Investigating the Effect and Mechanism of 3-Methyladenine Against Diabetic Encephalopathy by Network Pharmacology, Molecular Docking, and Experimental Validation
<b>Background/Objectives:</b> Diabetic encephalopathy (DE), a severe neurological complication of diabetes mellitus (DM), is characterized by cognitive dysfunction. 3-Methyladenine (3-MA), a methylated adenine derivative, acts as a biomarker for DNA methylation and exhibits hypoglycemic...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-04-01
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| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/18/5/605 |
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| Summary: | <b>Background/Objectives:</b> Diabetic encephalopathy (DE), a severe neurological complication of diabetes mellitus (DM), is characterized by cognitive dysfunction. 3-Methyladenine (3-MA), a methylated adenine derivative, acts as a biomarker for DNA methylation and exhibits hypoglycemic and neuroprotective properties. However, the pharmacological mechanisms underlying 3-MA’s therapeutic effects on diabetic microvascular complications remain incompletely understood, owing to the intricate and multifactorial pathogenesis of DE. <b>Methods</b>: This study employed network pharmacology and molecular docking techniques to predict potential targets and signaling pathways of 3-MA against DE, with subsequent validation through animal experiments to elucidate the molecular mechanisms of 3-MA in DE treatment. <b>Results</b>: Network pharmacological analysis identified two key targets of 3-MA in DE modulation: AKT and GSK3β. Molecular docking confirmed a strong binding affinity between 3-MA and AKT/GSK3β. In animal experiments, 3-MA significantly reduced blood glucose levels in diabetic mice, ameliorated learning and memory deficits, and preserved hippocampal neuronal integrity. Furthermore, we found that 3-MA inhibited apoptosis by regulating the expression of Bax and BCL-2. Notably, 3-MA also downregulated the expression of amyloid precursor protein (APP) and Tau while enhancing the expression of phosphorylated AKT and GSK-3β. <b>Conclusions</b>: Our findings may contribute to elucidating the therapeutic mechanisms of 3-MA in diabetic microangiopathy and provide potential therapeutic targets through activation of the AKT/GSK-3β pathway. |
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| ISSN: | 1424-8247 |