title: Protective effect of rhynchophylline and isorhynchophylline on in vitro ischemia-induced neuronal damage in the hippocampus: putative neurotransmitter receptors involved in their action.
abstract: Rhynchophylline and isorhynchophylline are major tetracyclic oxindole alkaloid components of Uncaira species, which have been long used as medicinal plants. In this study we examined the protective effects of rhynchophylline and isorhynchophylline on in vitro ischemia-induced neuronal damage in the hippocampus and interaction of these alkaloids with neurotransmitter receptors in a receptor expression model of Xenopus oocytes. In vitro ischemia was induced by exposing the hippocampal slices to oxygen- and D-glucose-deprived medium over 8 min. The resultant neuronal damage was elucidated as deterioration of population spike (PS) amplitudes evoked trans-synaptically by electrical stimulation of Schaffer collaterals and recorded in the CA1 area. Rhynchophylline and isorhynchophylline, as well as the N-methyl-D-aspartate (NMDA) antagonist (+/-)-2-amino-5-phosphono-valeric acid (APV), the muscarinic M1 receptor antagonist pirenzepine, and the 5-HT2 receptor antagonist ketanserin, attenuated the in vitro ischemia-induced neuronal damage in a concentration-dependent manner. There was no difference in the extent of protection against the neuronal damage between rhynchophylline and isorhynchophylline treatment. In Xenopus oocytes expressing the rat brain receptors encoded by total RNA, both rhynchophylline and isorhynchophylline reduced muscarinic receptor- and 5-HT2 receptor-mediated current responses in a competitive manner. Together with our previous findings that rhynchophylline and isorhynchophylline have a non-competitive antagonistic effect on the NMDA-type ionotropic glutamate receptors, the present results suggest that these alkaloids exert their protective action against ischemia-induced neuronal damage by preventing NMDA, muscarinic M1, and 5-HT2 receptors-mediated neurotoxicity during ischemia.
authors.affiliation: Division of Pharmacology, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Tai-Hyun
authors.initials: TH
authors.lastname: Kang
authors.forename: Yukihisa
authors.initials: Y
authors.lastname: Murakami
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Takayama
authors.forename: Mariko
authors.initials: M
authors.lastname: Kitajima
authors.forename: Norio
authors.initials: N
authors.lastname: Aimi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Kinzo
authors.initials: K
authors.lastname: Matsumoto
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D002545:Brain Ischemia / Q000517:prevention & control; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D066298:In Vitro Techniques; D026121:Indole Alkaloids; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D009865:Oocytes / Q000187:drug effects; D000078183:Oxindoles; D010890:Pirenzepine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D032070:Uncaria / Q000737:chemistry*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D000470:Alkaloids; D026121:Indole Alkaloids; D000078183:Oxindoles; D010890:Pirenzepine; C052714:rhyncophylline; C056639:2-amino-5-phosphopentanoic acid; D007650:Ketanserin; D014633:Valine