Erythropoietin prevents the effect of chronic restraint stress on the number of hippocampal CA3c dendritic terminals-relation to expression of genes involved in synaptic plasticity, angiogenesis, inflammation, and oxidative stress in male rats

Nadia Aalling; Ida Hageman; Kamilla Miskowiak; Dariusz Orlowski; Gregers Wegener; Gitta Wortwein

doi:10.1002/jnr.24107

Erythropoietin prevents the effect of chronic restraint stress on the number of hippocampal CA3c dendritic terminals-relation to expression of genes involved in synaptic plasticity, angiogenesis, inflammation, and oxidative stress in male rats

Nadia Aalling, Ida Hageman, Kamilla Miskowiak, Dariusz Orlowski, Gregers Wegener, Gitta Wortwein

8 Citations (Scopus)

Abstract

Stress-induced allostatic load affects a variety of biological processes including synaptic plasticity, angiogenesis, oxidative stress, and inflammation in the brain, especially in the hippocampus. Erythropoietin (EPO) is a pleiotropic cytokine that has shown promising neuroprotective effects. Recombinant human EPO is currently highlighted as a new candidate treatment for cognitive impairment in neuropsychiatric disorders. Because EPO enhances synaptic plasticity, attenuates oxidative stress, and inhibits generation of proinflammatory cytokines, EPO may be able to modulate the effects of stress-induced allostatic load at the molecular level. The aim of this study was therefore to investigate how EPO and repeated restraint stress, separately and combined, influence (i) behavior in the novelty-suppressed feeding test of depression/anxiety-related behavior; (ii) mRNA levels of genes encoding proteins involved in synaptic plasticity, angiogenesis, oxidative stress, and inflammation; and (iii) remodeling of the dendritic structure of the CA3c area of the hippocampus in male rats. As expected, chronic restraint stress lowered the number of CA3c apical dendritic terminals, and EPO treatment reversed this effect. Interestingly, these effects seemed to be mechanistically distinct, as stress and EPO had differential effects on gene expression. While chronic restraint stress lowered the expression of spinophilin, tumor necrosis factor α, and heat shock protein 72, EPO increased expression of hypoxia-inducible factor-2α and lowered the expression of vascular endothelial growth factor in hippocampus. These findings indicate that the effects of treatment with EPO follow different molecular pathways and do not directly counteract the effects of stress in the hippocampus.

Original language	English
Journal	Journal of Neuroscience Research
Volume	96
Issue number	1
Pages (from-to)	103–116
ISSN	0360-4012
DOIs	https://doi.org/10.1002/jnr.24107
Publication status	Published - Jan 2018

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Aalling, N., Hageman, I., Miskowiak, K., Orlowski, D., Wegener, G., & Wortwein, G. (2018). Erythropoietin prevents the effect of chronic restraint stress on the number of hippocampal CA3c dendritic terminals-relation to expression of genes involved in synaptic plasticity, angiogenesis, inflammation, and oxidative stress in male rats. Journal of Neuroscience Research, 96(1), 103–116. https://doi.org/10.1002/jnr.24107

Erythropoietin prevents the effect of chronic restraint stress on the number of hippocampal CA3c dendritic terminals-relation to expression of genes involved in synaptic plasticity, angiogenesis, inflammation, and oxidative stress in male rats. / Aalling, Nadia ; Hageman, Ida ; Miskowiak, Kamilla et al.

In: Journal of Neuroscience Research, Vol. 96, No. 1, 01.2018, p. 103–116.

Research output: Contribution to journal › Journal article › Research › peer-review

Aalling, N , Hageman, I , Miskowiak, K, Orlowski, D, Wegener, G & Wortwein, G 2018, 'Erythropoietin prevents the effect of chronic restraint stress on the number of hippocampal CA3c dendritic terminals-relation to expression of genes involved in synaptic plasticity, angiogenesis, inflammation, and oxidative stress in male rats', Journal of Neuroscience Research, vol. 96, no. 1, pp. 103–116. https://doi.org/10.1002/jnr.24107

Aalling N , Hageman I , Miskowiak K, Orlowski D, Wegener G, Wortwein G. Erythropoietin prevents the effect of chronic restraint stress on the number of hippocampal CA3c dendritic terminals-relation to expression of genes involved in synaptic plasticity, angiogenesis, inflammation, and oxidative stress in male rats. Journal of Neuroscience Research. 2018 Jan;96(1):103–116. doi: 10.1002/jnr.24107

Aalling, Nadia ; Hageman, Ida ; Miskowiak, Kamilla et al. / Erythropoietin prevents the effect of chronic restraint stress on the number of hippocampal CA3c dendritic terminals-relation to expression of genes involved in synaptic plasticity, angiogenesis, inflammation, and oxidative stress in male rats. In: Journal of Neuroscience Research. 2018 ; Vol. 96, No. 1. pp. 103–116.

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abstract = "Stress-induced allostatic load affects a variety of biological processes including synaptic plasticity, angiogenesis, oxidative stress, and inflammation in the brain, especially in the hippocampus. Erythropoietin (EPO) is a pleiotropic cytokine that has shown promising neuroprotective effects. Recombinant human EPO is currently highlighted as a new candidate treatment for cognitive impairment in neuropsychiatric disorders. Because EPO enhances synaptic plasticity, attenuates oxidative stress, and inhibits generation of proinflammatory cytokines, EPO may be able to modulate the effects of stress-induced allostatic load at the molecular level. The aim of this study was therefore to investigate how EPO and repeated restraint stress, separately and combined, influence (i) behavior in the novelty-suppressed feeding test of depression/anxiety-related behavior; (ii) mRNA levels of genes encoding proteins involved in synaptic plasticity, angiogenesis, oxidative stress, and inflammation; and (iii) remodeling of the dendritic structure of the CA3c area of the hippocampus in male rats. As expected, chronic restraint stress lowered the number of CA3c apical dendritic terminals, and EPO treatment reversed this effect. Interestingly, these effects seemed to be mechanistically distinct, as stress and EPO had differential effects on gene expression. While chronic restraint stress lowered the expression of spinophilin, tumor necrosis factor α, and heat shock protein 72, EPO increased expression of hypoxia-inducible factor-2α and lowered the expression of vascular endothelial growth factor in hippocampus. These findings indicate that the effects of treatment with EPO follow different molecular pathways and do not directly counteract the effects of stress in the hippocampus.",

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