Low dose intranasal nestorone self-emulsifying drug delivery system promotes neuroprotection in experimental stroke through modulation of glial cells
Document Type
Article (peer-reviewed)
Publication Date
5-23-2026
Abstract
Ischemic stroke is a leading cause of disability worldwide, with current therapies mainly focused on clot fibrinolysis rather than neuroprotection. Nestorone® (NES), a highly selective progesterone receptor agonist, has shown neuroprotective potential in experimental stroke. However, NES exhibits poor water solubility and high hepatic first-pass metabolism, limiting its oral bioavailability, which motivated us to develop new lipid-based NES formulations for nose-to-brain delivery. With that rationale, a nanoemulsion (NE) and a self-microemulsifying drug delivery system (SMEDDS) were herein evaluated for NES intranasal delivery post-stroke in mice. NES-loaded SMEDDS and NE aqueous dispersions showed highly homogeneous droplet sizes of approximately 20 and 90 nm. NES permeation across the MucilAir™ model was significantly higher with the NE, which also demonstrated excellent in vitro safety. The SMEDDS decreased resazurin reduction, induced a small increase in LDH release, and caused a transient TEER decrease (< 100 Ω·cm²) that recovered within 4 days. In mice, both intranasal formulations produced higher and faster plasma and brain NES Cmax values (tmax 5 min) compared with subcutaneous administration. Intranasal SMEDDS achieved the highest brain Cmax and significantly greater brain/plasma NES concentration ratios. A single low NES-SMEDDS intranasal dose administered 1 h after stroke induction reduced infarct volume by 27% compared with saline (7.55 ± 0.99% vs. 10.33 ± 0.43%) and improved locomotor asymmetries. This effect was correlated with a less reactive astrocyte and microglia morphology at 48 h after ischemia. These results highlight intranasal NES-SMEDDS as a promising neuroprotective strategy warranting further preclinical and clinical investigation.
Recommended Citation
Meirinho, Sara, Susana Alves Ferreira, Catarina Diniz, Gilberto Alves, Shimin Zhang, Narender Kumar, Regine Sitruk-Ware, Gaohong Di, Manuel Navarro-Oviedo, Jesús M. Pradillo, Ignacio Lizasoain, Graça Baltazar, and Adriana O. Santos. 2026. "Low dose intranasal nestorone self-emulsifying drug delivery system promotes neuroprotection in experimental stroke through modulation of glial cells," Drug Delivery and Translational Research, https://doi.org/10.1007/s13346-026-02150-5.
DOI
10.1007/s13346-026-02150-5
Language
English
https://doi.org/10.1007/s13346-026-02150-5