Battle of the wall for aromatic “orifice-opening” agents: defending and breaching the blood-brain barrier

The brain is the most stringently safeguarded organ in the human body. The 7-mm-thick cranial vault shields the central nervous system (CNS) from external damage, while the blood-brain barrier (BBB) functions as a specific physiological barrier, successfully safeguarding it from circulating toxins and pathogens. BBB disruption is closely linked to the emergence and development of various CNS disorders, and the strong constraints of BBB on substance exchange present a considerable obstacle to medicine administration for the treatment of neurological diseases. Aromatic orifice-opening agents (AOOAs), a specific class of traditional Chinese medicine (TCM), exhibit a unique bidirectional interaction with BBB. Such agents can loosen the BBB junctions, transiently enhance its permeability, and ease the passage of medications into the brain, a phenomenon referred to as the “permeability-promoting” effect on BBB. In contrast, under pathological conditions, AOOAs can preserve BBB integrity and exert a “permeability-restricting” effect by reducing inflammatory responses and alleviating oxidative stress. This review systematically analyzes the regulatory factors affecting BBB permeability, investigates the dual mechanisms by which AOOAs protect and penetrate the BBB, and highlights the innovative opportunities and significant potential these agents present for treating CNS disorders.