A comparative analysis of erythropoietin and carbamoylated erythropoietin-induced proteome profiles
Abstract 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. Carbamyolated 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 Neudesin, Chromogranin b, Cortactin, Elongation initiation factor 3a and Proteasome 26s subunit, ATPase. We examined the expression of a subset of regulated proteins by immunohistochemical analysis in mouse brain. The results of our study sheds light on potential mechanisms whereby EPO and CEPO produce cognitive enhancing effects in clinical and preclinical studies.