Abstract
Semen Strychni has been extensively used as a Chinese herb, but its therapeutic window is narrowed by the strong toxicity of the compound, which limits its effectiveness. Radix Paeoniae Alba has been reported to reduce the toxic effects and increase the therapeutic effects of Semen Strychni, but the underlying mechanism remains unknown. This research aimed to explore the mechanism through which P-glycoprotein (P-gp) is modulated by Semen Strychni combined with Radix Paeoniae Alba in vitro. An MTT assay was used to study cytotoxicity in an MDCK-MDR1 cell model. Rh123 efflux and accumulation were measured to assess P-gp function. The expression levels of MDR1 mRNA and P-gp protein in MDCK-MDR1 cells were investigated. A P-gp ATPase activity assay kit was applied to detect the effect on P-gp ATPase activity. Semen Strychni combined with Radix Paeoniae Alba could induce P-gp-mediated drug transport by inhibiting brucine and strychnine transport in MDCK-MDR1 cells, enhancing the P-gp efflux function, upregulating the P-gp expression and MDR1 mRNA levels, and stimulating P-gp ATPase activity.
Highlights
Semen Strychni has been used in the treatment of joint pain, arthritis, and rheumatic diseases in China
As the RPAE concentration increased, the ER value increased. These results showed that the combination of SSE and RPAE inhibited the absorption of brucine and strychnine
To investigate the underlying mechanism, the effect of RPAE on brucine and strychnine transport in MDCK-MDR1 cells was investigated, and the results showed that RPAE could inhibit brucine and strychnine transport in MDCK-MDR1 cells which might explain how RPAE reduces the toxicity of SSE to the central nervous system
Summary
Semen Strychni has been used in the treatment of joint pain, arthritis, and rheumatic diseases in China. Strychnos total alkaloids, which comprise more than 70% of the alkaloids isolated from Semen Strychni, have been shown to exert antitumour, analgesic, anti-inflammatory, antioxidant, and antiangiogenesis effects as well as other practical effects [1]. It is widely used as a folk medicine, the use of Semen Strychni is limited by its narrow therapeutic window due to its strong excitatory effects on the central nervous system [2]. Protective herbal therapy is considered a reliable method that can reduce the toxicity of Semen Strychni and increase its use in clinical practice. Radix Paeoniae Alba and its active ingredients have shown protective effects in previous cytotoxicology experiments [7, 8]
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