J Pharm Pharmacol. 2015 Dec;67(12):1716-22. doi: 10.1111/jphp.12473.

Serotonergic mechanisms are involved in antidepressant-like effects of bisbenzylisoquinolines liensinine and its analogs isolated from the embryo of Nelumbo nucifera Gaertner seeds in mice.

Sugimoto Y1,2, Nishimura K2, Itoh A2, Tanahashi T2, Nakajima H3, Oshiro H4, Sun S4, Toda T5, Yamada J5.
  • 1Department of Pharmacology, Faculty of Pharmaceutical Sciences, Yasuda Women’s University, Hiroshima, Japan.
  • 2Department of Organic Chemistry, Kobe Pharmaceutical University, Kobe, Japan.
  • 3Research Center for Industry Innovation, Osaka City University, Osaka, Japan.
  • 4Shanghai University of Traditional Chinese Medicine, Osaka, Japan.
  • 5Laboratory of Pharmacology, Department of Clinical Pharmacy, Yokohama College of Pharmacy, Yokohama, Japan.




We attempted to ascertain if bisbenzylisoquinoline alkaloids, liensinine and isoliensinine from Nelumbo nucifera Gaertner have antidepressant-like effects and compare the effects with those previously obtained by their analogue neferine.


Using mice, the forced swimming test (FST) was carried out after treatment with liensinine, isoliensinine and neferine.


Liensinine and isoliensinine elicited antidepressant-like effects in mice after the FST. Anti-immobility effects of liensinine and isoliensinine were antagonized by the 5-hydroxytryptamine1 A (5-HT1 A ) receptor antagonist WAY 100635, but not by the α1 -adrenoceptor antagonist prazosin. The anti-immobility effects of liensinine, isoliensinine and neferine were blocked by pretreatment with p-chlorophenylalanine (PCPA), which depletes serotonin (5-HT).


These data suggest that liensinine and isoliensinine from Nelumbo nucifera Gaertner have antidepressant-like effects and that antidepressant-like effects of liensinine and its analogues are closely related to serotonergic mechanisms.

KEYWORDS: Liensinine; Nelumbo nucifera Gaertner; antidepressant-like effects; isoliensinine; neferine

PMID: 26246025



Natural compounds that may be effective for the treatment of psychiatric disorders such as depression and anxiety have been isolated from medicinal plants. Nelumbo nucifera Gaertner is distributed in all parts of the world. Several parts of this plant (e.g., leaves, flowers, rhizomes) contain useful compounds such as flavonoids and alkaloids. Embryos of the seeds of Nelumbo nucifera Gaertner are used widely as Chinese traditional medicines presenting sedative, antipyretic and hypothermic effects in humans. Embryos of these seeds contain the bisbenzylisoquinoline alkaloids neferine, liensinine, or isoliensinine (Fig.1).


Fig.1 sugimoto-2


However, the detailed effects and mechanisms of pharmacologic action of bisbenzylisoquinoline alkaloids on the central nervous system (CNS) have not been investigated. Previously, we reported that the major alkaloid neferine reduces locomotor activity, elicits hypothermia, and potentiates thiopental-induced sleep in mice (1). Furthermore, we reported that neferine has anxiolytic effects similar to those of diazepam in the elevated plus maze test(1). In addition, neferine was shown to have antidepressant-like effects in mice when using the forced swimming test (FST) (2).

Recently, we found that liensinine and isoliensinine reduce locomotor activity (i.e., have sedative effects) in mice (3). These results raise the possibility that liensinine and isoliensinine may have antidepressant effects similar to those of neferine. Hence, we studied the effects of liensinine and isoliensinine on immobility in the FST and compared these effects with those of neferine. Further, the involvement of serotonergic and noradrenergic systems in antidepressant-like effects of liensinine, isoliensinine as well as neferine were examined.

We found that the bisbenzylisoquinoline alkaloids liensinine and isoliensinine induced antidepressant-like effects in mice (Fig.2). The selective 5-HT1A receptor antagonist WAY 100635 significantly reduced the anti-immobility effects of liensinine and isoliensinine. These results suggest that liensinine and isoliensinine elicit antidepressant-like effects through 5-HT1A receptors. The 5-HT deplete PCPA inhibited anti-immobility effects of neferine, liensinine and isoliensinine. The finding with PCPA suggested that bisbenzylisoquinolines were not direct 5-HT1A receptor agonists and that they modify neurotransmission at presynaptic sites. Our results suggest that the antidepressant-like effects of bisbenzylisoquinoline alkaloids are closely associated with serotonergic mechanisms.

Fig.2 Sugimoto



  1.  Sugimoto Y, Furutani S, Itoh A, Tanahashi T, Nakajima H, Oshiro H, Sun S, Yamada J. Effects of extracts and neferine from the embryo of Nelumbo nucifera seeds on the central nervous system. Phytomedicine 2008; 15: 1117-1124.
  2. Sugimoto Y, Furutani S, Nishimura K, Itoh A, Tanahashi T, Nakajima H, Oshiro H, Sun S, Yamada J. Antidepressant-like effects of neferine in the forced swimming test involve the serotonin1A (5-HT1A) receptor in mice. Eur J Pharmacol 2010; 634: 62-67.
  3. Nishimura K, Horii S, Tanahashi T, Sugimoto Y, Yamada J. Synthesis and pharmacological activity of alkaloids from embryo of lotus, Nelumbo nucifera. Chem Pharm Bull (Tokyo) 2013; 61: 59-68.



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