Transport of cryptotanshinone, a major active triterpenoid in Salvia miltiorrhiza Bunge widely used in the treatment of stroke and Alzheimers disease, across the blood-brain

Yu, Xi-Yong, Lin, Shu-Guang, Chen, Xiao, Zhou, Zhi-Wei, Liang, Jun, Duan, Wei, Chowbay, Balram, Wen, Jing-Yuan, Chan, Eli, Cao, Jie, Li, Chun-Guang and Zhou, Shu-Feng 2007, Transport of cryptotanshinone, a major active triterpenoid in Salvia miltiorrhiza Bunge widely used in the treatment of stroke and Alzheimers disease, across the blood-brain, Current drug metabolism, vol. 8, no. 4, pp. 365-377.


Title Transport of cryptotanshinone, a major active triterpenoid in Salvia miltiorrhiza Bunge widely used in the treatment of stroke and Alzheimers disease, across the blood-brain
Author(s) Yu, Xi-Yong
Lin, Shu-Guang
Chen, Xiao
Zhou, Zhi-Wei
Liang, Jun
Duan, Wei
Chowbay, Balram
Wen, Jing-Yuan
Chan, Eli
Cao, Jie
Li, Chun-Guang
Zhou, Shu-Feng
Journal name Current drug metabolism
Volume number 8
Issue number 4
Start page 365
End page 377
Publisher Bentham Science Publishers Ltd.
Place of publication Hilversum, Netherlands
Publication date 2007-05
ISSN 1389-2002
1875-5453
Keyword(s) Cryptotanshinone
blood-brain barrier
P-glycoprotein
multidrug resistance associated protein
middle cerebral artery occlusion
Summary Cryptotanshinone (CTS), a major constituent from the roots of Salvia miltiorrhiza (Danshen), is widely used in the treatment of coronary heart disease, stroke and less commonly Alzheimer's disease. Our recent study indicates that CTS is a substrate for Pglycoprotein (PgP/MDR1/ABCB1). This study has investigated the nature of the brain distribution of CTS across the brain-blood barrier (BBB) using several in vitro and in vivo rodent models. A polarized transport of CTS was found in rat primary microvascular endothelial cell (RBMVEC) monolayers, with facilitated efflux from the abluminal side to luminal side. Addition of a PgP (e.g. verapamil and quinidine) or multi-drug resistance protein 1/2 (MRP1/2) inhibitor (e.g. probenecid and MK-571) in both luminal and abluminal sides attenuated the polarized transport. In a bilateral in situ brain perfusion model, the uptake of CTS into the cerebrum increased from 0.52 ± 0.1% at 1 min to 11.13 ± 2.36 ml/100 g tissue at 30 min and was significantly greater than that of sucrose. Co-perfusion of a PgP/MDR1 (e.g. verapamil) or MRP1/2 inhibitor (e.g. probenecid) significantly increased the brain distribution of CTS by 35.1-163.6%. The brain levels of CTS were only about 21% of those in plasma, and were significantly increased when coadministered with verapamil or probenecid in rats. The brain levels of CTS in rats subjected to middle cerebral artery occlusion and rats treated with quinolinic acid (a neurotoxin) were about 2- to 2.5-fold higher than the control rats. Moreover, the brain levels in mdr1a(-/-) and mrp1(-/-) mice were 10.9- and 1.5-fold higher than those in the wild-type mice, respectively. Taken collectively, these findings indicate that PgP and Mrp1 limit the brain penetration of CTS in rodents, suggesting a possible role of PgP and MRP1 in limiting the brain penetration of CTS in patients and causing drug resistance to Danshen therapy and interactions with conventional drugs that are substrates of PgP and MRP1. Further studies are needed to explore the role of other drug transporters in restricting the brain penetration of CTS and the clinical relevance.
Language eng
Field of Research 110404 Traditional Chinese Medicine and Treatments
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2007, Bentham Science Publishers Ltd.
Persistent URL http://hdl.handle.net/10536/DRO/DU:30007442

Document type: Journal Article
Collection: School of Medicine
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