Amir Hasan Sarkardeh
1 
, Ramin Ardalani
1,2, Hossein Salehi
1, Ghorbangol Ashabi
1, Amirabbas Rahimi
3, Farzaneh Kianian
1, Elaheh Salmeh
4, Maryam Adelipour
5, Mina Ranjbaran
1* 1 Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
2 Department of Nanobiotechnology, Faculty of Fundamental Sciences, Comprehensive University of the Islamic Revolution, Tehran, Iran
3 Molecular Medicine Department, Pasteur Institute of Iran, Tehran, Iran
4 Department of Clinical Sciences, Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
5 Chemistry Department, Chungnam National University, Daejeon, South Korea
Abstract
Purpose: Effective disease-modifying treatments for Alzheimer’s disease remain limited. We examined low-concentration nano-niosomal dimethyl fumarate (N-DMF) in an acute bilateral hippocampal amyloid-β25–35 rat model. Methods: DMF-loaded niosomes were characterized by electron microscopy, dynamic light scattering, zeta-potential measurement, encapsulation analysis, and in vitro release. Forty adult male Wistar rats were randomly allocated to Sham, Aβ, Aβ+DMF, or Aβ+N-DMF groups (n=10/group). Free DMF was given orally at 25 mg/kg on four alternate days; N-DMF delivered 1.5 mg DMF per rat per administration (approximately 5.0–6.0 mg/kg). Behavioral outcomes, hippocampal oxidative and inflammatory markers (n=6/group), immunoblot endpoints (n=3/group), and qualitative Congo red staining (n=3 in Sham and Aβ groups) were assessed. Results: The pre-filtration dispersion had a DLS Z-average of 404.6 nm, a polydispersity index of 0.316, a zeta potential of −34.0 mV, and 78.39% encapsulation efficiency. Compared with untreated Aβ-injected rats, N-DMF was associated with higher phospho-Nrf2, NQO1, and SOD activity; lower BACE1, phospho-NF-κB p65, calcineurin A, NFATC1, C1q, C3, MDA, TNF-α, and IL-6; and better performance in the measured behavioral endpoints. Conclusion: In this acute model, low-concentration N-DMF was associated with molecular, biochemical, and behavioral changes. These findings do not establish improved brain delivery, carrier-specific efficacy, or a causal relationship between Nrf2 signaling and behavioral outcomes.