Cognitive dysfunction in diabetic rats is prevented by pyridoxamine treatment. A multidisciplinary investigation
Objective: The impact of diabetes mellitus on the central nervous system is less widely studied than in the peripheral nervous system, but there is increasing evidence that it elevates the risk of developing cognitive deficits. The aim of this study was to characterize the impact of experimental dia...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-10-01
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| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877819304624 |
| _version_ | 1811208364523257856 |
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| author | Sarah Kassab Paul Begley Stephanie J. Church Sanziana M. Rotariu Cleo Chevalier-Riffard Andrew W. Dowsey Alexander M. Phillips Leo A.H. Zeef Ben Grayson Joanna C. Neill Garth J.S. Cooper Richard D. Unwin Natalie J. Gardiner |
| author_facet | Sarah Kassab Paul Begley Stephanie J. Church Sanziana M. Rotariu Cleo Chevalier-Riffard Andrew W. Dowsey Alexander M. Phillips Leo A.H. Zeef Ben Grayson Joanna C. Neill Garth J.S. Cooper Richard D. Unwin Natalie J. Gardiner |
| author_sort | Sarah Kassab |
| collection | DOAJ |
| description | Objective: The impact of diabetes mellitus on the central nervous system is less widely studied than in the peripheral nervous system, but there is increasing evidence that it elevates the risk of developing cognitive deficits. The aim of this study was to characterize the impact of experimental diabetes on the proteome and metabolome of the hippocampus. We tested the hypothesis that the vitamin B6 isoform pyridoxamine is protective against functional and molecular changes in diabetes. Methods: We tested recognition memory using the novel object recognition (NOR) test in streptozotocin (STZ)-induced diabetic, age-matched control, and pyridoxamine- or insulin-treated diabetic male Wistar rats. Comprehensive untargeted metabolomic and proteomic analyses, using gas chromatography-mass spectrometry and iTRAQ-enabled protein quantitation respectively, were utilized to characterize the molecular changes in the hippocampus in diabetes. Results: We demonstrated diabetes-specific, long-term (but not short-term) recognition memory impairment and that this deficit was prevented by insulin or pyridoxamine treatment. Metabolomic analysis showed diabetes-associated changes in 13/82 identified metabolites including polyol pathway intermediates glucose (9.2-fold), fructose (4.9-fold) and sorbitol (5.2-fold). We identified and quantified 4807 hippocampal proteins; 806 were significantly altered in diabetes. Pathway analysis revealed significant alterations in cytoskeletal components associated with synaptic plasticity, glutamatergic signaling, oxidative stress, DNA damage and FXR/RXR activation pathways in the diabetic rat hippocampus. Conclusions: Our data indicate a protective effect of pyridoxamine against diabetes-induced cognitive deficits, and our comprehensive ‘omics datasets provide insight into the pathogenesis of cognitive dysfunction enabling development of further mechanistic and therapeutic studies. Keywords: Cognitive decline, Diabetes, Metabolomics, Proteomics, Pyridoxamine, Synaptic plasticity |
| first_indexed | 2024-04-12T04:19:55Z |
| format | Article |
| id | doaj.art-5729f0504db341cd97c70ad009936b48 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-12T04:19:55Z |
| publishDate | 2019-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-5729f0504db341cd97c70ad009936b482022-12-22T03:48:15ZengElsevierMolecular Metabolism2212-87782019-10-0128107119Cognitive dysfunction in diabetic rats is prevented by pyridoxamine treatment. A multidisciplinary investigationSarah Kassab0Paul Begley1Stephanie J. Church2Sanziana M. Rotariu3Cleo Chevalier-Riffard4Andrew W. Dowsey5Alexander M. Phillips6Leo A.H. Zeef7Ben Grayson8Joanna C. Neill9Garth J.S. Cooper10Richard D. Unwin11Natalie J. Gardiner12Faculty of Biology, Medicine and Health, University of Manchester, UKFaculty of Biology, Medicine and Health, University of Manchester, UKFaculty of Biology, Medicine and Health, University of Manchester, UKFaculty of Biology, Medicine and Health, University of Manchester, UKFaculty of Biology, Medicine and Health, University of Manchester, UKDepartment of Population Health Sciences and Bristol Veterinary School, Faculty of Health Sciences, University of Bristol, Bristol, BS8 2BN, UKDepartment of Electrical Engineering and Electronics, University of Liverpool, UKFaculty of Biology, Medicine and Health, University of Manchester, UKFaculty of Biology, Medicine and Health, University of Manchester, UKFaculty of Biology, Medicine and Health, University of Manchester, UKFaculty of Biology, Medicine and Health, University of Manchester, UK; School of Biological Sciences, University of Auckland, New ZealandFaculty of Biology, Medicine and Health, University of Manchester, UKFaculty of Biology, Medicine and Health, University of Manchester, UK; Corresponding author. University of Manchester, Faculty of Biology, Medicine and Health, Oxford Road, Manchester, M13 9PT, UK.Objective: The impact of diabetes mellitus on the central nervous system is less widely studied than in the peripheral nervous system, but there is increasing evidence that it elevates the risk of developing cognitive deficits. The aim of this study was to characterize the impact of experimental diabetes on the proteome and metabolome of the hippocampus. We tested the hypothesis that the vitamin B6 isoform pyridoxamine is protective against functional and molecular changes in diabetes. Methods: We tested recognition memory using the novel object recognition (NOR) test in streptozotocin (STZ)-induced diabetic, age-matched control, and pyridoxamine- or insulin-treated diabetic male Wistar rats. Comprehensive untargeted metabolomic and proteomic analyses, using gas chromatography-mass spectrometry and iTRAQ-enabled protein quantitation respectively, were utilized to characterize the molecular changes in the hippocampus in diabetes. Results: We demonstrated diabetes-specific, long-term (but not short-term) recognition memory impairment and that this deficit was prevented by insulin or pyridoxamine treatment. Metabolomic analysis showed diabetes-associated changes in 13/82 identified metabolites including polyol pathway intermediates glucose (9.2-fold), fructose (4.9-fold) and sorbitol (5.2-fold). We identified and quantified 4807 hippocampal proteins; 806 were significantly altered in diabetes. Pathway analysis revealed significant alterations in cytoskeletal components associated with synaptic plasticity, glutamatergic signaling, oxidative stress, DNA damage and FXR/RXR activation pathways in the diabetic rat hippocampus. Conclusions: Our data indicate a protective effect of pyridoxamine against diabetes-induced cognitive deficits, and our comprehensive ‘omics datasets provide insight into the pathogenesis of cognitive dysfunction enabling development of further mechanistic and therapeutic studies. Keywords: Cognitive decline, Diabetes, Metabolomics, Proteomics, Pyridoxamine, Synaptic plasticityhttp://www.sciencedirect.com/science/article/pii/S2212877819304624 |
| spellingShingle | Sarah Kassab Paul Begley Stephanie J. Church Sanziana M. Rotariu Cleo Chevalier-Riffard Andrew W. Dowsey Alexander M. Phillips Leo A.H. Zeef Ben Grayson Joanna C. Neill Garth J.S. Cooper Richard D. Unwin Natalie J. Gardiner Cognitive dysfunction in diabetic rats is prevented by pyridoxamine treatment. A multidisciplinary investigation Molecular Metabolism |
| title | Cognitive dysfunction in diabetic rats is prevented by pyridoxamine treatment. A multidisciplinary investigation |
| title_full | Cognitive dysfunction in diabetic rats is prevented by pyridoxamine treatment. A multidisciplinary investigation |
| title_fullStr | Cognitive dysfunction in diabetic rats is prevented by pyridoxamine treatment. A multidisciplinary investigation |
| title_full_unstemmed | Cognitive dysfunction in diabetic rats is prevented by pyridoxamine treatment. A multidisciplinary investigation |
| title_short | Cognitive dysfunction in diabetic rats is prevented by pyridoxamine treatment. A multidisciplinary investigation |
| title_sort | cognitive dysfunction in diabetic rats is prevented by pyridoxamine treatment a multidisciplinary investigation |
| url | http://www.sciencedirect.com/science/article/pii/S2212877819304624 |
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