Saka_2025_Biochem.Biophys.Res.Commun_778_152386

BACKGROUND: Diabetes is a growing health challenge with a global socio-economic burden. It is associated with several complications, such as cardiac injury. Diabetes-associated cardiac damage is linked with cardiac acetylcholinesterase (AchE) increase and apoptotic injury. Although metformin is established in diabetes management and donepezil is a known acetylcholinesterase (AchE) antagonist, the cardioprotective effect of combining metformin and donepezil in diabetes has yet to be reported. AIM: Consequently, the current study investigated the cardioprotective role of the metformin/donepezil combination in a Wistar rat model of high-fat diet/streptozotocin-induced diabetes. Moreover, the involvements of cardiac AchE and Bax/Bcl-2/caspase signaling were investigated. METHODS: Thirty-six 8-week-old male Wistar rats were acclimatized for a week and then randomly allotted into six equal groups (n = 6 rats per group): control, diabetes (DM), DM + metformin, donepezil, DM + donepezil, and DM + metformin + donepezil groups. Diabetes was induced with a high-fat diet/streptozotocin. In addition, DM + Metformin rats received 100 mg/kg of metformin per os, Donepezil received 10 mg/kg of donepezil per os, DM + Donepezil had 10 mg/kg of donepezil per os, and DM + Metformin + Donepezil had 100 mg/kg of metformin with 10 mg/kg of donepezil per os for six weeks. RESULTS: Metformin and donepezil independently improved fasting glucose, insulin and insulin resistance, and lipid profile in diabetic rats. Also, metformin and donepezil reduced the damage caused by diabetes to the heart, including high levels of injury markers, tissue damage, and amyloid buildup. In addition, metformin and donepezil attenuated oxidative stress (MDA), antioxidant (GSH, SOD, and catalase) decline, inflammation (CRP, TNF-alpha, IL-1beta, and IL-6), apoptosis (Bax/Bcl-2 and caspase-3), and AchE rise in the cardiac tissue of diabetic rats. The combined use of metformin and donepezil exerted a superior effect compared to either monotherapy. CONCLUSION: In conclusion, the metformin and donepezil combination exerts cardioprotective effects in diabetic rats through AchE inhibition and Bax/Bcl-2/caspase-3 modulation.