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Antidiabetic and Neuroprotective Effects of a Novel Repaglinide Analog Publisher Pubmed



Foroumadi R1, 2 ; Baeeri M2 ; Asgarian S3 ; Emamgholipour Z4 ; Goli F4 ; Firoozpour L4 ; Keykhaei M5 ; Gholami M2 ; Dehpour AR1 ; Abdollahi M2, 6 ; Foroumadi A4, 7
Authors
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Authors Affiliations
  1. 1. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences (TUMS), Tehran, Iran
  3. 3. Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
  4. 4. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
  6. 6. Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  7. 7. Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

Source: Journal of Biochemical and Molecular Toxicology Published:2022


Abstract

Repaglinide (RPG) is an oral insulin secretagogue used in the treatment of diabetes. In this study, a new RPG analog was synthesized. Its antidiabetic and neuroprotective effects on dorsal root ganglions (DRG) in streptozotocin (STZ)-induced diabetic rats were examined compared to RPG. To assess the effects of 2-methoxy-4-(2-((3-methyl-1-(2-(piperidin-1-yl)phenyl)butyl)amino)-2-oxoethoxy)benzoic acid (OXR), the impact of OXR on oxidative stress biomarkers, motor function, and the expression of the glutamate dehydrogenase 1 (GLUD1), SLC2A2/glucose transporter 2 (GLUT2), and glucokinase (GCK) genes in STZ-induced diabetic rats were assessed. DRGs were examined histologically using hemotoxylin and eosin staining. Molecular docking was used to investigate the interactions between OXR and the binding site of RPG, the ATP-sensitive potassium (KATP) channel. Following 5 weeks of treatment, OXR significantly increased the level of total antioxidant power, decreased reactive oxygen species, and lipid peroxidation in the DRGs of diabetic rats. OXR restored STZ-induced pathophysiological damages in DRG tissues. Administration of OXR improved motor function of rats with diabetic neuropathy. Administration of 0.5 mg/kg OXR reduced blood glucose while promoting insulin, mainly through upregulation of messenger RNA expression of GLUD1, GLUT2, and GCK in the pancreas. Molecular docking revealed a favorable binding mode of OXR to the KATP channel. In conclusion, OXR has neuroprotective effects in diabetic rats by lowering oxidative stress, lowering blood glucose, and stimulating insulin secretion. We report that 0.5 mg/kg OXR administration was the most effective concentration of the compound in this study. OXR may be a promising target for further research on neuroprotective antidiabetic molecules. © 2022 Wiley Periodicals LLC.