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

Abstract

The brain is the most stringently safeguarded organ in the human body. The 7-mm-thick cra- nial 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 ex- change present a considerable obstacle to medicine administration for the treatment of neur- ological 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 medic- ations 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 oxidat- ive stress. This review systematically analyzes the regulatory factors affecting BBB permeabil- ity, 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.

Keywords

Central nervous system / Blood-brain barrier / Aromatic “orifice-opening” agents

Funding

This work was supported by the Key Projects of Shandong Natural Science Fund (Nos. ZR2020KH003 and ZR2025MS1325), the Traditional Chinese Medicine Special Project of China Association of Chinese Medicine (No. CACMREZZ2025-A-26), and the Scientific Research Fund of Shandong University of Traditional Chinese Medicine (No. KYZK2024M01).

Declaration of competing interest

These authors have no conflict of interest to declare.

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