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The Therapeutic Potential of Berberis darwinii Stem-Bark: Quantification of Berberine and In Vitro Evidence for Alzheimer's Disease Therapy

Authors:
  • Herbal Analysis Services UK

Abstract

Berberis darwinii is native to South America but has been widely distributed in Europe and other continents following its discovery by Charles Darwin. Herewith, the therapeutic potential of stem-bark of the plant for treating Alzheimer's disease was studied using an in vitro acetylcholinesterase inhibition assay. It was found that the methanolic extract of the stem-bark was a potent inhibitor of the enzyme with an IC50 value of 1.23 +/- 0.05 microg/mL. An HPLC-based berberine quantification study revealed an astonishing 38% yield of the dried methanolic extract.
The Therapeutic Potential of Berberis darwinii Stem-Bark:
Quantification of Berberine and In Vitro Evidence for
Alzheimer’s Disease Therapy
Solomon Habtemariam
Pharmacognosy Research Laboratories, Medway School of Science, University of Greenwich,
Chatham Maritime, Kent, ME4 4TB, United Kingdom.
S.Habtemariam@gre.ac.uk
Received: February 22nd, 2011; Accepted: May 16th, 2011
Berberis darwinii is native to South America but has been widely distributed in Europe and other continents following its discovery by
Charles Darwin. Herewith, the therapeutic potential of stem-bark of the plant for treating Alzheimer's disease was studied using an in vitro
acetylcholinesterase inhibition assay. It was found that the methanolic extract of the stem-bark was a potent inhibitor of the enzyme with an
IC50 value of 1.23 ± 0.05 µg/mL. An HPLC-based berberine quantification study revealed an astonishing 38% yield of the dried methanolic
extract.
Keywords: Berberis darwinii, Berberidaceae, berberine, acetylcholinesterase, Alzheimer’s disease.
As a single chemical entity and a major constituent in
plants extracts, berberine has been used as potent
antimicrobial, anticancer, hepatoprotective, antidiabetic,
cholesterol lowering effects, anti-inflammatory,
immunomodulatory and many more activities [1a and
references therein]. Recent studies further revealed that
berberine has potent neuroprotective effects [1b]. Such
neuroprotective effects combined with antioxidant activity
are of particular significance to Alzheimer’s disease (AD)
where cholinergic neurons apoptosis is the major feature of
the disease process. The other predominant feature of AD
is the accumulation and aggregation of amyloid-β protein
leading to the formation of intracellular neurofibrillary
tangles and loss of normal neuronal functions [1c].
Interestingly, berberine has been shown to suppress the
release of amyloid-β from the membrane-associated
glycoprotein precursor amyloid protein [1d]. A further key
therapeutic approach for AD is the inhibition of
acetylcholinesterase (ACHE) enzyme thereby increasing
the lifespan of the neurotransmitter, acetylcholine [1e].
Since berberine has also been demonstrated to potently
inhibit ACHE [1f], berberine containing plants are likely to
have therapeutic potential for AD.
Berberis darwinii Hook (Berberidaceae) is native to South
America; southern Chile and Argentina. The plant is
known to be discovered in 1835 by Charles Darwin during
the voyage of the 'Beagle' and was named in his honor
[2a]. Known by its common names such as Darwin’s
Barberry and (Argentinean-Chilean Spanish) Michay, the
fruits are edible though they are acidic and rather favored
by birds [2a, personal observation]. B. darwinii is now one
of the popular garden and hedge plant in Britain. Except
for the earlier report by Cromwell in 1933 [2b] that
documented the biosynthesis of berberine, no
pharmacological or phytochemical studies have ever been
reported on the plant. Owing to the above mentioned
therapeutic potential of berberine and/or berberine-
containing plants, the present study focused on establi-
shing the therapeutic potential of B. darwinii for AD.
It was previously noted that the berberine content of B.
darwinii was the highest in the root-bark of the plant with
estimated average dry weight content of 11%, while the
stem-bark was reported to contain 2.67-4.93% [2b]. In
contrast to the bark of B. darwinii, the most common
source of berberine plant, Goldenseal (Hydrastis
canadensis L., Ranunculaceae), was shown to contain up
to a maximum content of 4.62% in the dried Rhizome,
while the other principal constituent, hydrastine, was
2.77% [2c]. The other well known berberine containing
commercial plant is the dried root of Coptis chinensis,
which is reported to contain up to a maximum level of
7.27% berberine together with small amount (less than
2%) of other principal constituents, palmatine and
jatrorrhizine [2d]. Based on these literature information,
there is no doubt that the bark of B. darwinii is just as good
source (if not better) of berberine as Goldseal and Coptis.
An HPLC method with reverse phase C-18 column and
ammonium acetate-acetonitrile gradient elution system
was used for berberine analysis. The separations of the
NPC Natural Product Communications 2011
Vol. 6
No. 8
1089 - 1090
1090 Natural Product Communications Vol. 6 (8) 2011 Habtemariam
Table 1: Anti-ACHE activity of Berberine, B. darwinii stem-bark extract and
eserine.*
Drugs IC50, μg/mL IC50, μM
Berberine 0.44±0.02 1.18 ± 0.06
B. darwinii 1.23±0.05 -
Eserine 0.28 ±0.05 1.01 ± 0.16
*IC50 values obtained from 4 independent experiments are shown.
stem-bark constituents were achieved during the first 10
minutes of the 25 min analysis time. The study revealed
that berberine was the major constituent of the crude
methanolic extract of B. darwinii. In order to quantify the
content of berberine in the extract, a calibration curve for
berberine as an external standard was plotted. Straight line
equations with regression line, correlation coefficient (r2)
of 0.9998 to 0.9999, were obtained. Based on this analysis,
the berberine content in the methanolic extract of the fresh
stem-bark was calculated as 38.09 ± 0.966% (n=10). This
means that the content of berberine in fresh stem-bark of
B. darwinii was 4.57 ± 0.12% (n=10). Considering that a
fresh plant material was used for the analysis, the observed
high yield of berberine was rather astonishing.
With the level of berberine in the extract established, the
therapeutic potential of the stem-bark of B. darwinii for AD
was further assessed by analyzing its anti-ACHE effect
using the Ellman et al. [2e] method. In agreement with
previous reports [1f] the present study demonstrated that
berberine is a potent ACHE inhibitor (Table 1). The activity
of berberine was comparable with the standard anti-ACHE
drug, eserine (Table 1): the mean values were not
significantly different from each other (p > 0.05; unpaired
t-test). As evidenced by the IC50 values (Table 1), the
crude extract was about 3-fold less potent than berberine:
which appear to be in good agreement with the observed
percentage yield (38%) of berberine in the crude extract.
In conclusion, the stem-bark of B. darwinii may be used as
an alternative source of berberine and has a potential to be
used for AD. Given that berberine has a wide range of
other biological activities, further studies on the
therapeutic potential of B. darwinii is well merited.
Experimental
Plant material and extraction: B. darwinii grown in our
medicinal garden and believed to be over 20 years old has
been used. The plant was authenticated and voucher
specimens deposited at our laboratory collections. The
fresh stem-bark (142 g) from the main stem of the plant
was chopped into pieces and placed in a large extraction
flask. The plant material was then soaked in methanol (2.5
L) and left in the dark for two weeks. The resulting extract
was concentrated under reduced vacuum using rotary
evaporator to yield 17 g of the crude extract.
Quantification of berberine by HPLC: Samples (20 µL)
were injected onto a reverse phase column (Agilent –
Eclipse XDB-C18, 5 µm, 4.6 x 150 mm). The mobile
phase was a mixture of 10 mM ammonium acetate
containing 0.08% formic acid (A) and acetonitrile (B). The
composition of the mobile phase at a flow rate of 1
mL/min was rising from 30% to 70% B over a period of 20
minutes. The composition of B was further increased to
90% B over 5 minutes. The berberine concentration in the
crude extracts was quantified from the standard curves
constructed from two-fold standard berberine dilutions
made from a stock solution of 1 mg/mL. All experiments
were repeated at least ten times and the amount of
berberine, based on the peak area at λ = 280 nm, was
calculated using GraphPad InStat software (GraphPad, San
Diego, USA).
Anti-ACHE assay: The Ellman et al. [2e] colorimetric
method of anti-ACHE assay was adopted for microtitre-
based assay.
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Berberine is an isoquinoline alkaloid isolated from Coptidis rhizoma, a major herb widely used in Chinese herbal medicine. Berberine's biological activity includes antidiarrheal, antimicrobial, and anti-inflammatory effects. Recent findings show that berberine prevents neuronal damage due to ischemia or oxidative stress and that it might act as a novel cholesterol-lowering compound. The accumulation of amyloid-beta peptide (Abeta) derived from amyloid precursor protein (APP) is a triggering event leading to the pathological cascade of Alzheimer's disease (AD); therefore the inhibition of Abeta production should be a rational therapeutic strategy in the prevention and treatment of AD. Here, we report that berberine reduces Abeta levels by modulating APP processing in human neuroglioma H4 cells stably expressing Swedish-type of APP at the range of berberine concentration without cellular toxicity. Our results indicate that berberine would be a promising candidate for the treatment of AD.
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A new method based on accelerated solvent extraction (ASE) followed by ultra performance liquid chromatography (UPLC) analysis has been developed for the identification and quantification of major alkaloids in extracts of Coptis chinensis Franch. The UPLC system consisted of a dual detection system of photodiode array detector (PDA) and positive ion electrospray ionization-tandem mass spectrometry (ESI-MS/MS) in sequential configuration. The operational parameters of ASE including extraction solvent, extraction temperature, static extraction time and extraction cycles were optimized. UPLC analysis was performed on an ACQUITY UPLC BEH C(18) column eluted by a mobile phase of acetonitrile spiked with a buffer solution consisting of 0.50% acetic acid and 20 mmol L(-1) ammonium acetate. A tandem quadrupole spectrometer operating in either full scan mode or in MS/MS mode for multiple reaction monitoring (MRM) was used for the identification and quantitative analysis of eight major alkaloids in C. chinensis Franch extracts. The samples were also analyzed on a high-performance liquid chromatography-electrospray ionization-time-of-flight mass spectrometry (HPLC-ESI-TOF-MS) system to confirm the identification results. Three of the eight major alkaloids, berberine, palmatine and jatrorrhizine were quantified by UPLC-PDA and UPLC-MS/MS. The results indicated that both UPLC-PDA and UPLC-MS/MS methods were simple, sensitive and reliable for the determination of alkaloids in C. chinensis Franch. Seven Huanglian samples from different locations were analyzed using the established methods. UPLC fingerprints based on the distribution of the eight major alkaloids can serve as a rapid and reliable method for the authentication and quality evaluation of traditional Chinese medicine (TCM) herbs.