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Background The neuroprotective and trophic actions of erythropoietin (EPO) have been tested in several animal models of insult, injury, and neurodegeneration. Recent studies in human volunteers demonstrated that EPO improves cognition and also elicits antidepressant effects. It is believed that the behavioral effects are mediated by EPO's trophic effect on neuronal systems. We therefore tested whether EPO is able to alter behavior and brain gene expression in rats. Methods The expression of EPO and EPO receptor (EPOR) in multiple brain regions was examined by quantitative polymerase chain reaction, in situ hybridization, and immunohistochemistry. The regulation of EPO and the transcription factor hypoxia-induced factor–alpha (HIF1α) after electroconvulsive seizure (ECS) was investigated. Behavioral effects of EPO were tested in the rodent forced swimming and novelty-induced hypophagia (NIH) models. EPO gene profiles were obtained by microarray analysis of the hippocampus after intracerebroventricular infusion. Results EPO and EPOR were widely expressed in the brain albeit at low levels. Highest level of EPO and EPOR were in the choroid plexus and striatum, respectively. Peripheral administration of EPO was sufficient to produce a robust antidepressant-like effect in the forced swim and NIH tests. Gene expression profiles revealed that EPO induces the expression of neurotrophic genes such as brain-derived neurotrophic factor, VGF (nonacronymic), and neuritin. Conclusions EPO is induced by ECS and independently exhibits antidepressant-like efficacy in the forced swim and NIH tests. EPO regulates the expression of genes implicated in antidepressant action and appears to be a candidate molecule for further testing in neuropsychiatry.

Electroconvulsive seizure has a proven therapeutic application in the treatment of severe depression and treatment-resistant depression. Despite the efficacy of electroconvulsive seizure as a non-chemical antidepressant treatment, the mechanism of action is unclear. Elevation in hippocampal trophic factor expression and concomitant cellular proliferation are thought to play a role in its action. We examined whether the reported induction of angiogenic factors and endothelial cell proliferation leads to an increase in vascular density. Two hippocampal regions, the dentate gyrus and the stratum lacunosum moleculare (SLM), were examined employing a combination of vascular density quantification, angiogenic gene expression analysis and immunohistochemistry. A 6% increase in vascular density was observed in the dentate gyrus but this did not achieve statistical significance. The SLM of the hippocampus exhibited a robust 20-30% increase in vascular density and was accompanied by an increase in expression of inhibitor of differentiation-3. There was also an induction of the angiogenesis markers alphaVbeta3 integrin and Del1. Increases in the vascular density of the SLM could be in response to enhanced metabolic activity in this region. This is supported by the induction of glutamine synthetase and the glutamate transporter GLT1.

Background Non-steroidal anti-inflammatory drugs such as indomethacin are widely used to treat inflammatory diseases and manage pain, fever and inflammation in several conditions, including neuropsychiatric disorders. Although they predominantly function by inhibiting cyclooxygenase (COX) activity, important COX-independent actions also occur. These actions could be responsible for the adverse side effects associated with chronic and/or high dose usage of this popular drug class. Results We examined gene regulation in the hippocampus after peripheral administration of indomethacin by employing a microarray approach. Secondary confirmation and the brain expression pattern of regulated genes was examined by in situ hybridization and immunohistochemistry. Transglutaminase 2, serum glucocorticoid inducible kinase, Inhibitor of NF-kappa B and vascular endothelial growth factor were among genes that were prominently upregulated, while G-protein coupled receptor 56 and neuropeptide Y were among genes that were downregulated by indomethacin. Co-localization studies using blood vessel markers revealed that transglutaminase 2 was induced specifically in brain vasculature. Conclusions The data demonstrate that COX-inhibitors can differentially regulate gene transcription in multiple, functionally distinctly cell types in the brain. The results provide additional insight into the molecular actions of COX-inhibitors and indicate that their effects on vasculature could influence cerebral blood flow mechanisms.