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Amos Sunday Onikanni,1– 3,* Bashir Lawal,4,5,* Augustine O Olusola,1 Janet O Olugbodi,6 Saidu Sani,7 Basiru Olaitan Ajiboye,8 Omotayo B Ilesanmi,9 Mohammed Alqarni,10 Gomaa Mostafa-Hedeab,11,12 Ahmad J Obaidullah,13,14 Gaber El-Saber Batiha,15 Alexander TH Wu16– 21 1Toxicology and Environmental Laboratory, Department of Biochemistry, Faculty of Science, Adekunle Ajasin University, Akungba-Akoko, Ondo State, Nigeria; 2Biochemistry Unit, Department of Chemical Sciences, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria; 3Graduate Institute of Biomedical Science, College of Medicine, China Medical University, Taipei, Taiwan; 4PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, 11031, Taiwan; 5Graduate Institute of Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan; 6Department of Biochemistry, Bingham University, Karu, Nigeria; 7Department of Biochemistry, Faculty of Biological Science, Alex Ekwueme Federal University Ndufu Alike IkwoD, Abakaliki, Ebonyi State, Nigeria; 8Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Faculty of Science, Federal University, Oye-Ekiti, Ekiti State, Nigeria; 9Department of Biochemistry, Faculty of Science, Federal University Otuoke, Ogbia, Bayelsa State, 23401, Nigeria; 10Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif, 21944, Saudi Arabia; 11Pharmacology Department & Health Research Unit, Medical College, Jouf University, Sakakah, Saudi Arabia; 12Pharmacology Department, Faculty of Medicine, Beni-Suef University, Beni Suef, Egypt; 13Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia; 14Drug Exploration and Development Chair (DEDC), Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia; 15Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, AlBeheira, Egypt; 16The PhD Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan; 17International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan; 18TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 11031, Taiwan; 19Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, 11031, Taiwan; 20Taipei Heart Institute, Taipei Medical University, Taipei, 11031, Taiwan; 21Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, 11490, Taiwan*These authors contributed equally to this workCorrespondence: Alexander TH Wu Tel +886 2 2697 2035Email chaw1211@tmu.edu.twBackground: Sterculia tragacantha is a medicinal plant commonly used in the western part of Nigeria, for managing diabetes mellitus. However, there is a dearth of scientific information on the antidiabetic and neuroprotective properties of the plant.Methods: The in silico, in vitro and in vivo models were used to evaluate the antioxidants, antidiabetic, anti-inflammatory and neuroprotective potential of aqueous extract of Sterculia tragacantha leaf (AESTL) in streptozotocin (STZ)-induced diabetic rats. Thirty (30) male albino rats (155.34± 6.33 g) were intraperitoneal injected with 40 mg/kg of freshly prepared streptozotocin and were divided into 5 groups (A-E) of 6 animals each. Groups A–D were treated with 0, 150 and 300 mg/kg of AESTL, and 200 mg/kg body weight of metformin respectively, while group E serve as the normal control.Results: The results of in vitro analysis revealed dose-dependent antioxidant activities; ABTS (IC50 = 63.03± 2.57 μg/mL), DPPH (117.49± 2.35 μg/mL), FRAP (15.19± 0.98 mmol/100g), TAC (43.38± 0.96 mg/100g), hypoglycaemic effect; α-amylase (IC50 = 77.21± 4.35 μg/mL) and α-glucosidase (IC50 = 443.25± 12.35), and anti-cholinesterase; AChE (IC50 = 113.07± 3.42 μg/mL) and BChE (IC50 = 87.50± 4.32 μg/mL) activities of AESTL. In vivo study revealed dose-dependent hypoglycemic effect and body weight improvement in rats treated with the AESTL. In addition, AESTL improved the antioxidant status and attenuated STZ-induced dysregulations of Na+-K+-ATPase, cholinesterases and neurotransmitters in the brain tissue of experimental rats. The results also demonstrated that AESTL could regulate anti-inflammatory response via inhibition of COX-2/NO signaling axis in the brain of diabetic rats. Molecular docking analysis revealed that epicatechin and procyanidin B2, the bioactive compounds from AESTL, docked well to the binding cavities of acetylcholinesterase, butyrylcholinesterase, α-amylase and α-glucosidase with binding affinities ranges between – 8.0 and – 11.4 kcal/mol, suggesting that these compounds are the bioactive component that could be responsible for the antidiabetic and neuroprotective activities of AESTL.Conclusion: The results of the present study strongly suggested that the AESTL extract could be very useful for halting diabetes progression and its associated neuroinflammation complications.Keywords: Sterculia tragacantha, cholinesterase, antidiabetic, neurotransmitters, oxidative stress markers