Borneol and Α-asarone as adjuvant agents for improving blood–brain barrier permeability of puerarin and tetramethylpyrazine by activating adenosine receptors

Puerarin (PUE) and tetramethylpyrazine (TMP) are central nervous system (CNS) drugs used in cerebrovascular diseases. Poor brain–blood barrier (BBB) permeability limited their clinical application. Borneol and α-asarone have been proposed as an oral brain-targeting enhancer. In this study, we aimed to first evaluate the ‘orifice-opening’ effect of borneol and α-asarone, both aromatic resuscitation drugs, on improvement of brain delivery of PUE and TMP and second to investigate whether the enhancing effects were associated with adenosine receptors (ARs)-mediated trans-BBB pathway. In vitro BBB model was established and borneol and α-asarone significantly increased the cumulative amount of permeated PUE and TMP and the enhancing effects could be counteracted by AR inhibitors. Borneol and α-asarone could decrease expression of ZO-1, an important BBB junction protein, but inversely increase the expression of A(1)AR and A(2A)AR. In vivo pharmacokinetic study also confirmed that oral co-administration of borneol or α-asarone significantly increased AUC(brain) for PUE and TMP. These results suggested that borneol and α-asarone are both effective adjuvant agents for delivery of PUE and TMP to the brain.