MINI REVIEW
published: 15 February 2016
doi: 10.3389/fphar.2016.00028
Plant Alkaloids as an Emerging
Therapeutic Alternative for the
Treatment of Depression
Sadia Perviz, Haroon Khan * and Aini Pervaiz
Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan, Pakistan
Depression is a heterogeneous mood disorder that has been classified and treated in
a variety of ways. Although, a number of synthetic drugs are being used as standard
treatment for clinically depressed patients, but they have adverse effects that can
compromise the therapeutic treatments and patient’s compliance. Unlike, synthetic
medications, herbal medicines are widely used across the globe due to their wide
applicability and therapeutic efficacy associated with least side effects, which in turn has
initiated the scientific research regarding the antidepressant activity. This review is mostly
based on the literature of the last decade, aimed at exploring the preclinical profile of
plant-based alkaloids (the abundant secondary metabolite) as an emerging therapy for
depression.
Keywords: plants, alkaloids, antidepressant effects, multiple mechanisms, future therapies
Edited by:
Ashok Kumar,
University of Florida, USA
Reviewed by:
Yogesh Dwivedi,
University of Alabama at Birmingham,
USA
Kunjan Dave,
University of Miami, USA
*Correspondence:
Haroon Khan
hkdr2006@gmail.com
Specialty section:
This article was submitted to
Neuropharmacology,
a section of the journal
Frontiers in Pharmacology
Received: 11 January 2016
Accepted: 31 January 2016
Published: 15 February 2016
Citation:
Perviz S, Khan H and Pervaiz A (2016)
Plant Alkaloids as an Emerging
Therapeutic Alternative for the
Treatment of Depression.
Front. Pharmacol. 7:28.
doi: 10.3389/fphar.2016.00028
INTRODUCTION
Depression is a state of low mood and aversion to activity that can affect a person’s thoughts,
behavior, feelings and sense of well-being (Sandra, 1997; Rosenbaum et al., 2016). People with
depressed mood can feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable,
ashamed, or restless. They may lose interest in activities that were once pleasurable, experience loss
of appetite or overeating (Ingram, 2016). Physical changes also occur, particularly in severe, vital,
or melancholic depression. These include insomnia or hypersomnia; altered eating patterns, with
anorexia and weight loss or sometimes overeating; decreased energy and libido; and disruption of
the normal circadian and ultradian rhythms of activity, body temperature, and many endocrine
functions (Tondo et al., 2003). The depressed mood is a feature of some psychiatric syndromes
such as major depressive disorder, but it may also be a normal reaction to living events such as
bereavement, a symptom of some bodily ailments or a side effect of some drugs and medical
treatments. Patients with major depression have symptoms that reflect changes in the brain,
monoamine neurotransmitters, specifically norepinephrine, serotonin, and dopamine (Gold et al.,
1988). Some features of depressive disorder overlap those of the anxiety disorders, including severe
phobias, generalized anxiety disorder, social anxiety disorder, post-traumatic stress disorder, and
obsessive-compulsive disorder (Muhammad et al., 2013). The disorder is also often associated with
suicide and there are between 10 and 20 million suicide attempt every year (Calvó-Perxas et al.,
2016; Gadassi and Mor, 2016). According to World Health Report, about 450 million people suffer
from a mental or behavioral disorder. This amounts to 12.3% of the global burden of disease and
predicted to rise up to 15% by 2020 (Ridout et al., 2016).
The current antidepressant drugs are facing many challenges as mentioned by Alexander and
Preskorn (2014), in his review published on the same issue (Alexander and Preskorn, 2014).
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Plant Alkaloids and Depression
an active compound found in Ziziphus apetala which showed
strong activity against 11-β-hydroxysteroid dehydrogenase
inhibition in vitro (Han et al., 2011). The diterpene alkaloids
(Napelline, songorine, hypaconitine, and mesaconitine) has been
isolated from Aconitum baicalens exhibited an antidepressantlike effect in an animal model of depression (Nesterova et al.,
2011). An Dhingra and Valecha (2014) isolated Punaravine an
alkaloid from Boerhaavia diffusa Linn. It showed significant
antidepressant activity in unstressed and stressed mice in
different models (Dhingra and Valecha, 2014). Jiang et al. (2015)
purified Evodamine from Evodia fructus and found that it
could reverse the decreases of sucrose preference, a number of
crossing, 5-HT, and Na level and also increase immobility time
(Jiang et al., 2015). A group of researcher led by Loria et al.
(2014) from the USA established that Mesembrine present in
Sceletium tortuosum have antidepressant property in animal
studies (Loria et al., 2014). Wattanathorn and his field workers
from Thailand assessed that Piperine, a major alkaloid isolated
from Piper nigrum. Its antidepressant activity has been observed
in mice exposed to both chronic and acute stress. It caused a
significant change in both immobility and swimming times
(Wattanathorn et al., 2008). A team from the China School of
Pharmacy isolated Leatispicine, an amide alkaloid from Piper
laetispicum. When tested in the forced swim test, it caused a
significant dose-dependent decrease in mobility at various test
doses and thus possessed antidepressant activity (Yao et al.,
2009). Xu and coworkers obtained protopine from a Chinese
plant, Dactylicapnos scandens Hutch, had an antidepressant
effect in mice. It dose-dependently reduced the immobility
time in the tail suspension test and thus could be effective for
the moderate state of depression (Xu et al., 2006). Addition
to all those, pramipexole is a non-ergoline alkaloid showed
significant clinical efficacy in a double-blind, placebo-controlled
study in bipolar and unipolar depressive patients (Zarate et al.,
2004).
They pointed out that even the first line antidepressants such
as the selective serotonin reuptake inhibitors (SSRIs) and
serotonin-norepinephrine reuptake inhibitors have limitation
like poor response and remission rates, slow onset of action,
poor tolerability, persistent adverse effects, and the potential
for clinically significant pharmacokinetic drug interactions. It is,
therefore, the novel antidepressant is required to be free from
above limitations.
Alkaloids are a group of naturally occurring chemical
compounds that contain mostly basic nitrogen atoms. This group
also includes some related compounds with neutral (McNaught
and Wilkinson, 1997) and even weakly acidic properties (Manske,
1965). Alkaloids are produced by a large variety of organisms,
including bacteria, fungi, plants, and animals, and are part of
the group of natural products (also called secondary metabolites).
Many alkaloids can be purified from crude extracts by acid-base
extraction. Many alkaloids are toxic to other organisms. They
often have pharmacological effects and are used as medications,
as recreational drugs, or in entheogenic rituals. The present
review contained a detail note of the antidepressant activity of
various plants alkaloids and are a candidate for further detail
studies to evaluate their clinical utility.
ALKALOIDS—AS ANTIDEPRESSANT
AGENTS
The antidepressant effect of various plant alkaloids has been
reported in the literature (Table 1). Brazilian group of researcher
isolated strictosidinic acid from Psychotria myriantha Mull.
which exhibited antidepressant-like effect when studied on
a 5-HT system in rat hippocampus (Farias et al., 2012). Lee
et al. (2012) showed that berberine administration significantly
decreased immobility and increased climbing behavior in the
Forced swim test. However, there was no effect on swimming
time, while increased open-arm exploration in the elevated
plus maze test which confirmed that the antidepressant-like
activity (Lee et al., 2012). Martínez-Vázqueza et al. (2012)
isolated certain alkaloids from Annona cherimolia, including
1,2-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzoquinoline3,8,9,10-tetraol, anonaine, liriodenine, and nornuciferine. The
results showed that repeated treatment with this plant produced
an antidepressant-like action in mice (Martínez-Vázqueza et al.,
2012). The β-carboline alkaloids such harmane, norharmane, and
harmine dose-dependently reduced the immobility time in the
mouse forced swim test and thus produced an antidepressantlike effect (Farzin and Mansouri, 2006). A team of the researcher
isolated Akuammidine, rhaziminine, and tetrahydrosecamine
from Rhazya stricta. Acute administration of the lyophilized
extract of R. stricta resulted in a significant antidepressant-like
effect in experimental animals (Ali et al., 1998). Idayu and
his co-researchers from Malaysia (2011) isolated mitagynine
as an active component of Mitagyna spicosa. Mitagynine i.p
injection significantly reduced the immobility time of mice
in both forced swim test and tail suspension test without any
significant effect on locomotor activity (Idayu et al., 2011).
A team from the Republic of China outlined Mauritine A as
Frontiers in Pharmacology | www.frontiersin.org
ANTIDEPRESSANT MECHANISM (S) OF
PLANTS ALKALOIDS
Strictosidinic acid probably exhibited antidepressant effect due to
an inhibition of monoamine oxidase activity (Farias et al., 2012).
1,2-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzoquinoline3,8,9,10-tetraol, anonaine, liriodenine, and nornuciferine
produced an antidepressant-like action from a generalized
increase in monoaminergic turnover (Martínez-Vázqueza
et al., 2012). Berberine, an isoquinoline alkaloid of barberry
demonstrated antidepressant like effect mediated through
serotonergic, noradrenergic, and dopaminergic intervention
(Kulkarni and Dhir, 2008; Lee et al., 2012). The β-carboline
alkaloids (harmane, norharmane, and harmine) provoked
antidepressant-like effects by interfering with MAO-A and
several cell-surface receptors, including serotonin receptor
2A (Glennon et al., 2000; Kim et al., 2001). Akuammidine,
rhaziminine, and tetrahydrosecamine possible mechanism
resulted in a biphasic effect on the MAOA inhibitory
component of tribulin (Ali et al., 1998). Mitagynine
2
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Plant Alkaloids and Depression
TABLE 1 | List of isolated alkaloids with plant alkaloids with antidepressant effect.
Plant name
Structure
Berberis aristata
Mechanism
References
Serotonergic, noradrenergic, and
dopaminergic interventions
Kulkarni and Dhir, 2008; Lee
et al., 2012
MAO inhibition
Farias et al., 2012
Increase in monoaminergic
turnover
Martínez-Vázqueza et al., 2012
MAOA inhibition
Ali et al., 1998
Berberine
Psychotria myriantha
Strictosidine acid
Annona cherimolia
Anonaine
Liriodenine
Rhazya stricta
Akuammine
(Continued)
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Plant Alkaloids and Depression
TABLE 1 | Continued
Plant name
Structure
Mitagyna speciosa
Mechanism
References
Reducing the release of
corticosterone
Idayu et al., 2011
Interfering with MAO-A and
several cell-surface receptors,
including serotonin receptor 2A
Farzin and Mansouri, 2006
11-β-hydroxysteroid
dehydrogenase inhibition
Han et al., 2011
Improved serotonergic system
Nesterova et al., 2011
Mitagynine
Peganum harmala
Norharmane
Harmane
Harmine
Ziziphus apetala
Mauritine A
Aconitum baicalense
Songorine
(Continued)
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Plant Alkaloids and Depression
TABLE 1 | Continued
Plant name
Structure
Boerhaavia diffusa
Mechanism
References
MAO inhibition and decreased
plasma corticosterone level
Dhingra and Valecha, 2014
Effects on the monoamine
transmitters and BDNF-TrkB
signaling in the hippocampus
Jiang et al., 2015
5HT reuptake inhibition
Loria et al., 2014
Inhibition of MAO enzymes,
elevation of brain 5-HT and
BDNF levels
Wattanathorn et al., 2008
Mechanism not studied yet
Yao et al., 2009
Inhibition of serotonin transporter
and Noradrenaline transporter
Xu et al., 2006
Punarnavine E
Evodia fructus
Evodiamine
Sceletrium tortuosum
Mesembrine
Piper nigrum
Piperine
Piper laetispicum
Leatispicine
LeatispiamideA
Dactylicapnos scanens
protopine
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Plant Alkaloids and Depression
CONCLUSION
exhibited antidepressant-like action by reducing the release
of corticosterone (Idayu et al., 2011). Mauritine A show strong
activity against 11-β-hydroxysteroid dehydrogenase inhibition
in vitro and, therefore, could be the possible mechanism for its
antidepressant effect (Han et al., 2011). The diterpene alkaloids
of Aconitum baicalense, improved serotonergic system activity
in an animal model of depression (Nesterova et al., 2011).
Punaravin E acts probably through inhibition of MAOA activity
in the brain and, in addition, it also showed antidepressant
activity possibly through decreased plasma corticosterone level
(Dhingra and Valecha, 2014). The underlying mechanism of
Evodamine can be potentially linked to their modulating effects
on the monoamine transmitters and BDNF-TrkB signaling
in the hippocampus (Jiang et al., 2015). Mesembrine an
alkaloid elicited its antidepressant effect by inhibiting 5HT
reuptake (Loria et al., 2014). Piperine is reported to increase
the serotonin level in the cerebral cortex and limbic areas
and thus produced the anti-depression like activity. However,
further investigations about precise underlying mechanism
are still required (Wattanathorn et al., 2008). Leatispicine
mechanisms of action were presumed to be acting on the central
nervous system monoaminergic neurotransmitters (Yao et al.,
2009). Protopine is identified as an inhibitor of both serotonin
transporter and noradrenaline transporter in vitro assays (Xu
et al., 2006).
Our review on the basis of available literature suggested that
alkaloids could play a potential role as natural antidepressants.
Keeping in mind their abundance in nature, the alkaloids could
be an economical source of healing the depressive disorder.
The available therapeutic agents fail to produced effect in all
patients; approximately 30–40% failure has been reported to
first-line antidepressant drugs accompanied by the very slow
onset of action. Several alkaloids are in clinical practice and
producing outstanding results in different therapeutic classes.
These reported alkaloids though evoked antidepressant effects
in various animal studies, but still deficient in clinical evidence.
In conclusion, enough scientific evidence gathered in our review
supported that the plant-based alkaloids can serve as leads for
antidepressant drug discovery. It is key to subject these alkaloids
to further clinical studies for efficacy, potency, and safety to
ensure their clinical status.
AUTHOR CONTRIBUTIONS
SP carried out all the literature survey and written an initial draft
of the review and AK draw the structures of compounds and help
in review-draft. HK supervised the overall project and finalized
the final version of the review.
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Conflict of Interest Statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Copyright © 2016 Perviz, Khan and Pervaiz. This is an open-access article
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