In Vitro and In Vivo Characterization of the Alkaloid Nuciferine

Abstract

RationaleThe sacred lotus (Nelumbo nucifera) contains many phytochemicals and has a history of human use. To determine which compounds may be responsible for reported psychotropic effects, we used in silico predictions of the identified phytochemicals. Nuciferine, an alkaloid component of Nelumbo nucifera and Nymphaea caerulea, had a predicted molecular profile similar to antipsychotic compounds. Our study characterizes nuciferine using in vitro and in vivo pharmacological assays.MethodsNuciferine was first characterized in silico using the similarity ensemble approach, and was followed by further characterization and validation using the Psychoactive Drug Screening Program of the National Institute of Mental Health. Nuciferine was then tested in vivo in the head-twitch response, pre-pulse inhibition, hyperlocomotor activity, and drug discrimination paradigms.ResultsNuciferine shares a receptor profile similar to aripiprazole-like antipsychotic drugs. Nuciferine was an antagonist at 5-HT2A, 5-HT2C, and 5-HT2B, an inverse agonist at 5-HT7, a partial agonist at D2, D5 and 5-HT6, an agonist at 5-HT1A and D4 receptors, and inhibited the dopamine transporter. In rodent models relevant to antipsychotic drug action, nuciferine blocked head-twitch responses and discriminative stimulus effects of a 5-HT2A agonist, substituted for clozapine discriminative stimulus, enhanced amphetamine induced locomotor activity, inhibited phencyclidine (PCP)-induced locomotor activity, and rescued PCP-induced disruption of prepulse inhibition without induction of catalepsy.ConclusionsThe molecular profile of nuciferine was similar but not identical to that shared with several approved antipsychotic drugs suggesting that nuciferine has atypical antipsychotic-like actions.

Pharmacological profiling an abundantly expressed schistosome serotonergic GPCR identifies nuciferine as a potent antagonist

“…Aporphine compounds isolated from Nelumbo nucifera leaves have been previously shown to have anticestodal profiles, with the mechanistic basis for these effects being ascribed to a free radical scavenging effect (Lin et al., 2014). A more recent study investigating the psychotropic properties of nuciferine demonstrated an affinity for several mammalian serotonergic GPCRs, encompassing action as an inverse agonist at the human 5-HT 7 receptor (Hs.5HT 7 R (Farrell et al., 2016)). Hs.5HT 7 R is the closest human homolog of Sm.5HTR L , the abundantly expressed schistosome serotonergic GPCR that controls parasite movement (Patocka et al., 2014, Chan et al., 2016b).…”

“…Several aporphine compounds have previously been demonstrated to impair neuromuscular function in a variety of helminth parasites (Ayers et al., 2007, Chan et al., 2014, Lin et al., 2014), although the molecular target of these drugs in parasites is uncharacterized. The affinity of aporphinoids for mammalian 5-HT GPCRs (Munusamy et al., 2013, Ponnala et al., 2014, Ponnala et al., 2015, Farrell et al., 2016) was especially intriguing to us in this context. Here, we examine the action of four aporphinoid natural products at Sm.5HTR L and demonstrate a close correlation between receptor blockade and a hypomotive action on schistosome larvae and adults.…”

A Comprehensive Review on Chemical Profiling of Nelumbo Nucifera: Potential for Drug Development

“…Nuciferine has been reported to have a receptor profile similar to aripiprazole-like antipsychotic drugs. Administration of nuciferine blocked head-switch responses and enhanced amphetamine-induced locomotor activity suggesting the (Farrell et al, 2016). Administration of hydroalcoholic extract of flowers from N. nucifera inhibited acetylcholinesterase and monoamine oxidases (MAO-A and MAO-B) activities in hippocampus of stress-induced rats, suggesting that N. nucifera extract could be a potential neuroprotective and memory enhancing agent (Prabsattroo et al, 2016).…”

The Blue Lotus Flower (Nymphea caerulea) Resin Used in a New Type of Electronic Cigarette, the Re-Buildable Dripping Atomizer

“…Nuciferine is an antagonist at 5-HT 2A , 5-HT 2C , and 5-HT 2B , an inverse agonist at 5-HT 7 , a partial agonist at D2, D5 and 5-HT 6 , an agonist at 5-HT 1A and D4 receptors, and inhibits the dopamine transporter (Farrell et al 2016). Behavioral effects produced in rats include catalepsy, potentiation of hexobarbitone hypnosis, morphine analgesia, and anticonvulsant action (Bhattacharya et al 1978).…”

“…Behavioral effects produced in rats include catalepsy, potentiation of hexobarbitone hypnosis, morphine analgesia, and anticonvulsant action (Bhattacharya et al 1978). It has been suggested that nuciferine may have potential therapeutic applications as an anti-psychotic drug (Farrell et al 2016) and on vascular diseases associated with aberrant vasoconstriction (Wang et al 2015). …”