Valencia Fernandes1, Anika Sood1, Kumari Preeti1, Dharmendra Kumar Khatri2, Shashi Bala Singh3. 1. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telanagana, 500037, India. 2. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telanagana, 500037, India. dkkhatri10@gmail.com. 3. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telanagana, 500037, India. sbsingh.dipas@gmail.com.
Abstract
BACKGROUND: DNA methylation changes have known to downregulate several regulatory proteins epigenetically during various neurodegenerative disorders. Our study aims to understand the effect of this global DNA methylation on the cerebral complications of type 2 diabetes mice, and its notable effect on maintaining the synaptic fidelity. METHODS AND RESULTS: Chronic high fat diet and streptozotocin-induced diabetic mice were studied for the neurobehavioral and neuroanatomic parameters pertaining to prefrontal cortex, subsequently elucidating the associated changes in DNA methylation within these diabetic brains. Further, the impact of this epigenetic dysregulation on HSF1, BDNF and PSD95 were studied by assessing the binding affinity and level of % methylation within the promoter site of their respective genes. Our study suggest increased DNMT aberrations within the prefrontal cortex, with increased MeCP2 levels, confirming DNA hypermethylation. This was in accordance with the altered neurobehavioral changes. Further, the hypermethylation was found to participate in gene silencing of HSF1, BDNF and PSD95 proteins, responsible for maintaining the synaptic fidelity. CONCLUSION: Overall, our study concludes the plausible involvement of neuroepigenetic alterations in the prefrontal cortex (PFC) of the type 2 diabetes mice, specifically DNA hypermethylation. PFC plays a central role in modulating cognitive and other executive functions through its connection with several brain regions, and thus therapeutic strategies targeting epigenetic modulations in it, can pave a way in controlling several neurological alterations in the brain.
BACKGROUND: DNA methylation changes have known to downregulate several regulatory proteins epigenetically during various neurodegenerative disorders. Our study aims to understand the effect of this global DNA methylation on the cerebral complications of type 2 diabetes mice, and its notable effect on maintaining the synaptic fidelity. METHODS AND RESULTS: Chronic high fat diet and streptozotocin-induced diabetic mice were studied for the neurobehavioral and neuroanatomic parameters pertaining to prefrontal cortex, subsequently elucidating the associated changes in DNA methylation within these diabetic brains. Further, the impact of this epigenetic dysregulation on HSF1, BDNF and PSD95 were studied by assessing the binding affinity and level of % methylation within the promoter site of their respective genes. Our study suggest increased DNMT aberrations within the prefrontal cortex, with increased MeCP2 levels, confirming DNA hypermethylation. This was in accordance with the altered neurobehavioral changes. Further, the hypermethylation was found to participate in gene silencing of HSF1, BDNF and PSD95 proteins, responsible for maintaining the synaptic fidelity. CONCLUSION: Overall, our study concludes the plausible involvement of neuroepigenetic alterations in the prefrontal cortex (PFC) of the type 2 diabetes mice, specifically DNA hypermethylation. PFC plays a central role in modulating cognitive and other executive functions through its connection with several brain regions, and thus therapeutic strategies targeting epigenetic modulations in it, can pave a way in controlling several neurological alterations in the brain.
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