Anna Maria Piras, Angeloni Elisa, Eduardo Scalzi, Chiara Migone, Angela Fabiano, Marinella De Leo, Alessandra Braca & Barbara Costa
University of Pisa, Department of Pharmacy, 56126 Pisa, Italy
Summary
Nose-to-brain delivery offers a non-invasive, direct route to the central nervous system, bypassing the blood–brain barrier, providing a critical advantage in treating neurodegenerative diseases (NDs). Neurosteroidogenesis, a cholesterol-dependent pathway regulating microglial cholesterol homeostasis and immune function, its dysregulation has recently recognized key driver of neuroinflammation in NDs. Phytosterols, structurally similar to cholesterol, can serve as alternative substrates for the first and rate-limiting step of neurosteroidogenesis, the conversion to pregnenolone. Remarkably, this study is the first to demonstrate that a phytosterol-rich phytocomplex extract (PPs) from Urtica dioica roots can modulate this pathway. PPs treatment significantly enhanced neurosteroidogenesis in activated human microglia without depleting cholesterol stores or stimulating new synthesis. Instead, it promoted reverse cholesterol transport, preventing harmful cholesterol accumulation and inducing an anti-inflammatory, restorative microglial phenotype. Excitingly, the biological activity of the extract was fully preserved following simulation of nose-to-brain delivery in an in vitro permeation model, confirming effective brain targeting after intranasal administration. Building on these promising results, a nasal formulation of the Urtica dioica phytocomplex will be developed to enable targeted, non-invasive treatment for neurodegenerative diseases.