Erythropoietin Induction by Electroconvulsive Seizure, Gene Regulation, and Antidepressant-Like Behavioral Effects

• Published in: Biological psychiatry (1969) Vol. 66; no. 3; pp. 267 - 274
• Main Authors: Girgenti, Matthew J, Hunsberger, Joshua, Duman, Catharine H, Sathyanesan, Monica, Terwilliger, Rose, Newton, Samuel S
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-08-2009; Elsevier
• Subjects: Animal models; Animals; Antidepressant; Antidepressive Agents - therapeutic use; Behavior, Animal - drug effects; Biological and medical sciences; Brain-Derived Neurotrophic Factor - genetics; Brain-Derived Neurotrophic Factor - metabolism; Depression - drug therapy; Disease Models, Animal; electroconvulsive seizure; Electroshock - adverse effects; erythropoietin; Erythropoietin - metabolism; Erythropoietin - therapeutic use; Exploratory Behavior - drug effects; forced swimming test; gene expression; Gene Expression Profiling - methods; Gene Expression Regulation - physiology; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Locomotion - drug effects; Male; Medical sciences; microarray; Nervous system (semeiology, syndromes); Neurology; Neuropharmacology; Oligonucleotide Array Sequence Analysis - methods; Pharmacology. Drug treatments; Psychiatry; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin - metabolism; Seizures - etiology; Seizures - metabolism; Seizures - physiopathology; Swimming; Antidepressant; microarray; electroconvulsive seizure; gene expression; forced swimming test; erythropoietin; Nervous system diseases; Erythropoietin; Induction; Psychotropic; Epilepsy; Gene expression; Genetic determinism; Stress; Cerebral disorder; Convulsion; Gene; Polypeptide; Central nervous system disease; Genetics; Antidepressant agent; Behavior; Neurological disorder
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2008.12.005

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.