Potential Involvement of Redox and Inflammatory Signalling in the Antihyperglycemic and Antioxidant Effects of Harmaline in Male Mice With Type 2 Diabetes
Farima Malekinia, Akram Ahangarpour, Khojasteh Hoseinynejad, Seyyed Ali Mard, Maryam Radan, Fereshteh NejaddehbashiABSTRACT
Introduction
Type 2 diabetes mellitus (T2DM) is strongly associated with oxidative stress and inflammation. Harmaline (HAR), an alkaloid with antioxidant and anti‐inflammatory properties, has been suggested to possess antidiabetic potential. This study investigated the effects of HAR in experimental T2DM and its association with changes in the nuclear factor erythroid 2‐related factor 2 (Nrf2) and nuclear factor kappa‐B (NF‐κB) pathways.
Methods
In vitro experiments were performed using mouse pancreatic cells cultured under different glucose concentrations to evaluate insulin secretion and antioxidant status. For the in vivo study, T2DM was induced in mice by nicotinamide (120 mg/kg) and streptozotocin (65 mg/kg). Fasting blood glucose (FBG) was measured 1 week after induction. Forty‐eight adult male NMRI mice were randomly assigned to four groups: normal control (NC), diabetic control (DC), HAR‐treated (30 mg/kg), and metformin‐treated (150 mg/kg). Treatments were administered once daily for 10 days.
Results
HAR enhanced insulin secretion and antioxidant capacity while reducing lipid peroxidation in vitro. In diabetic mice, HAR significantly reduced FBG, improved the lipid profile, and restored pancreatic antioxidant status. These effects were accompanied by increased expression of miR‐200a, Nrf2, and NAD(P)H: quinone oxidoreductase 1 and reduced Keap1 expression. In addition, HAR increased miR‐125b expression and reduced the expression of NF‐κB, TNF‐α, IL‐1β, and IL‐6. Decreased changes in RAS‐related markers were also observed after HAR treatment.
Conclusion
HAR improved glycemic control and pancreatic antioxidant status and reduced inflammatory responses in experimental T2DM. These beneficial effects were associated with modulation of Nrf2, NF‐κB, and RAS‐related signalling pathways, suggesting their potential involvement in the observed protective effects. Further studies are needed to establish the underlying mechanisms and evaluate the long‐term efficacy and safety of HAR.