Combination of Donepezil and Memantine Attenuated Cognitive Impairment Induced by Mixed Endocrine-Disrupting Chemicals: an In Silico Study.

Little is known about the effects of endocrine-disrupting chemicals (EDCs) and the combination of memantine and donepezil on the pathogenesis of cognitive impairment. Here, we aimed to identify in silico the molecular mechanisms of the combination of memantine and donepezil that combat cognitive impairment induced by nine common EDCs using GeneMania, AutoDock Vina, Metascape, SwissADME, MIENTURNET, and miRNAsong. We observed that the mixture of memantine and donepezil had therapeutic effects on mixed EDC-induced cognitive impairment via five genes (TNF, ACHE, BAX, IL1B, and CASP3). With ACHE and TNF, donepezil and memantine both had a high docking score, respectively. The predominant connections among five mutual genes were physical interactions (77.6%). The major pathways associated with memantine and donepezil countering cognitive impairment generated by mixed EDCs were discovered to be "AGE-RAGE signaling pathway in diabetic complications," "pro-survival signaling of neuroprotectin D1," and "non-alcoholic fatty liver disease." The miRNAs and transcription factors implicated in memantine and donepezil protecting against mixed EDCs were hsa-miR-128-3p and hsa-miR-34a-5p, NFKB1, NFKB2, IRF8, and E2F4. The sponges' tertiary structure predictions for two major miRNAs were provided. The physicochemical and pharmacokinetic properties of memantine and donepezil highlighted the need for a therapeutic combination of these medications to treat cognitive impairment.