuroprotective effect of PACAP38. The data show that incubation of neuronal cultures with both PACAP38 and sodium nitroprusside (SNP) reduces the neuronal cell death evoked by SNP alone. PACAP38 dose-dependently increases immunodetectable levels of both RANTES and MIP-1α released in the media by cultured neurons. Co-treatment with a neutralizing antibody to RANTES decreases the PACAP38-mediated protection against SNP. Although RANTES treatment of neurons increased MIP-1α levels in the media and MIP-1α supports neuronal survival in unstressed cultures, MIP-1α does not protect neurons from SNP-induced toxicity. Furthermore, co-treatment with a MIP-1α neutralizing antibody did not affect PACAP38-induced protection against SNP. These results show that the protective effect of PACAP38 on cultured neurons is mediated, in part, by release of RANTES. The ability of PACAP to directly enhance neuronal survival through multiple intracellular signaling pathways as well as via the release of neuroprotective mediators such as RANTES highlights its utility as a potential therapeutic agent for the treatment of neurodegenerative diseases.

The chemokine, macrophage inflammatory protein-2γ, reduces the expression of glutamate transporter-1 on astrocytes and increases neuronal sensitivity to glutamate excitotoxicity

“…Chemokines regulate leukocyte trafficking to the CNS, but are also involved in pathophysiological processes other than chemotaxis [21-23]. Here, we demonstrated for the first time that MIP-2γ overexpression decreases GLT-1 expression (mRNA and protein) and glutamate uptake in primary cortical astrocytes, an effect that could be blocked by MIP-2γ siRNA (Figure 3), but did not affect GLAST expression.…”

PACAP27 is Protective Against Tat-Induced Neurotoxicity

“…Relevant for Tat toxicity is the fact that PACAP38 and related neuropeptide VIP can also induce the release of CCL5 from astrocytes (Brenneman et al, 2002). Released CCL5, in turn, is neuroprotective against neurotoxins (Sanchez et al, 2009a) including the HIV viral protein gp120 (Brenneman et al, 1988; Avdoshina et al, 2010). Therefore, we tested whether PACAP27 releases CCL5 in our neuronal cultures.…”

Macrophage Resistance to HIV-1 Infection Is Enhanced by the Neuropeptides VIP and PACAP

“…VIP and PACAP can inhibit β-chemokine production upon pro-inflammatory induction [40], [42], but they are also able to stimulate the production of chemokines in different settings [31], [32], [43]–[45], pointing out their ability to regulate the chemokine axis. VIP and PACAP have been suggested to confer a protective role against HIV-1 in the central nervous system through CCL3 and CCL5 production [46], and our results now imply that these neuropeptides can offer a systemic protection against HIV-1 by boosting macrophage resistance to viral growth by augmenting the secretion of these mediators.…”