Effects of hyperforin on the fluidity of brain membranes.

Hyperforin, an acylphloroglucinol derivative isolated from Hypericum perforatum (St. John's wort, SJW), affects several ionic conductance mechanisms in brain cells by an as yet unknown mechanism. We tested the effects of hyperforin on the fluidity of crude brain membranes from young guinea pigs. We performed fluidity measurements with three different fluorescent probes. Diphenylhexatriene (DPH) and trimethylammonium-diphenylhexatriene (TMA-DPH) anisotropy measurements were inversely correlated with the flexibility of fatty acids in the membrane hydrocarbon core and in the hydrophilic area of membrane phospholipids, respectively. The ratio of pyrene excimer to monomer fluorescence intensities was used as an indicator of membrane annular and bulk fluidity. Incubation of brain membranes with relatively high concentrations of hyperforin sodium salt (10 micromol/l) resulted in increased DPH and decreased TMA-DPH anisotropy, respectively, indicating that hyperforin modifies specific membrane structures in different ways. It decreases the flexibility of fatty acids in the membrane hydrocarbon core, but fluidizes the hydrophilic region of membrane phospholipids. Interestingly, relatively low concentrations of hyperforin (0.3 micromol/l) significantly decreased the annular fluidity of lipids close to membrane proteins. These findings are remarkable, as inhibition of several neurotransmitter-uptake systems and modulation of several ionic conductance mechanisms by hyperforin occur in the same concentration range. However, bulk fluidity was unchanged by this low hyperforin concentration. The results emphasise a physicochemical interaction of hyperforin with specific membrane structures that probably contribute to its novel pharmacological properties.