Tiwari Neeraj K, Sathyanesan Monica, Kumar Vikas, Newton Samuel S
Pediatrics and Rare Disease Group, Sanford Research, Sioux Falls, SD 57104, USA.
Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA.
Life (Basel). 2021 Apr 19;11(4):359. doi: 10.3390/life11040359.
In recent years, erythropoietin (EPO) has emerged as a useful neuroprotective and neurotrophic molecule that produces antidepressant and cognitive-enhancing effects in psychiatric disorders. However, EPO robustly induces erythropoiesis and elevates red blood cell counts. Chronic administration is therefore likely to increase blood viscosity and produce adverse effects in non-anemic populations. Carbamoylated erythropoietin (CEPO), a chemically engineered modification of EPO, is non-erythropoietic but retains the neurotrophic and neurotrophic activity of EPO. Blood profile analysis after EPO and CEPO administration showed that CEPO has no effect on red blood cell or platelet counts. We conducted an unbiased, quantitative, mass spectrometry-based proteomics study to comparatively investigate EPO and CEPO-induced protein profiles in neuronal phenotype PC12 cells. Bioinformatics enrichment analysis of the protein expression profiles revealed the upregulation of protein functions related to memory formation such as synaptic plasticity, long term potentiation (LTP), neurotransmitter transport, synaptic vesicle priming, and dendritic spine development. The regulated proteins, with roles in LTP and synaptic plasticity, include calcium/calmodulin-dependent protein kinase type 1 (Camk1), Synaptosomal-Associated Protein, 25 kDa (SNAP-25), Sectretogranin-1 (Chgb), Cortactin (Cttn), Elongation initiation factor 3a (Eif3a) and 60S acidic ribosomal protein P2 (Rplp2). We examined the expression of a subset of regulated proteins, Cortactin, Grb2 and Pleiotrophin, by immunofluorescence analysis in the rat brain. Grb2 was increased in the dentate gyrus by EPO and CEPO. Cortactin was induced by CEPO in the molecular layer, and pleiotrophin was increased in the vasculature by EPO. The results of our study shed light on potential mechanisms whereby EPO and CEPO produce cognitive-enhancing effects in clinical and preclinical studies.
近年来，促红细胞生成素（EPO）已成为一种有用的神经保护和神经营养分子，在精神疾病中产生抗抑郁和认知增强作用。然而，EPO强烈诱导红细胞生成并提高红细胞计数。因此，长期给药可能会增加血液粘度并在非贫血人群中产生不良反应。氨甲酰化促红细胞生成素（CEPO）是EPO的化学工程修饰产物，无促红细胞生成作用，但保留了EPO的神经营养活性。给予EPO和CEPO后的血液分析表明，CEPO对红细胞或血小板计数无影响。我们进行了一项基于质谱的无偏倚定量蛋白质组学研究，以比较研究EPO和CEPO诱导的神经元表型PC12细胞中的蛋白质谱。蛋白质表达谱的生物信息学富集分析揭示了与记忆形成相关的蛋白质功能上调，如突触可塑性、长时程增强（LTP）、神经递质转运、突触小泡启动和树突棘发育。在LTP和突触可塑性中起作用的调节蛋白包括钙/钙调蛋白依赖性蛋白激酶1型（Camk1）、突触体相关蛋白25 kDa（SNAP-25）、分泌粒蛋白-1（Chgb）、皮层肌动蛋白（Cttn）、延伸起始因子3a（Eif3a）和60S酸性核糖体蛋白P2（Rplp2）。我们通过免疫荧光分析在大鼠脑中检测了一部分调节蛋白（皮层肌动蛋白、Grb2和多效生长因子）的表达。EPO和CEPO使齿状回中的Grb2增加。CEPO在分子层诱导皮层肌动蛋白，EPO使脉管系统中的多效生长因子增加。我们的研究结果揭示了EPO和CEPO在临床和临床前研究中产生认知增强作用的潜在机制。
