A new frontier in neuropharmacology: Recent progress in natural products research for blood–brain barrier crossing

Neuropharmacology faces challenges due to the intricate nervous system, diverse neurological disorders, and existence of the blood–brain barrier (BBB), which hinder the development of effective treatments. Although the primary function of the BBB is to expel toxins and pathogens, this structure also prevents optimal drug delivery. Natural products, with their chemical diversity and sustainability, have long been recognized as potential neuroprotective compounds, making BBB permeability studies mandatory. Over the last ten years, biotechnological advances in two-dimensional in vitro BBB models (monoculture and co-culture), in vivo imaging techniques, and pharmacokinetic modeling have contributed to expanding our current knowledge. In this study, we have reviewed the BBB crossing of natural products such as different terpenoids, polyphenolic compounds, and alkaloids. The findings, obtained through in vitro, in vivo, and silico methods, revealed moderate to high permeability for many of these natural products. However, other compounds showed not to be able to reach the brain. To better understand the behavior of natural products in humans and improve their ability to pass across the blood-brainier, the development of new three-dimensional and dynamic models of the BBB, new nanosystems complexes for encapsulation or in-depth studies of the transport mechanism are current and future lines of research.