Carbamoylated erythropoietin modulates cognitive outcomes of social defeat and differentially regulates gene expression in the dorsal and ventral hippocampus
| Autor: | Pawel Ciborowski, Michael J. Watt, Samuel S. Newton, Monica Sathyanesan, Jamie L. Scholl, Riley T Paulsen, Jacob M Haiar, Jayme Wiederin, Shaydel R. Davies |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Hippocampus Hippocampal formation Spatial memory Mass Spectrometry Article lcsh:RC321-571 Rats Sprague-Dawley Social defeat Mice 03 medical and health sciences Cellular and Molecular Neuroscience Cognition 0302 clinical medicine medicine Animals Cognitive Dysfunction lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Erythropoietin Biological Psychiatry Spatial Memory Memory Disorders Mice Inbred BALB C Psychological Tests Protein Carbamylation Arc (protein) biology business.industry medicine.disease Rats 3. Good health Disease Models Animal Psychiatry and Mental health 030104 developmental biology Schizophrenia biology.protein Female business Neuroscience Stress Psychological 030217 neurology & neurosurgery medicine.drug Neurotrophin |
| Zdroj: | Translational Psychiatry Translational Psychiatry, Vol 8, Iss 1, Pp 1-13 (2018) |
| ISSN: | 2158-3188 |
| Popis: | Cognitive deficits are widespread in psychiatric disorders and frequently as debilitating as the affective component. Widely prescribed antidepressants for treating depressive disorders have limited efficacy in normalizing cognitive function. Erythropoietin (Epo) has been shown to improve cognitive function in schizophrenia and treatment resistant depressed patients. However, the potent elevation of red blood cell counts by Epo can cause hematological complications in non-anemic patients. We investigated a chemically engineered, posttranslational modification of Epo, carbamoylation, which renders it non-erythropoietic. We conducted mass-spectrometry-based peptide mapping of carbamoylated Epo (Cepo) and tested its ability to improve cognitive function after social defeat stress. Gene expression analysis in discrete brain regions was performed to obtain mechanistic insight of Cepo action. Cepo reversed stress-induced spatial working memory deficits while affecting long-term (24 h) novel object recognition in these rats. Contextual fear conditioning following defeat was enhanced by Cepo, but attenuated in controls. However, Cepo improved fear extinction in all rats compared to vehicle treatment. Cepo induced differential gene expression of BDNF, VGF, Arc, TH. and neuritin in the mPFC and discrete hippocampal subfields, with strongest induction in the dorsal hippocampus. Analysis of gene–brain region–behavior interactions showed that Cepo-induced neurotrophic mechanisms influence cognitive function. Carbamoylated erythropoietin can be developed as a therapeutic neurotrophic agent to treat cognitive dysfunction in neuropsychiatric diseases. Due to its distinct mechanism of action, it is unlikely to cross react with the activity of currently prescribed small molecule drugs and can be used as an add-on biologic drug. |
| Databáze: | OpenAIRE |
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