RANTES release contributes to the protective action of PACAP38 against sodium nitroprusside in cortical neurons.
RANTES release contributes to the protective action of PACAP38 against sodium nitroprusside in cortical neurons.
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DOI：
10.1016/j.npep.2009.05.002
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发表时间：
2009-08
期刊：
影响因子：
2.9
通讯作者：
Grammas, Paula
中科院分区：
文献类型：
--
作者：
Sanchez, Alma;Tripathy, Debjani;Grammas, Paula
脑垂体腺苷环化酶激活多肽(PACAP)是一种很有前景的神经保护性多肽，在神经系统发育和损伤后的再生过程中发挥着重要作用。PACAP通过神经元中的多个信号系统直接促进存活。该神经肽还具有免疫调节作用，可调节非神经细胞中趋化因子等多种炎性介质的表达。趋化因子及其G蛋白偶联受体广泛分布于脑内，提示这些炎性蛋白在中枢神经系统具有重要的功能。脑内皮细胞和神经胶质细胞释放趋化因子的能力已经得到了很好的证明，但神经元是否也是这些介质的来源尚不清楚。本研究的目的是探讨PACAP38对培养神经元中活化正常T细胞表达和分泌调节因子(RANTES)和巨噬细胞炎性蛋白1-α(MIP1-α)表达的影响，以及这些趋化因子是否参与了PACAP38的神经保护作用。数据显示，PACAP38和硝普钠(SNP)共同孵育神经细胞可减少SNP单独引起的神经细胞死亡。PACAP38可剂量依赖性地增加培养神经元在培养液中释放的RANTES和MIP-1α的免疫可检测水平。与RANTES中和抗体共同处理可降低PACAP38介导的对SNP的保护作用。尽管RANTES处理的神经元增加了培养液中mip-1α的水平，并且mip-1α支持神经元在非应激培养中存活，但mip-1α不能保护神经元免受硝普钠诱导的毒性。此外，与MIP-1α中和抗体共同处理不影响PACAP38对SNP的保护作用。这些结果表明，PACAP38对培养神经元的保护作用部分是通过释放RANTES介导的。PACAP通过多种细胞内信号通路以及RANTES等神经保护性介质的释放直接提高神经元存活的能力，突显了其作为治疗神经退行性疾病的潜在治疗剂的有效性。
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.
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