Inhibition of aquaporin-1 but not aquaporin-4 water permeability by bacopaside I derived from Bacopa monnieri

Aquaporin (AQP) water channels mediate transmembrane water permeability and maintain body fluid homeostasis. They are widely expressed in human body including proximal tubules in kidney (AQP1) and end-feet of astroglia cells in brain (AQP4). Bacopa monnieri has been used in traditional Indian medicine for centuries to improve memory. Recent study has demonstrated the antitumor effect of bacopa in several cancer cell lines in which AQP expression is upregulated [1]. We hypothesized the block of AQP water channel by bacopa and its derived molecules. Whole bacopa plant was dried and extracted in methanol reflux. We show that the osmotic water flux in AQP1-expressing Xenopus lavis oocytes was reduced by pre-incubation in saline containing bacopa methanol extract (BME). BME was further fractionated and the active compound has been identified as bacopaside I (BI) by both NMR and mass spectrography. BI inhibits AQP1 water permeability (IC₅₀ ˜ 118mM, applied extracellularly) but not AQP4. The efficacy of block was significantly impaired by mutagenesis of intracellular AQP1 arginines-159, 160 to alanines (R 159,160 A), which supports the binding of BI to the intracellular loop D region. In silico docking of BI further supported the loop D binding and suggested the occlusion of AQP1 water pore by BI. Our study identified BI, a phytochemical isolated from medicinal plant Bacopa monnieri, is an AQP type-selective pharmacological agent. With further in vivo study and chemical modification, BI will be a breakthrough strategy in treatment of AQP1 related disorders.

Fig. 1 An active component of Bacopa monnieri, Bacopaside I (insert) causes dose-dependent block of wild type AQP1 but not AQP4 channels.

References:

[1] Peng L, Zhou Y, Kong de Y et al. Antitumor activities of dammarane triterpene saponins from Bacopa monniera. Phytotherapy research: PTR 2010; 24: 864 – 868