Université de Tunis El Manar, Faculté des Sciences de Tunis, Research Unit UR/11ES09, Laboratory of Functional Neurophysiology and Pathology, 2092, Tunis, Tunisia.
Inserm U1239, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen Normandie, 76128, Mont-Saint-Aignan, France.
Mol Neurobiol. 2018 Jun;55(6):4596-4611. doi: 10.1007/s12035-017-0630-3. Epub 2017 Jul 11.
Astroglial cells are important actors in the defense of brain against oxidative stress injuries. Glial cells synthesize and release the octadecaneuropeptide ODN, a diazepam-binding inhibitor (DBI)-related peptide, which acts through its metabotropic receptor to protect neurons and astrocytes from oxidative stress-induced apoptosis. The purpose of the present study is to examine the contribution of the endogenous ODN in the protection of astrocytes and neurons from moderate oxidative stress. The administration of HO (50 μM, 6 h) induced a moderate oxidative stress in cultured astrocytes, i.e., an increase in reactive oxygen species, malondialdehyde, and carbonyl group levels, but it had no effect on astrocyte death. Mass spectrometry and QPCR analysis revealed that 50 μM HO increased ODN release and DBI mRNA levels. The inhibition of ODN release or pharmacological blockage of the effects of ODN revealed that in these conditions, 50 μM HO induced the death of astrocytes. The transfection of astrocytes with DBI siRNA increased the vulnerability of cells to moderate stress. Finally, the addition of 1 nM ODN to culture media reversed cell death observed in DBI-deficient astrocytes. The treatment of neurons with media from 50 μM HO-stressed astrocytes significantly reduced the neuronal death induced by HO; this effect is greatly attenuated by the administration of an ODN metabotropic receptor antagonist. Overall, these results indicate that astrocytes produce authentic ODN, notably in a moderate oxidative stress situation, and this glio- and neuro-protective agent may form part of the brain defense mechanisms against oxidative stress injury.
星形胶质细胞是大脑抵御氧化应激损伤的重要因素。神经胶质细胞合成并释放十八烷神经肽 ODN，一种苯二氮䓬结合抑制剂（DBI）相关肽，通过其代谢型受体作用，保护神经元和星形胶质细胞免受氧化应激诱导的细胞凋亡。本研究的目的是研究内源性 ODN 在保护星形胶质细胞和神经元免受中度氧化应激中的作用。HO（50μM，6h）的给药导致培养的星形胶质细胞发生中度氧化应激，即活性氧、丙二醛和羰基水平增加，但对星形胶质细胞死亡没有影响。质谱和 QPCR 分析显示，50μM HO 增加了 ODN 的释放和 DBI mRNA 水平。ODN 释放的抑制或 ODN 作用的药理学阻断表明，在这些条件下，50μM HO 诱导星形胶质细胞死亡。用 DBI siRNA 转染星形胶质细胞会增加细胞对中度应激的脆弱性。最后，将 1nM ODN 添加到培养基中可逆转 DBI 缺陷型星形胶质细胞中观察到的细胞死亡。用来自 50μM HO 应激星形胶质细胞的培养基处理神经元可显著减少 HO 诱导的神经元死亡；这种作用被 ODN 代谢型受体拮抗剂的给药大大减弱。总体而言，这些结果表明星形胶质细胞产生真正的 ODN，特别是在中度氧化应激情况下，这种神经保护剂可能是大脑抵御氧化应激损伤的防御机制的一部分。
