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Journal of Biosciences and Medicines, 2019, 7, 22-34
http://www.scirp.org/journal/jbm
ISSN Online: 2327-509X
ISSN Print: 2327-5081
DOI:
10.4236/jbm.2019.77003 Jul. 11, 2019 22
Journal of Biosciences and Medicines
Morinda citrifolia (Noni) Fruit Juice Inhibits
Endocannabinoid Degradation Enzymes
Brett J. West, Shixin Deng, C. Jarakae Jensen
Research and Development, Morinda, Inc., American Fork, Utah, USA
Abstract
Morinda citrifolia
(noni) fruit juice has been shown to have a
wide variety of
potential health benefits in human clinical trials. It may also influence the
endocannabinoid system of the body. Since the main ingredient of the prod-
uct studied in these clinical trials was juice made from noni fruit puree from
French Polynesia, it was evaluated for its ability to inhibit the two major en-
docannabinoid degradation enzymes
in vitro
. Noni fruit juice inhibited both
fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) in a
concentration-dependent manner, sugges
ting that it may help maintain
anandamide and 2-arachidonoylglycerol levels. Samples of the puree were al-
so analyzed for the presence of characteristic phytochemical markers of au-
thentic noni fruit such as scopoletin, rutin, quercetin, deacetylasperulosidic
acid and asperulosidic acid,
all of which were present. Also present was
scandoside,
which is reported for the first time as being identified in noni
fruit or its juice. Some of these compounds may contribute to the FAAH and
MAGL inhibiting activity of
noni juice. These results reveal another set of
mechanisms by which noni juice possibly supports mental health,
maintains
joint health, relieves discomfort and modulates the immune system.
Keywords
Morinda citrifolia
, Endocannabinoid System, Fatty Acid Amide Hydrolase,
Monoacylglycerol Lipase
1. Introduction
The endocannabinoid system (ECS) serves an important regulatory function
within the human body. It influences the nervous and immune systems exten-
sively and has an impact on digestion, reproduction and bone mass [1] [2]. The
ECS also has interrelations with the respiratory, renal, endocrine and cardiovas-
How to cite this paper:
West, B.J.,
Deng,
S.X. and
Jensen, C.J. (2019)
Morinda citr
i-
folia
(Noni) Fruit Juice Inhibits Endocan-
nabinoid Degradation Enzymes
.
Journal of
Biosciences and Medicines
,
7
, 22-34.
https://doi.org/10.4236/jbm.2019.77003
Received:
May 22, 2019
Accepted:
July 8, 2019
Published:
July 11, 2019
Copyright © 201
9 by author(s) and
Scientific
Research Publishing Inc.
This work is licensed
under the Creative
Commons Attribution International
License (CC BY
4.0).
http://creativecommons.org/licenses/by/4.0/
Open Access
B. J. West et al.
DOI:
10.4236/jbm.2019.77003 23
Journal of Biosciences and Medicines
cular systems [3] [4]. Indeed, the ECS has a wide effect on the body and helps
maintain overall health. The ECS is composed of G protein-coupled receptors
(GPCRs) within cell membranes, lipid signaling molecules (endocannabinoids)
and the enzymes responsible for endocannabinoid synthesis and catabolism. The
two most prominent ECS receptors are cannabinoid receptor type 1 (CB1) and
cannabinoid receptor type 2 (CB2). Other GPCRs, currently designated as or-
phan receptors, have been more recently discovered. There are two main endo-
cannabinoids produced by the body, N-arachidonoylethanolamine (anandamide
or AEA) and 2-arachidonoylglycerol (2-AG). AEA and 2-AG are synthesized
from arachidonic acid derivatives, N-arachidonoyl phosphatidylethanolamine
(NAPE) and diacylglycerol, by phospholipases and diacylglycerol lipases. AEA is
eventually degraded by fatty acid amide hydrolase (FAAH) to arachidonic acid
and ethanolamine. 2-AG is hydrolyzed by monoacylglycerol lipase (MAGL) and
FAAH [5]. AEA and 2-AG are CB1 and CB2 ligands, and it is through their in-
teractions with these receptors that many of their physiological effects are me-
diated [6].
Morinda citrifolia
is a small to medium sized tree that grows in tropical re-
gions. It is commonly known as noni or Indian mulberry. The tree produces
fruit year-round, which has been used as both food and medicine [7]. The leaves
and other plant parts also had significant roles in the Pacific, South Asian,
Southeast Asian, and the Caribbean traditional medicine [8]. The noni tree was
reportedly the most important and widely used Polynesian medicinal plant prior
to the European era [9]. Various parts of the plant were used by local healers for
a broad range of health conditions [10] [11] [12]. Traditional perceptions of the
health benefits of noni appear to be validated by the results of human clinicals
trials, especially those involving noni fruit juice. Among the recorded effects of
noni juice ingestion are control of inflammation, improved joint mobility, relief
of discomfort, immune system modulation, protection against oxidative damage,
maintenance of bone health, and improved mental health outcomes [13].
The array of noni juice benefits observed in human studies suggests that it in-
teracts with multiple bodily systems, among which the ECS may have a signifi-
cant role. In fact, we have previously reported that noni juice exhibits CB2 re-
ceptor agonist activity [14]. But as the major endocannabinoids produce effects
within the body that are similar to those reported for noni juice, we further in-
vestigated noni juice’s interaction with the ECS by assessing its potential to
maintain AEA and 2-AG levels through FAAH and MAGL inhibition.
2. Materials and Methods
Noni fruit was harvested in French Polynesia and allowed to fully ripen. The
fruit was then processed into a puree by mechanical removal of the seeds and
skin, followed by pasteurization at a good manufacturing certified fruit
processing facility in Mataiea, Tahiti. This source of noni fruit puree was ap-
proved by the European Commission in 2003 as a safe novel food for use in pas-
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Journal of Biosciences and Medicines
teurized beverages [15]. It was also later approved as a safe novel food ingredient
for use in a wide variety of food categories within the European Union [16]. For
our study, the noni fruit puree was centrifuged to remove insoluble fiber. The
resultant clarified juice was then filtered through a 0.45 μm PTFE filter.
Samples of this filtered noni juice were analyzed by high performance liquid
chromatography (HPLC), according to a previously validated method, for irido-
id markers of authentic noni fruit, including deacetylasperulosidic acid (DAA)
and asperulosidic acid (AA) [17]. As we have since discovered the presence of
scandoside in noni fruit by LC-MS analysis, we included this in our HPLC ana-
lyses. Samples were diluted with methanol-H2O (1:1) and filtered through a 0.45
µm nylon membrane filter. Chromatographic separation was performed with a
C-18 column (4.6 mm × 250 mm; 5 μm, Waters Corporation, Milford, MA,
USA). Two mobile phases were used: A; acetonitrile (MeCN), and B; 0.1% for-
mic acid in H2O (v/v). The elution rate was 0.8 mL/min. with consecutive linear
gradients of 100% B for 0 - 5 min. followed by 70% B and 30% A for 40 min. A
photodiode array (PDA) detector was used to monitor the eluted compounds
within 210 - 400 nm. Sample injection volume was 10 µL, and column tempera-
ture was 25˚C.
Analyses of scopoletin, rutin, and quercetin—additional phytochemical
markers of authentic noni fruit—were also performed by HPLC according to a
previously validated method [18]. Chromatographic separation was performed
on a Waters 2690 separations module, coupled with a Waters 996 photodiode
array (PDA) detector, and a C-18 column. Three solvents were used to compose
the mobile phase. These were MeCN (solvent A), MeOH (solvent B), and 0.1%
formic acid in H2O (solvent C). The following linear gradient was used for the
separation: 0 min. of 10% A, 10% B, and 80% C; 15 min. of 20% A, 20% B, and
60% C; 26 min. of 40% A, 40% B, and 20% C; 28 - 39 min. of 50% A, 50% B, and
0% C; and 40 - 45 min. of 10% A, 10% B, and 80% C. The flow rate was 1.0
mL/min. Chromatograms were integrated at 365 nm. In both HPLC methods,
retention times and peak areas were compared against standards to determine
analyte concentrations in the samples.
The total polyphenol content of each sample was determined by the Fo-
lin-Ciocalteu method [19]. Samples were centrifuged and diluted 1:10 with deio-
nized water. Next, 10 µL of each sample was mixed with 50 µL Folin-Ciocalteu
(2N) and an additional 800 µL deionized water. The mixture was incubated at
room temperature for a few minutes, followed by addition of 150 µL Na2CO3
(saturated) and incubation at room temperature for 2 hours. Gallic acid stan-
dards were prepared with the same procedure. Afterwards, the absorbance of
each sample and standard was measured at 765 nm with a microplate reader.
Sample absorbance vs. gallic acid concentration was used to determine the total
phenol content of the samples, expressed as gallic acid equivalents (GAE).
FAAH and MAGL inhibition assays were carried out as previously described,
but with some modifications [20]. Human recombinant FAAH, human recom-
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Journal of Biosciences and Medicines
binant MAGL, 7-amino-4-methyl coumarin-arachidonamide (AMC-AA), and
4-nitrophenylacetate were obtained from Cayman Chemical Company (Ann
Arbor, MI, USA). For the FAAH inhibition assay, the recombinant FAAH was
diluted with Tris-HCl buffer (125 mM, pH 9.0) containing 1 mM EDTA. Noni
juice samples were added in varying volumes to separate wells of a black plastic
96-well microplate, with deionized water also being added to make up a total
volume of 10 μL. Vehicle control (no inhibitor) wells did not receive noni juice,
only water. Inhibitor (noni juice) and control wells received 10 μL FAAH solu-
tion as well as additional 170 μL of buffer. Background fluorescence wells, to
which no FAAH was added, received 180 μL buffer. The microplate was then
incubated for five minutes at 37˚C. Ten μL of AMC-AA solution was then added
to each well with a final concentration of 20 μM. The microplate was then incu-
bated again at 37˚C for 30 minutes. Following incubation, the fluorescence in-
tensity of each well was measured in a Synergy™ HT microplate reader (BioTek
Instruments, Winooski, VT, USA) with 360 ± 40 nm excitation and 460 ± 40 nm
emission. All samples and the control were evaluated in triplicate. The relative
increase in fluorescence intensity was determined by the ratio of the intensities
of the inhibitor well and its corresponding background well. Percent FAAH in-
hibition was calculated from the difference between the relative increase in fluo-
rescence intensity of the vehicle control and the sample divided by that of the ve-
hicle control alone. DAA, the major phytochemical constituent of noni fruit, was
also evaluated in this assay but with DMSO as the solvent and vehicle control.
In the MAGL inhibition assay, the recombinant MAGL was diluted with
Tris-HCl buffer (10 mM, pH 7.2) containing 1 mM EDTA. Noni juice samples
were added in varying volumes to separate wells of a clear plastic 96-well micro-
plate, with deionized water added to make up a total volume of 10 μL. As in the
previous assay, vehicle control (no inhibitor) wells only received water. Inhibitor
(noni juice) and control wells received 10 μL MAGL solution as well as
additional 150 μL of buffer. Background absorbance wells, with no MAGL, re-
ceived 160 μL buffer. The microplate was then incubated at room temperature
for five minutes. Enzymatic reactions were then begun by the addition of 10 μL
of 4-nitrophenylacetate in ethanol (236 μM in final reaction solution), which
proceeded at room temperature for 10 minutes. Absorbance at 405 nm was then
read with an ELX800 microplate reader (BioTek Instruments, Winooski, VT,
USA). All samples and the control were evaluated in triplicate. Absorbance val-
ues were corrected by subtracting background well values from those of corres-
ponding sample wells. Percent MAGL inhibition was calculated from the differ-
ence between control and sample absorbance divided by that of the absorbance
of just the control. Mean results, as well as standard deviations, were calculated
for each set of replicate samples in both the FAAH and MAGL inhibition assays.
3. Results and Discussion
HPLC analyses revealed that our noni juice samples contained phytochemical
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Journal of Biosciences and Medicines
constituents that are present in a commercial source of authentic noni juice that
has been reported to protect lymphocyte DNA, improve serum lipid profiles,
and reduce high-sensitivity C-reactive protein (hs-CRP) and homocysteine levels
of cigarette smokers [21] [22]. The concentrations (mean ± standard deviation)
of DAA, AA, scopoletin, rutin, and quercetin were, respectively, 1.3827 ± 0.0170,
0.4033 ± 0.0057, 0.0463 ± 0.0006, 0.0136 ± 0.0005 and 0.0014 ± 0.0001 mg/mL.
Scandoside, which is reported here for the first time in noni fruit or juice, was
present at 0.0823 ± 0.0153 mg/mL. The total polyphenol content was 0.8903 ±
0.0243 mg GAE/mL.
Noni juice inhibited FAAH activity in a concentration dependent manner,
Figure 1. Between 2.50 and 8.33 μ/mL, inhibition vs. noni juice concentration is
linear—reducing AMC-AA hydrolysis by (mean ± standard deviation) 25.22% ±
5.43% to 68.75% ± 5.03%. But above this range, the incremental decrease in
FAAH activity is much less, with suppression of 82.55% ± 0.55% enzyme activity
at 16.66 μL/mL. There was also a concentration-dependent suppression of
MAGL activity by noni juice, Figure 2. The lowest concentration, 2.78 μ/mL,
reduced hydrolysis of 4-nitrophenylacetate by 32.88% ± 3.62%. MAGL activity is
Figure 1. Inhibition of fatty acid amide hydrolase (FAAH) by increasing concentrations
of noni juice. Note: % inhibition by vehicle control (water) is zero.
Figure 2. Inhibition of monoacylglycerol lipase (MAGL) by increasing concentrations of
noni juice. Note: % inhibition by vehicle control (water) is zero.
B. J. West et al.
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Journal of Biosciences and Medicines
reduced by 55.71% ± 4.40% with 5.56 μL/mL and continues to decline until it is
completed prevented with 18.52 μL noni juice/mL.
These enzyme inhibition assays reveal that noni juice has the potential to in-
fluence AEA and 2-AG levels or prolong their interactions with CB1, CB2, and
the orphan G-protein receptors. This maintenance of endocannabinoid tone, or
levels, likely contributes to pain management since endocannabinoids accumu-
late at sites of injury and inflammation where they interact with cannabinoid re-
ceptors, transient receptor potential vanilloid 1 (TRPV1) ion channels and G
protein-coupled GPR55 receptors to produce analgesia and anti-inflammatory
effects [23] [24] [25]. Mice with a genetic deletion for FAAH had increased pain
tolerance in the tail flick test and the formalin and carrageenan models of in-
flammation [26]. A selective FAAH inhibitor, URB597, reduced neuropathic
pain in Sprague-Dawley rats. This analgesic effect was reduced when CB1 re-
ceptor and peroxisome proliferator-activated receptor alpha (PPAR alpha) an-
tagonists were administered before URB597 [27].
Selective MAGL inhibitors significantly reduced neuropathic pain (allodynia)
resulting from chronic constriction injury of the sciatic nerve [28]. The dual
FAAH/MAGL inhibitor JZL195 reduce allydonia, motor incoordination, and
catalepsy in C57BL/6 mice subjected to chronic constriction injury [29]. The
reduction in neuropathic pain in these animals was greater with the dual
FAAH/MAGL inhibitor than with selective FAAH or MAGL inhibitors alone.
This suggests that substances which impact both AEA and 2-AG levels are more
effective in treating pain and can do so at much lower doses, thus reducing the
potential for side effects.
The antinociceptive properties of noni juice have been demonstrated in mul-
tiple in vivo studies and in human clinical trials. Mice fed noni fruit puree for
four days experience reduced pain sensitivity; an effect comparable to the central
analgesic drug tramadol [30]. This was only partial reversed by naloxone, re-
vealing the involvement of other non-opioid mechanisms. The authors of this
study also reported that a noni fruit extract reduced matrix metalloproteinase-9
(MMP-9) from human monocytes following lipopolysaccharide (LPS) stimula-
tion and suggested that this is one immunomodulating mechanism responsible
for the analgesic and anti-inflammatory action of noni. Interestingly, MMP-9
levels in CB2 knockout mice reached significantly higher levels following LPS
challenge than those in normal mice [31]. This provides supportive in vivo evi-
dence for noni’s potential MAGL and FAAH inhibitor activities since 2-AG is
the principle ligand for CB2.
Clinical trials of noni juice have also been conducted in patients with os-
teoarthritic conditions in which MMP-9 expression has a contributing role [32]
[33]. The first of two open-label clinical trials to demonstrate the potential joint
health benefits of noni juice reported pain reduction and improved range of mo-
tion (flexion, extension, lateral flexion, and rotation) in patients suffering from
cervical spondylosis after four weeks [34]. In this study, 90 patients were ran-
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Journal of Biosciences and Medicines
domly assigned to either a standard physiotherapy treatment group (positive
control), a noni juice treatment group, or a combined treatment group (physio-
therapy plus noni juice). Measurements of pain intensity and neck flexibility
(cervical range of motion) were compared among the treatment groups. Before
the trial, all subjects in the noni juice group fell within the 5 - 7 (moderate to se-
vere) pain intensity range. But the pain intensity range of this group decreased to
0 - 4 (none to very moderate) after four weeks, with complete relief of neck pain
in 60% of patients. The combined treatment group also experienced significant
reduction in pain symptoms, experiencing even greater reduction in pain inten-
sity. Range of motion improved among all three treatment groups. Lateral flex-
ion and rotation doubled in the noni juice group.
In the second open label intervention study, 82 osteoarthritis (hip and/or
knee) patients drank 88.5 mL noni juice daily for 90 days [35]. Arthritis Impact
Measurement Scales (AIMS2) were used to measure pain/discomfort levels. The
Short Form-36, version 2 (SF-36 V2) was used to measure patient quality of life.
Noni juice ingestion significantly improved mean quality of life measurements.
These included reduced duration of arthritis pain, including a 23.7% decrease in
the frequency of severe pain, and a 16.4% decrease in pain severity. Improve-
ments in average mobility and patient psychological state also occurred. Satisfac-
tion with personal health increased by approximately 19%. The improved
symptoms observed in these two human studies provide further support for the
MAGL and FAAH inhibitory effect of noni juice, since compelling evidence
points to the active involvement of the ECS in mitigating the progress osteoarth-
ritis [36].
The ECS is an important regulator of stress and mental health [37]. As men-
tioned briefly above, noni juice ingestion significantly improved AIMS2 mental
health scores of patients in the 90-day osteoarthritis trial, especially those that rate
anxiety levels and overall mood. A similar effect was reported in post-menopausal
women in a three-month placebo-controlled pilot study [38]. When compared
to the placebo group, drinking 59 mL noni juice twice per day significantly im-
proved the average SF-36 mental health subgroup score.
Feeding of noni juice from Tahiti to rabbits for four weeks resulted in in-
creased sleep duration after receiving general anesthesia as well as improved
basal heart and respiration rates [39]. Further, sponteneous movements were
reduced while under anesthesia, and animals receiving noni juice had smoother
inductions and smoother recoveries. The authors of this study reported that no-
ni juice increased calmness, muscle relaxation, and reduced anxiety in the anes-
thetized rabbits. Another study evaluated the influence of noni juice on
stress-induced impairment of cognitive function of male ICR mice [40]. Those
that had been fed noni juice performed better in a Morris water maze (MWM)
test following chronic restraint stress (CRS). Immunohistochemical analysis re-
vealed that noni juice prevented stress-induced reduction in blood vessel density
in the dentate gyrus of the hippocampus, but the underlying mechanism of ac-
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Journal of Biosciences and Medicines
tion for this was not elucidated. Even so, CRS increases FAAH activity and low-
ers AEA concentrations in the amygdalas of C57/Bl6 mice, as well as causes
changes in amygdalar structure and increases anxiety-like behavior. But these
changes are absent in FAAH deficient mice [41]. Further, testing with MAGL
knockout mice in hippocampus-dependent learning paradigms indicate that
2-AG signaling is important for learning and memory [42]. Therefore, the inhi-
bition of FAAH and MAGL by noni juice may also be responsible for improved
MWM performance following CRS.
In our study, DAA inhibited FAAH activity modestly at 28.26% ± 4.61%.
Other compounds may also have contributed to the activity of noni juice in our
assays. Quercetin is reported to be a weak FAAH inhibitor, although kaempferol
is reportedly more active [43]. Both of these compounds are in noni fruit and
inhibit 5- and 15-lipoxygenases, with quercetin also weakly inhibiting cycloox-
ygenase-2 (COX-2) [44]. It is worth noting that COX-2 and lipoxygenases de-
grade AEA and 2-AG [45]. Noni fruit juice inhibited these enzymes
in vitro
and
dramatically reduced the expression of COX-2 in neonatal foals, thereby revealing
another set of pathways by which noni juice may influence endocannabinoid levels
[46] [47]. An extract from noni fruit significantly reduced time-to-recovery fol-
lowing epileptic seizures in Wistar albino rats, with accompanying restoration of
serotonin, dopamine and noradrenaline levels in the forebrain [48]. Similar an-
ti-epileptic effects have been reported for cannabidiol, a known FAAH inhibitor,
in human clinical trials [49] [50]. However, no such phytocannabinoid com-
pounds occur in any part of the noni plant. Further, cannabidiol is reported to be
an ineffective MAGL inhibitor [51]. Therefore, the phytochemical constituents in
noni juice modulate endocannabinoid levels in a different manner with dual
FAAH/MAGL inhibition. Noni fruit juice is a source of polyphenols and con-
tains many other biologically active compounds [52]. So, any number of these
may contribute to FAAH and MAGL inhibition, including the lignans [53].
Therefore, additional phytochemical studies are needed to determine which
compounds in noni fruit are responsible for inhibiting endocannabinoid hydro-
lysis enzymes.
4. Conclusion
The results of this study provide another possible explanation as to why noni
juice has been observed to have such a broad range of therapeutic effects. The
ability of noni juice to reduce FAAH and MAGL activity
in vitro
indicates the
possibility that ingesting it may subsequently elevate AEA and 2-AG levels or
prolong their interactions with CB1, CB2, and orphan G-protein receptors. The
increased opportunity for receptor agonism by these endocannabinoids elicits
physiological responses that have also occurred with repeated daily noni juice
consumption. The presence of phytochemicals with FAAH and MAGL inhibito-
ry potential lends further credence to the hypothesis that noni juice promotes
health and wellbeing by interacting with the body’s ECS. However, further
in vi-
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Journal of Biosciences and Medicines
tro
research should be conducted to confirm this.
Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this paper.
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