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<p>Ischemic stroke is a leading cause of disability worldwide, with current therapies mainly focused on clot fibrinolysis rather than neuroprotection. Nestorone<sup>®</sup> (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 (&lt; 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.</p>

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Low dose intranasal nestorone self-emulsifying drug delivery system promotes neuroprotection in experimental stroke through modulation of glial cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月23日

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  • Sara Meirinho,
  • 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,
  • Adriana O. Santos

摘要

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.