Subcommissural organ (SCO)-spondin is a brain-specific glycoprotein produced during embryogenesis, that strongly contributes to neuronal development. The SCO becomes atrophic in adults, halting SCO-spondin production and its neuroprotective functions. Using rat and human neuronal cultures, we evaluated the neuroprotective effect of an innovative peptide derived from SCO-spondin against glutamate excitotoxicity. Primary neurons were exposed to glutamate and treated with the linear (NX210) and cyclic (NX210c) forms of the peptide. Neuronal survival and neurite networks were assessed using immunohistochemistry or biochemistry. The mechanism of action of both peptide forms was investigated by exposing neurons to inhibitors targeting receptors and intracellular mediators that trigger apoptosis, neuronal survival, or neurite growth. NX210c promoted neuronal survival and prevented neurite network retraction in rat cortical and hippocampal neurons, whereas NX210 was efficient only in neuronal survival (cortical neurons) or neurite networks (hippocampal neurons). They triggered neuroprotection via integrin receptors and γ-secretase substrate(s), activation of the PI3K/mTOR pathway and disruption of the apoptotic cascade. The neuroprotective effect of NX210c was confirmed in human cortical neurons via the reduction of lactate dehydrogenase release and recovery of normal basal levels of apoptotic cells. Together, these results show that NX210 and NX210c protect against glutamate neurotoxicity through common and distinct mechanisms of action and that, most often, NX210c is more efficient than NX210. Proof of concept in central nervous system animal models are under investigation to evaluate the neuroprotective action of SCO-spondin-derived peptide.

连合下器官（SCO）-spondin是胚胎发生期间产生的大脑特异性糖蛋白，对神经元的发育有重要作用。SCO在成年人中萎缩，停止SCO-spondin的产生及其神经保护功能。使用大鼠和人类神经元文化，我们评估了源自SCO-spondin的创新肽对谷氨酸兴奋性毒性的神经保护作用。将原代神经元暴露于谷氨酸盐并用线性（NX210）和环状（NX210c）形式的肽处理。使用免疫组织化学或生物化学评估神经元存活和神经突网络。通过将神经元暴露于靶向受体和细胞内介质的抑制剂中，研究了两种肽形式的作用机理，这些抑制剂触发细胞凋亡，神经元存活或神经突生长。NX210c促进了大鼠皮层和海马神经元的神经元存活并阻止了神经元网络的收缩，而NX210c仅在神经元存活（皮质神经元）或神经元网络（海马神经元）中有效。他们通过整联蛋白受体和γ-分泌酶底物触发了神经保护作用，激活了PI3K / mTOR途径并破坏了细胞凋亡级联反应。NX210c的神经保护作用通过减少乳酸脱氢酶的释放和恢复正常的基础凋亡细胞水平而在人皮层神经元中得到证实。这些结果加在一起，表明NX210和NX210c通过共同的独特作用机制来防御谷氨酸神经毒性，并且最常见的是NX210c比NX210更有效。