18β-Glycyrrhetinic Acid-Loaded Silver Nanoparticles Mitigate Neuroinflammation and Endoplasmic Reticulum Stress in the Brain Tissue of Diabetic Rats

Abstract

Objective(s): Diabetes mellitus (DM) causes oxidative stress, neuroinflammation, and endoplasmic reticulum (ER) dysfunction that contribute to neurodegeneration. This study investigated the effects of 18 beta-glycyrrhetinic acid-loaded silver nanoparticles (18 beta-GA-AgNPs) on brain injury in diabetic rats. Materials and Methods: Fifty-six male Wistar rats were divided into eight groups: Sham, 18 beta-GA, AgNPs, 18 beta-GA-AgNPs, DM, DM+18 beta-GA, DM+AgNPs, and DM+18 beta-GA-AgNPs. Diabetes was induced by alloxan (120 mg/kg, IP), and treatments were administered orally for 14 days. Biochemical markers (MDA, GSH, SOD), histopathology, and expression of ER stress and apoptotic proteins (ATF6, IRE1, Caspase-3, BCL-2, CREB, TNF-alpha, and IL-1 beta) were evaluated. Results: The DM group exhibited significant increases in MDA, TNF-alpha, IL-1 beta, ATF6, and Caspase-3 with reduced GSH, SOD, and BCL-2, indicating oxidative stress, inflammation, apoptosis, and ER stress. In contrast, IRE1 levels remained unchanged in DM rats but showed a slight elevation in the AgNPs group. Treatment with 18 beta-GA-AgNPs markedly reduced MDA, TNF-alpha, IL-1 beta, ATF6, and Caspase-3, while restoring GSH, SOD, BCL-2, and CREB expression. Histopathological analysis confirmed neuronal apoptosis and perivascular and extracellular space enlargement in DM rats, whereas 18 beta-GA-AgNPs substantially attenuated these changes. Overall, 18 beta-GA-AgNPs provided synergistic neuroprotection by suppressing oxidative stress, inflammation, and ER stress while enhancing antioxidant and anti-apoptotic defenses. Conclusion: These findings suggest that 18 beta-GA-AgNPs may represent a promising therapeutic strategy against diabetes-associated neurodegeneration, although further long-term, ultrastructural, and sex-inclusive studies are warranted.