Neuroprotective effects of semaglutide and metformin against rotenone-induced neurobehavioral changes in male diabetic rats

Esraa A Salem; Saad Misfer Alqahtani; Ehab A M El-Shoura; Sameh S Zaghlool; Lobna A Abdelzaher; Sally A M Mohamed; Ibrahim S Alalhareth; Alzahraa A M Sheref

doi:10.1007/s00210-025-03920-7

Neuroprotective effects of semaglutide and metformin against rotenone-induced neurobehavioral changes in male diabetic rats

Naunyn Schmiedebergs Arch Pharmacol. 2025 Mar 15. doi: 10.1007/s00210-025-03920-7. Online ahead of print.

Authors

Esraa A Salem¹, Saad Misfer Alqahtani², Ehab A M El-Shoura³, Sameh S Zaghlool⁴, Lobna A Abdelzaher⁵, Sally A M Mohamed⁶, Ibrahim S Alalhareth⁷, Alzahraa A M Sheref¹

Affiliations

¹ Department of Medical Physiology, Faculty of Medicine, Menoufia University, Shebeen ElKom, 32511, Egypt.
² Department of Pathology, College of Medicine, The University Hospital, Najran University, Najran, Saudi Arabia.
³ Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, Egypt. ehabel-shoura@azhar.edu.eg.
⁴ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University of Technology and Information (MTI), Mokattam, Cairo, 11571, Egypt.
⁵ Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt.
⁶ Department of Histology and Cytology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt.
⁷ College of Pharmacy, The University Hospital, Najran University, Najran, Saudi Arabia.

PMID: 40088335
DOI: 10.1007/s00210-025-03920-7

Abstract

Pre-existing diabetes raises the likelihood of Parkinson's disease (PD), according to epidemiological and animal research. Our study aimed to investigating the likely neuroprotective effect of metformin (Met) and/or semaglutide (Sem) in model of PD in male diabetic rats and the possible underlying mechanism. Type 2 diabetes (T2DM) was induced by giving high-fat diet (HFD) for 3 weeks followed by a single streptozotocin (STZ) injection (40 mg/kg, i.p., once dose) followed by injection of 9 doses of rotenone every 48 ± 2 h for induction of PD. Met and/or Sema were administered to DM+PD via gastric gavage once daily for 4 weeks. In comparison with the DM+PD group, Met and/or Sem significantly lowered blood glucose levels, HOMA-IR, HbA1C, cholesterol, triglycerides, and LDL with significantly increased insulin and HDL levels. In addition, there was enhanced brain antioxidant status with lower oxidative-inflammatory stress biomarkers associated with improved rat cognitive, locomotor, and olfactory functions. A significant downregulation of caspase 3 and GFAP with concomitant upregulation of NRF2 protein expressions were observed in treated groups. Overall, co-treatment with Met and Sem elicited more efficacy than that of the individual regimen. When combined, the results of this study have demonstrated for the first time that Met and Sem work in concert to create neuroprotection in PD model of male diabetic rats compared to when taken separately. The study's findings indicate that Met and/or Sem have a restorative effect on T2DM and PD-induced changes in neurobehavioral and biochemical/molecular indices ascribed to the improvement of endogenous antioxidant systems, decreased lipid peroxidation, suppression of oxidative/inflammatory stress, and-most importantly-regulation of Nrf2 and caspase 3.

Keywords: CX3Cl1, Nrf2; Diabetes; GFAP; Metformin; Parkinson; Semaglutide.