Background
Colivelin (CLN) is A brain-permeable neuroprotective peptide that has effective long-term effects on Aβ deposition, neuronal apoptosis and synaptic plasticity defects in neurodegenerative diseases. Colivelin is a STAT3 activator.
MFG-E8 regulated OGD-induced microglial M1/M2 polarization by inhibiting p-STAT3 and SOCS3 expressions, which was reversed by STAT3 activator (Colivelin TFA)[6]. The administration of the STAT3 activator colivelin could offset the inhibitory effect of RPN2 silencing on the survival and apoptosis of NPC cells[9].
Colivelin as a potent synthetic humanin derivative, is a potential therapeutic compound to restore endothelial stability and improve outcomes of sepsis[1]. In vivo animal studies have further indicated that intracerebroventricular administration of Colivelin not only completely suppresses impairment in spatial working memory induced by repetitive intracerebroventricular injection of Abeta25-35 or Abeta1-42, but also it antagonizes neuronal loss in the CA1 region of hippocampus induced by hippocampal injection of Abeta1-42[2]. Histological analysis demonstrated increased motoneuronal survival in spinal cords of Colivelin-treated mice as compared with saline- or ADNF-treated mice, indicating that Colivelin is a promising neurotrophic peptide for treatment of ALS[3]. Colivelin blocked the alcohol-induced decline in brain weight and prevented alcohol-induced: apoptosis, activation of caspase-3 and increases of cytosolic cytochrome c, and decreases of mitochondrial cytochrome c Analysis of proteins in the upstream signaling pathway revealed that CLN down-regulated the phosphorylation of the c-Jun N-terminal kinase[4]. Colivelin administration decreased the neurological deficits and infarct lesion induced by brain ischemia. Colivelin inhibited axonal damage and neuronal death in brain tissue, which was associated with elevated anti-apoptotic gene expression in ischemic neurons as well as increased axonal growth up until two-weeks post-stroke[5]. Colivelin has strong neuroprotective effects on learning and memory behaviors in APP/PS1 mice and that this behavioral improvement is closely associated with the reduction of Aβ deposition and alleviation of LTP suppression in the hippocampus, supporting the potential of CLN for the prevention and treatment of AD[7]. Intrahippocampal injection of colivelin (0.2 nmol) effectively prevented Aβ25-35 (4 nmol)-induced deficits in spatial learning and memory of rats in Morris water maze test; the suppression of in vivo hippocampal long term potentiation (LTP) by Aβ25-35 was nearly completely prevented by CLN; in addition, CLN pretreatment also effectively inhibited Aβ25-35-induced calcium overload in primary cultured hippocampal neurons[8].
参考文献:
[1]. Urban C, Hayes HV, et,al. Colivelin, a synthetic derivative of humanin, ameliorates endothelial injury and glycocalyx shedding after sepsis in mice. Front Immunol. 2022 Sep 2;13:984298. doi: 10.3389/fimmu.2022.984298. PMID: 36119052; PMCID: PMC9478210.
[2]. Chiba T, Yamada M, et,al. Development of a femtomolar-acting humanin derivative named colivelin by attaching activity-dependent neurotrophic factor to its N terminus: characterization of colivelin-mediated neuroprotection against Alzheimer's disease-relevant insults in vitro and in vivo. J Neurosci. 2005 Nov 2;25(44):10252-61. doi: 10.1523/JNEUROSCI.3348-05.2005. PMID: 16267233; PMCID: PMC6725789.
[3]. Chiba T, Yamada M, et,al. Colivelin prolongs survival of an ALS model mouse. Biochem Biophys Res Commun. 2006 May 12;343(3):793-8. doi: 10.1016/j.bbrc.2006.02.184. Epub 2006 Mar 10. PMID: 16564029.
[4]. Sari Y, Chiba T, et,al. A novel peptide, colivelin, prevents alcohol-induced apoptosis in fetal brain of C57BL/6 mice: signaling pathway investigations. Neuroscience. 2009 Dec 29;164(4):1653-64. doi: 10.1016/j.neuroscience.2009.09.049. Epub 2009 Sep 25. PMID: 19782727; PMCID: PMC2783970.
[5]. Zhao H, Feng Y, et,al. Colivelin Rescues Ischemic Neuron and Axons Involving JAK/STAT3 Signaling Pathway. Neuroscience. 2019 Sep 15;416:198-206. doi: 10.1016/j.neuroscience.2019.07.020. Epub 2019 Jul 30. PMID: 31374230.
[6]. Fang YY, Zhang JH. MFG-E8 alleviates oxygen-glucose deprivation-induced neuronal cell apoptosis by STAT3 regulating the selective polarization of microglia. Int J Neurosci. 2021 Jan;131(1):15-24. doi: 10.1080/00207454.2020.1732971. Epub 2020 Mar 12. PMID: 32098538.
[7]. Wu M, Shi H, et,al. Colivelin Ameliorates Impairments in Cognitive Behaviors and Synaptic Plasticity in APP/PS1 Transgenic Mice. J Alzheimers Dis. 2017;59(3):1067-1078. doi: 10.3233/JAD-170307. PMID: 28731445.
[8]. Wu MN, Zhou LW, et,al. Colivelin ameliorates amyloid β peptide-induced impairments in spatial memory, synaptic plasticity, and calcium homeostasis in rats. Hippocampus. 2015 Mar;25(3):363-72. doi: 10.1002/hipo.22378. Epub 2014 Oct 30. PMID: 25332198.
[9]. Wang B, Liu W, et,al. Overexpression of ribophorin II is required for viability of nasopharyngeal cancer cells by regulating JAK1/STAT3 activation. Immunopharmacol Immunotoxicol. 2021 Aug;43(4):471-477. doi: 10.1080/08923973.2021.1942038. Epub 2021 Jun 29. PMID: 34184962.
Colivelin (CLN) 是一种脑渗透性神经保护肽，对 Aβ 具有长期有效的作用；神经退行性疾病中的沉积、神经元凋亡和突触可塑性缺陷。 Colivelin 是一种 STAT3 激活剂。
MFG-E8 通过抑制 p-STAT3 和 SOCS3 的表达来调节 OGD 诱导的小胶质细胞 M1/M2 极化，而这种极化可被 STAT3 激活剂 (Colivelin TFA)[6] 逆转。 STAT3 激活剂 colivelin 的给药可以抵消 RPN2 沉默对 NPC 细胞存活和凋亡的抑制作用[9]。
Colivelin 作为一种有效的合成人脑肽衍生物，是一种潜在的治疗化合物，可恢复内皮稳定性并改善脓毒症的预后[1]。体内动物研究进一步表明，Colivelin 脑室内给药不仅可以完全抑制重复脑室内注射 Abeta25-35 或 Abeta1-42 引起的空间工作记忆损伤，而且还可以拮抗海马 CA1 区神经元丢失引起的海马注射 Abeta1-42[2]。组织学分析表明，与盐水或 ADNF 处理的小鼠相比，Colivelin 处理的小鼠脊髓中的运动神经元存活率增加，表明 Colivelin 是一种很有前途的神经营养肽，可用于治疗 ALS[3]。 Colivelin 阻断了酒精引起的脑重量下降，并阻止了酒精引起的:细胞凋亡、caspase-3 的激活和细胞溶质细胞色素 c 的增加，以及线粒体细胞色素 c 的减少上游信号通路中的蛋白质分析表明，CLN 下调c-Jun氨基末端激酶[4]的磷酸化。 Covelin 给药减少了由脑缺血引起的神经功能缺损和梗塞病变。 Colivelin 抑制脑组织中的轴突损伤和神经元死亡，这与缺血神经元中抗凋亡基因表达升高以及中风后两周轴突生长增加有关[5]。 Colivelin 对 APP/PS1 小鼠的学习和记忆行为具有很强的神经保护作用，并且这种行为改善与 Aβ 的减少密切相关； LTP 抑制在海马区的沉积和缓解，支持 CLN 防治 AD 的潜力[7]。海马内注射colivelin (0.2 nmol) 有效预防A77777#946;25-35 (4 nmol)诱导的莫里斯水迷宫大鼠空间学习记忆缺陷； Aβ 对体内海马长时程增强 (LTP) 的抑制；25-35 几乎完全被 CLN 阻止；此外，CLN预处理还有效抑制Aβ25-35诱导的原代培养海马神经元钙超载[8]。
Protocol
| Cell experiment [1]: |
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Cell lines
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BV-2 cells
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Preparation Method
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BV-2 cells were treated with recombinant murine MFG-E8 (rmMFG-E8) or/and Colivelin TFA after exposing for 4 h with oxygen glucose deprivation (OGD).
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Reaction Conditions
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50 μg/ml Colivelin for 4h
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Applications
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MFG-E8 regulated OGD-induced microglial M1/M2 polarization by inhibiting p-STAT3 and SOCS3 expressions, which was reversed by STAT3 activator (Colivelin).
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| Animal experiment [2]: |
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Animal models
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Male C57BL/6 mice
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Preparation Method
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After a midline laparotomy, the cecum was exteriorized, ligated and punctured twice with a 23-G needle. The cecum was then returned into the peritoneal cavity and the abdominal incision was closed. After the procedure, mice were randomly assigned to three treatment groups: a vehicle-treated group received distilled water (200 ul/mouse) intraperitoneally (i.p.); a 100 ug colivelin-treated group received the colivelin at 100 ug/kg i.p., and a 200 ug colivelin-treated group received the colivelin at 200 ug/kg i.p. at 1 h after CLP.
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Dosage form
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100-200 ug/kg colivelin
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Applications
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Colivelin as a potent synthetic humanin derivative, is a potential therapeutic compound to restore endothelial stability and improve outcomes of sepsis.
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参考文献:
[1]. Fang YY, Zhang JH. MFG-E8 alleviates oxygen-glucose deprivation-induced neuronal cell apoptosis by STAT3 regulating the selective polarization of microglia. Int J Neurosci. 2021 Jan;131(1):15-24. doi: 10.1080/00207454.2020.1732971. Epub 2020 Mar 12. PMID: 32098538.
[2]. Urban C, Hayes HV, et,al.Colivelin, a synthetic derivative of humanin, ameliorates endothelial injury and glycocalyx shedding after sepsis in mice. Front Immunol. 2022 Sep 2;13:984298. doi: 10.3389/fimmu.2022.984298. PMID: 36119052; PMCID: PMC9478210.
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