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 Barrier

Abstract

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 P-glycoprotein (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.

Proteomic screening of antioxidant effects exhibited by Radix Salvia miltiorrhiza aqueous extract in cultured rat aortic smooth muscle cells under homocysteine treatment

“…brovascular diseases for decades (Wu et al, 1998;Ling et al, 2005;Cheng, 2007;You et al, 2007;De Palma et al, 2008;Han et al, 2008). The other major constituents of Salvia miltiorrhiza roots as the lipophilic diterpenoid quinines (tashinones) (De Palma et al, 2008), now available in the form of standardized TTE-50 extract (Sun et al, 2007), have recently been demonstrated to exert their effects in preventing aging and Alzheimer's disease via an antioxidant pathway (Yu et al, 2007) and decreasing matrix metalloproteinases activity on diet induced atherosclerosis (Fang et al, 2008). In the present study, we evaluated the protective effects of single-and polyphenol containing aqueous SMAE against Hcy-induced oxidative damage exerted on the cultured rat aortic smooth muscle A10 cells, which were used as the in vitro SMCs model.…”

Targeting BuChE-inflammatory Pathway by SK0506 to Manage Type 2 Diabetes and Alzheimer Disease

“…There are various in vitro and in vivo studies that have suggested that Dan Shen improves microcirculation, dilates the coronary arteries, possesses anti-arthrosclerotic properties, and prevents myocardial necrosis under ischemic states [8]. It is also a Chinese herb commonly included in prescriptions to treat AD [9]. In a recent study using high fat diet (HFD) fed rats, we have demonstrated that a Chinese herbal extract, containing S. miltiorrhiza and Gardenia jasminoides (coded SK0506), reduced central obesity, lowered triglycerides and free fatty acid levels in the blood stream and prevented TG deposition in liver and skeletal muscles [10].…”

Cryptotanshinione Inhibits β-Amyloid Aggregation and Protects Damage from β-Amyloid in SH-SY5Y Cells

“…It can cross the blood-brain barrier and improve the cognitive deficits in mice [13], and provide beneficial effects in stroke and ischaemic diseases [14], with few or no side effects. CTS has been suggested to be a leading compound for drug development to treat AD [15].…”