Abstract
Chronic diabetic conditions have been associated with certain cerebral complications, that include neurobehavioral dysfunctional patterns and morphological alterations of neurons, especially the hippocampus. Neuroanatomical studies done by the authors have shown decreased total dendritic length, intersections, dendritic length per branch order and nodes in the CA1 hippocampal region of the diabetic brain as compared to its normal control group, indicating reduced dendritic arborization of the hippocampal CA1 neurons. Epigenetic alterations in the brain are well known to affect age-associated disorders, however its association with the evolving diabetes-induced damage in the brain is still not fully understood. DNA hypermethylation within the neurons, tend to silent the gene expression of several regulatory proteins. The findings in the study have shown an increase in global DNA methylation in palmitic acid-induced lipotoxic Neuro-2a cells as well as within the diabetic mice brain. Inhibiting DNA methylation, restored the levels of HSF1 and certain HSPs, suggesting plausible effect of DNMTs in maintaining the proteostasis and synaptic fidelity. Neuroinflammation, as exhibited by the astrocyte activation (GFAP), were further significantly decreased in the 5-azadeoxycytidine group (DNMT inhibitor). This was further evidenced by decrease in proinflammatory cytokines TNF⍺, IL-6, and mediators iNOS and Phospho-NFkB. Our results suggest that changes in DNA methylation advocate epigenetic dysregulation and its involvement in disrupting the synaptic exactitude in the hippocampus of diabetic mice model, providing an insight into the pathophysiology of diabetes-induced neuroepigenetic changes.
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Data Availability
The data that supports the findings of this study are available from the corresponding author upon reasonable request.
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Acknowledgements
The authors would like to acknowledge the financial support provided by the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India for carrying out this work.
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The authors would like to acknowledge the financial support provided by the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India for carrying out this work.
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VF, DKK and SBS: have contributed to the study conception and design. Material preparation, data collection and analysis were performed by VF, KP, AS, KN and SK. The manuscript was written by VF. All authors read and approved the manuscript.
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Fernandes, V., Preeti, K., Sood, A. et al. Neuroepigenetic Changes in DNA Methylation Affecting Diabetes-Induced Cognitive Impairment. Cell Mol Neurobiol 43, 2005–2020 (2023). https://doi.org/10.1007/s10571-022-01278-5
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DOI: https://doi.org/10.1007/s10571-022-01278-5