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Erythropoietin (EPO), a hematopoietic hormonal cytokine induced in response to hypoxia, has neuroprotective effects. EPO receptor (EPOR) is expressed in microglia, resident immune cells in the brain. However, the effect of EPO on microglial activation is not clear. In the present study, we demonstrated that the EPOR is highly expressed in microglia, rather than in neurons or astrocytes, in in vitro experiments. Therefore, we investigated whether EPO could attenuate lipopolysaccharide (LPS)-mediated activation of microglia in vitro . The BV-2 microglial cell line was treated with LPS in the absence or presence of EPO. In the presence of EPO, microglial expression of LPS-induced inflammatory cytokine genes was significantly decreased. In addition, EPO suppressed the LPS-induced phagocytic activity of BV-2 cells towards fluorescent beads, as well as induction of inducible nitric oxide synthase. In in vivo experiments, EPO significantly decreased the LPS-induced expression of inflammatory cytokine genes in mouse brains. Furthermore, morphological analysis of cortical microglia in the brains of mice stimulated with LPS revealed that combined treatment with EPO alleviated LPS-induced morphological changes in the microglia. These data indicate that EPO attenuates microglial activation, including morphological changes in vivo , phagocytosis in vitro , and the production of inflammatory cytokines in vivo and in vitro . Further investigation of EPO modulation of LPS-induced microglial activation may contribute to the development of novel neuroprotective therapies. [ABSTRACT FROM AUTHOR]

Abstract: Hypoxia-inducible factor 1α (HIF-1α) is a master regulator of cellular adaptation to hypoxia and has been proposed as a potent therapeutic target for cerebral ischemia. However, research on the expression and effects of HIF-1α in subarachnoid hemorrhage (SAH) is limited. The aim of the present study was to investigate the expression of HIF-1α in the hippocampus and its possible protective effect against hippocampal apoptosis and cognitive dysfunction in a rat model of SAH. Seventy-two Sprague–Dawley (SD) rats were randomly divided into the sham group, the SAH+vehicle group, and the SAH+YC-1 group. Immunohistochemical staining and western blotting analyses revealed that the expression of HIF-1α and its downstream effectors, vascular endothelial growth factor (VEGF), erythropoietin (EPO), and glucose transporter 1 (GLUT1), increased in the hippocampus 48h after the induction of SAH. YC-1 blocked this upregulation. The number of active caspase-3-positive cells and the expression of active caspase-3 in the hippocampus significantly increased in the YC-1 group relative to the vehicle group. A cell death assay further revealed that DNA fragmentation was significantly increased at 48h in the YC-1 group compared with the vehicle group. In Morris water maze (MWM) tests, the YC-1 group showed increased escape latency times and distances as well as reduced time spent and distance traveled in the target quadrant. These results indicate that hippocampal apoptosis increased and cognitive function deteriorated when HIF-1α was inhibited, suggesting that HIF-1α has a neuroprotective effect in SAH and may represent an effective therapeutic target. [Copyright &y& Elsevier]

Although oxidative stress may influence the fluid properties of blood, resulting in a potential decrement in blood flow and oxygen delivery to the brain during aging, very little is known about age-related changes in Epo expression. Therefore, we examined age-related changes in Epo expression in the cerebral cortex and hippocampus with an immunohistochemical technique. In aged rats, there was a significant decrease in Epo immunoreactivity in the pyramidal cells in the cortical regions. In the hippocampus of adult rats, a distinct immunoreactivity pattern was observed in the CA1-3 areas and dentate gyrus. In aged hippocampus, Epo immunoreactivity was significantly deceased in the pyramidal layer of CA1 regions, and the granule cell layer of dentate gyrus. It was noted that there was distinct pattern of Epo immunoreactivity in the pyramidal layer of CA2–CA3 region of aged rats. Epo immunoreactivity was relatively strong, but was observed only in the periphery of the cytoplasm. The first demonstration of age-related decreases in Epo expression in the cerebral cortex and hippocampus may provide useful data for investigating the pathogenesis of age-related neurodegenerative diseases, suggesting that age-related decreases in Epo may contribute to degenerative events following age-related decreases in brain flow and oxygen supply. [Copyright &y& Elsevier]

In the present study, we investigated the changes of erythropoietin (Epo) expression in the central nervous system (CNS) of SOD1G93A transgenic mice as an in vivo model of amyotrophic lateral sclerosis (ALS). In wild-type SOD1 (wtSOD1) transgenic mice, little immunoreactivity was found in all cortical regions. In the cerebral cortex of symptomatic SOD1G93A transgenic mice, there was a significant increase in Epo immunoreactivity. In the hippocampal formation, layer-specific alterations in the staining intensity were observed in the CA1-3 areas and dentate gyrus. Epo immunoreactivity was significantly increased in the midbrain, cerebellar cortex and brainstem of SOD1G93A transgenic mice. On the contrary, Epo immunoreactivity was moderately stained in the spinal cord and was not different between wtSOD1 and SOD1G93A transgenic mice at the age of 8 weeks, 13 weeks and 18 weeks. In the staining of Epo receptor (EpoR), the changing pattern was similar with that of Epo in the spinal cord and hippocampal formation in wtSOD1 and SOD1G93A transgenic mice. Although further studies of functional features of Epo in ALS are needed, the first demonstration of increased immunoreactivity for Epo in the CNS of SOD1G93A transgenic mice may provide initial insights into the development of interventional strategies to alleviate motor neuron degeneration in human ALS. [Copyright &y& Elsevier]