Sen_2025_Mol.Nutr.Food.Res__e70172

The current study was carried out to explore the neuroprotective efficacy of the synthesized compound 2-(1,3-benzodioxol-5-yl)-4H-chromen-4-one 5 (2BDC45) in diabetes-associated neurodegeneration through in silico and in vivo assessments. In silico exploration of molecular docking showed a significant binding energies of -8.5, -9.3, and -7.4 kcal/mol for 2BDC45 against the target enzymes, i.e., acetylcholinesterase, butyrylcholinesterase, and DPP-4, respectively. These findings were further confirmed through 100 ns molecular dynamics simulations, assessing parameters like RMSD, RMSF, SASA, MMPBSA, and PCA. Treatment with 2BDC45 exhibited the neuroprotective changes in the hippocampus and cortex regions of type 2 diabetes-associated neurodegenerations. Consequently, histopathological analysis of these brain regions, supported by molecular biological analyses of key genes such as GLUT-3, GSK, MAP, and PPARgamma corroborated the neuroprotection. The lipid profile, HOMA, and antioxidants exhibited notable changes by the interference of the treatments. The treatments shown significant ameliorations in glucose metabolism by following the expressions of GLUT-3 and GSK, while MAP kinase and PPARgamma showed significant restorations in the cortex and hippocampus. In conclusion, it can be implied the test flavone derivative has the capacity to amplify neural plasticity by following the scavenging of free radicals, improved glucose metabolism, and targeted genes expression.