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

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The understanding of how stress impacts brain structure and behavior comes prominently from studies of the hippocampus, because this was the first higher brain center that was recognized as a target of stress hormones (McEwen, 2007). A major consequence of allostatic load from chronic stress involves plastic remodeling of neurons (i.e., neural plasticity on the cellular and subcellular levels). Plastic remodeling includes changes in neuronal structure and connectivity and involves shortening of dendrites, loss of spine synapses, and suppression of neurogenesis in the dentate gyrus region of the hippocampus (McEwen & Gianaros, 2011). Some of the other major effects of chronic stress and allostatic load involve increased levels of extracellular glutamate, leading to oxidative stress and inflammation (McEwen & Gianaros, 2011; Snyder et al., 2011). A possible candidate to circumvent these effects is the pleiotropic cytokine erythropoietin (EPO), which has shown neuroprotective potential in addition to its well‐known role in erythropoiesis (Alnaeeli et al., 2012; Sargin, Friedrichs, El‐Kordi, & Ehrenreich, 2010).
In the central nervous system (CNS), EPO and its receptors are expressed in astrocytes, endothelial cells, and neurons (Newton, Fournier, & Duman, 2013). The expression of EPO is regulated primarily at the transcription level by the hypoxia‐inducible factor‐2 (HIF‐2) complex, consisting of the constitutive active β domain (also called HIF‐1β) and the hypoxia‐sensitive α domain of HIF‐2 (HIF‐2α) (Mimura & Nangaku, 2010). The mechanisms by which EPO exerts its neuroprotective effects include (i) endothelial response by increased blood flow and oxygen delivery through increased vascular relaxation and angiogenesis, (ii) antiapoptotic response in neurons, and (iii) anti‐inflammatory and (iv) anti‐oxidant effects (Alnaeeli et al., 2012; Byts & Siren, 2009; Chateauvieux, Grigorakaki, Morceau, Dicato, & Diederich, 2011).
In the forced swim test, which has been used extensively to identify novel antidepressant compounds (Cryan, Markou, & Lucki, 2002; Dulawa & Hen, 2005), both short‐term EPO treatment (4 days) of healthy rats and longer‐term EPO treatment (three weekly doses over 2 weeks) of social defeat–stressed and nonstressed rats were shown to reduce despair‐like behavior (Girgenti et al., 2009; Osborn et al., 2013). Another study with long‐term EPO treatment (twice weekly for 5 weeks) of healthy mice, however, found no effects of EPO on despair‐like behavior in the tail suspension test (Leconte et al., 2011). The effect of EPO in the novelty‐suppressed feeding (NSF) test has not yet been examined. This test is proposed to be a more valid test of depression‐related behavior, as it responds to subchronic, but not acute, treatment with established antidepressant drugs (Santarelli et al., 2003).
The effect of recombinant human EPO has also been tested in patients with depression, where the results from a series of functional magnetic resonance imaging studies suggest that EPO improves memory accuracy and reduces the neural and cognitive response to negative (vs. positive) emotional facial expressions in depressed individuals, in the absence of changes in the number of red blood cells (for review, see Miskowiak, Vinberg, Harmer, Ehrenreich, & Kessing, 2012). Since negative bias in attention, interpretation, and memory in depression correlates with the severity and duration of the disorder (Bradley, Mogg, & Williams, 1995) and is reduced by antidepressant drugs (Harmer & Cowen, 2013), the EPO‐associated reversal of negative emotional bias points to EPO as a new candidate treatment for depression (Hayley & Litteljohn, 2013; Miskowiak et al., 2012). In a subsequent clinical efficacy (phase II) study, we therefore investigated the effects of eight weekly EPO versus saline treatments on depressive symptoms in patients with treatment‐resistant depression (Miskowiak et al., 2014).
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