Comparative evaluation of borneol as a context-dependent modulator of blood-brain barrier function:...

The blood-brain barrier (BBB) is an obstacle to effective therapy in neurological disease because it restricts drug access to the brain. Borneol, a lipophilic bicyclic monoterpene used in traditional Chinese medicine, has been associated with opposing effects on BBB function: barrier integrity restoration in ischaemic stroke models and barrier permeability enhancement in drug-delivery models. This mini-review evaluates whether these findings represent a true contradiction or a context-dependent pattern of BBB modulation. The impact of borneol treatment on the intact and damaged barrier was compared by aligning matched readouts within the physical and selective barrier phenotype categories. For example, physical barrier integrity measures explored ionic permeability, tight junction (TJ) organization and macromolecular leakage and selective barrier function measures assessed transcytosis and transport related outcomes. Molecular markers of endothelial state and extracellular matrix integrity were also compared. Across stroke models, borneol was consistently associated with improved barrier resistance, junctional structure preservation and reduced pathological leakage, with the major facilitator superfamily domain-containing protein 2a (Mfsd2a) and caveolin-1 (Cav-1)-mediated transcytosis representing the most clearly defined downstream mechanistic pathway. In delivery models, borneol was associated with transient TEER reduction, TJ protein (claudin-5) redistribution and enhanced tracer or payload passage, consistent with reversible barrier loosening. When these findings were compared through matched readouts, these differences became less contradictory and more conditionally structured. Overall, borneol is better understood as a context-sensitive modulator of BBB function rather than a uniformly barrier-opening or barrier-protective agent. However, translation remains limited by substantial heterogeneity in model, dose and timing, together with unresolved upstream mechanisms.