Rhynchophylline and isorhynchophylline inhibit NMDA receptors expressed in Xenopus oocytes

Rhynchophylline and isorhynchophylline are major tetracyclic oxindole alkaloid components of Uncaira species, which have been long used as medicinal plants. In this study, the effects of rhynchophylline and isorhynchophylline on the ionotropic and metabotropic glutamate receptor-mediated current responses were examined using Xenopus oocytes injected with total RNA prepared from rat cortices or cerebelli. Rhynchophylline and isorhynchophylline (1-100 muM) per se failed to induce membrane current, but these alkaloids reversibly reduced N-methyl-D-aspartate (NMDA)-induced current in a concentration-dependent but voltage-independent manner. The IC50 values of rhynchophylline and isorhynchophylline were 43.2 and 48.3 muM, respectively Substitution of Ba2+ for Ca2+ in the recording medium did not alter the extent of rhynchophylline- and isorhynchophylline-induced suppression of NMDA currents. In contrast, neither alkaloid had an effect on the currents mediated by ionotropic kainic acid-type and (+/-)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors or by the metabotropic glutamate receptor(1 and 5) (mGlu(1/5)). Rhynchophylline and isorhynchophylline (30 muM) significantly reduced the maximal current responses evoked by NMDA and glycine (a co-agonist of NMDA receptor), but had no effect on the EC50 values and Hill coefficients of NMDA and glycine for inducing currents. These alkaloids showed no interaction with the polyamine binding site, the Zn2+ site, proton site or redox modulatory site on the NMDA receptor. These results suggest that rhynchophylline and isorhynchophylline act as noncompetitive antagonists of the NMDA receptor and that this property may contribute to the neuroprotective and anticonvulsant activity of the Uncaira species plant extracts. (C) 2002 Elsevier Science B.V. All rights reserved.