Kang Tai-Hyun, Murakami Yukihisa, Matsumoto Kinzo, Takayama Hiromitsu, Kitajima Mariko, Aimi Norio, Watanabe Hiroshi
Department of Pharmacology, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
Eur J Pharmacol. 2002 Nov 22;455(1):27-34. doi: 10.1016/s0014-2999(02)02581-5.
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 microM) 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 IC(50) values of rhynchophylline and isorhynchophylline were 43.2 and 48.3 microM, respectively. Substitution of Ba(2+) for Ca(2+) 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 microM) significantly reduced the maximal current responses evoked by NMDA and glycine (a co-agonist of NMDA receptor), but had no effect on the EC(50) values and Hill coefficients of NMDA and glycine for inducing currents. These alkaloids showed no interaction with the polyamine binding site, the Zn(2+) 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.
钩藤碱和异钩藤碱是钩藤属植物的主要四环氧化吲哚生物碱成分，钩藤属植物长期以来一直被用作药用植物。在本研究中，使用注射了从大鼠皮层或小脑制备的总RNA的非洲爪蟾卵母细胞，检测了钩藤碱和异钩藤碱对离子型和代谢型谷氨酸受体介导的电流反应的影响。钩藤碱和异钩藤碱（1-100微摩尔）本身未能诱导膜电流，但这些生物碱以浓度依赖性但电压非依赖性的方式可逆地降低了N-甲基-D-天冬氨酸（NMDA）诱导的电流。钩藤碱和异钩藤碱的半数抑制浓度（IC50）值分别为43.2和48.3微摩尔。在记录介质中用钡离子（Ba2+）替代钙离子（Ca2+）不会改变钩藤碱和异钩藤碱诱导的NMDA电流抑制程度。相反，这两种生物碱对离子型海人藻酸型和（±）-α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）型谷氨酸受体或代谢型谷氨酸受体（1和5）（mGlu(1/5)）介导的电流均无影响。钩藤碱和异钩藤碱（30微摩尔）显著降低了NMDA和甘氨酸（NMDA受体的协同激动剂）诱发的最大电流反应，但对NMDA和甘氨酸诱导电流的半数有效浓度（EC50）值和希尔系数没有影响。这些生物碱在NMDA受体上与多胺结合位点、锌离子（Zn2+）位点、质子位点或氧化还原调节位点均无相互作用。这些结果表明，钩藤碱和异钩藤碱作为NMDA受体的非竞争性拮抗剂，这一特性可能有助于钩藤属植物提取物的神经保护和抗惊厥活性。
