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

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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.
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
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
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.
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.
[1] (a) Tang J, Feng Y, Ts ao S, Wang N, Curtain R, Wang Y. (2009) Berberine and Coptidis rhizoma as novel antineoplastic agents: A
review of traditional use and biomedical investigations. Journal of Ethnopharmacology, 126, 5-17; (b) Zhou X-Q, Zeng X-N,
Kong, H, Sun XL. (2008) Neuroprotective effects of berberine on stroke models in vitro and in vivo. Neuroscience Letters, 447, 31-
36; (c) Klein WL. (2002) Aβ toxicity in Alzheimer's disease: globular oligomers (ADDLs) as new vaccine and drug targets.
Neurochemistry International, 41, 345–352; (d) Asai M, Iwata N, Yoshikawa A, Aizaki Y, Ishiura S, Saido TC, Maruyama K.
(2007) Berberine alters the processing of Alzheimer’s amyloid precursor protein to decrease Aβ secretion. Biochemical and
Biophysical Research Communication, 52, 498-502; (e) Racchi M, Mazzucchelli M, Porrello E, Lanni C, Govoni S. (2004)
Acetylcholinesterase inhibitors: novel activities of old molecules. Pharmacological Research, 50, 441-445, (f) Huang L, Luo Z,
He F, Lu J, Li X.(2010) Synthesis and biological evaluation of a new series of berberine derivatives as dual inhibitors of
acetylcholinesterase and butyrylcholinesterase. Bioorganic & Medicinal Chemistry Letters, 18, 4475-4484.
[2] (a) Wikipedia: Accessed – February 2011; (b) Cromwell BT. (1933)
Experiments on the origin and function of berberine in Berberis Darwinii. Biochemical Journal, 27, 860–872. Douglas JA, Follett
JM, Parmenter GA, Sansom CE, Perry NB, Littler RA. (2010) Seasonal variation of biomass and bioactive alkaloid content of
goldenseal, Hydrastis canadensis. Fitoterapia, 81, 925-928; (c) Douglas JA, Follett JM, Parmenter GA, Sansom CE, Perry NB,
Littler RA. (2010) Seasonal variation of biomass and bioactive alkaloid content of goldenseal, Hydrastis canadensis. Fitoterapia,
81, 925-928; (d) Chen J, Wang F, Liu J, Lee FS-C, Wang X, Yang H. (2008) Analysis of alkaloids in Coptis chinensis Franch by
accelerated solvent extraction combined with ultra performance liquid chromatographic analysis with photodiode array and tandem
mass spectrometry detections. Analytica Chimica Acta, 613, 184-195; (e) Ellman GL, Courtney KD, Andres V, Featherstone RM.
(1961) A new and rapid colourimetric determination of acetylcholinesterase activity. Biochemical Pharmacology, 7, 88-95.
... In a separate investigation, stem-bark of Berberis darwinii was studied for AChE inhibitory activity using an in vitro AChE inhibition assay. Methanolic extract was found to be a potent inhibitor of the AChE with an IC 50 value of 1.23 ± 0.05 µg/mL, most likely due to the presence of berberine which was separated from the extract using high performance liquid chromatography (HPLC) [41]. Another plant from this family, Epimedium koreanum was investigated for AChE inhibitory activity and the results showed that its methanolic extract possesses significant inhibitory activity against AChE [38]. ...
... The investigation showed AChE inhibitory activity by the saffron extract. IC 50 values of safranal (40), crocetin (41), and dimethylcrocetin (42) were found to be in low micromolar range [115]. In a separate study, Iris germanica var. ...
Alzheimer's disease (AD), is the most common type of dementia primarily affecting the later years of life. Its prevalence is likely to increase in any aging population and will be a major burden on healthcare system by the mid of the century. Despite scientific and technological breakthroughs in the last 50 years, that have expanded our understanding of the disease on a system, cellular and molecular level, therapies that could stop or slow the progression of the disease are still unavailable. The Food and Drug Administration (FDA), has approved acetylcholinesterase (AChE) inhibitors (donepezil, galantamine, tacrine and rivastigmine) and glutamate receptor antagonist (memantine) for the treatment of AD. In this review we summarize the studies reporting phytocompounds and extracts from medicinal plants that show AChE inhibitory activities and could be of potential benefit in AD. Future research directions are suggested and recommendations made to expand the use of medicinal plants and their formulations to prevent, mitigate and treat AD.
... Traditional Chinese medicine (TCM), also known as botanical medicine or phytomedicine, is a scientific and technological resource with treatment or other health benefits. BBR is an isoquinoline alkaloid derived from the stems and roots of Berberis species, including B. Aristata, B. Darwinii, B. Petiolaris, and B. Vulgaris (75)(76)(77). BBR or herbs containing BBR have been used to treat intestinal infections, especially bacterial diarrhea in China for thousands of years (78). In recent years, its curative effect on T2DM patients has also been effectively proven (79)(80)(81) and it is widely believed to be an antidiabetic drug that regulates insulin signal transduction (82). ...
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Type 2 diabetes mellitus (T2DM) and its complications are major public health problems that seriously affect the quality of human life. The modification of intestinal microbiota has been widely recognized for the management of diabetes. The relationship between T2DM, intestinal microbiota, and active ingredient berberine (BBR) in intestinal microbiota was reviewed in this paper. First of all, the richness and functional changes of intestinal microbiota disrupt the intestinal environment through the destruction of the intestinal barrier and fermentation/degradation of pathogenic/protective metabolites, targeting the liver, pancreas, visceral adipose tissue (VAT), etc., to affect intestinal health, blood glucose, and lipids, insulin resistance and inflammation. Then, we focus on BBR, which protects the composition of intestinal microbiota, the changes of intestinal metabolites, and immune regulation disorder of the intestinal environment as the therapeutic mechanism as well as its current clinical trials. Further research can analyze the mechanism network of BBR to exert its therapeutic effect according to its multi-target compound action, to provide a theoretical basis for the use of different phytochemical components alone or in combination to prevent and treat T2DM or other metabolic diseases by regulating intestinal microbiota.
... Berberine, also known as Coptis rhizome, is a pentacyclic isoquinoline alkaloid. It can be found in the Chinese herb Coptis chinensis and numerous Berberis plants, such as Berberis aristata (81), Berberis vulgaris (87), and Berberis darwinii (88). The molecular formula of BBR is C 20 H 18 NO 4 , and the molecular weight is 336.337 ...
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Colorectal cancer (CRC) is one of the most commonly diagnosed and deadly malignancies worldwide. The incidence of CRC has been increasing, especially in young people. Although great advances have been made in managing CRC, the prognosis is unfavorable. Numerous studies have shown that berberine (BBR) is a safe and effective agent presenting significant antitumor effects. Nevertheless, the detailed underlying mechanism in treating CRC remains indistinct. In this review, we herein offer beneficial evidence for the utilization of BBR in the management and treatment of CRC, and describe the underlying mechanism(s). The review emphasizes several therapeutic effects of BBR and confirms that BBR could suppress CRC by modulating gene expression, the cell cycle, the inflammatory response, oxidative stress, and several signaling pathways. In addition, BBR also displays antitumor effects in CRC by regulating the gut microbiota and mucosal barrier function. This review emphasizes BBR as a potentially effective and safe drug for CRC therapy.
... For ages, berberine has been used in the traditional Chinese system of medicines for the treatment of various illnesses [12][13][14] . Berberine can be found in the stems and roots of various Berberis species such as Berberis aristate, 15 B. petiolaris, 16 Berberis vulgaris, 17 and Berberis darwinii, 18,19 Other plants containing berberine includes Tinospora cordifolia, 20 Argemone Mexicana, 21 Coptis chinensis, 22 Coptis teeta, 23 Eschscholzia californica, 24 Hydrastis Canadensis, 25 Mahonia aquifolium, 26,27 Xanthorhiza simplicissima, 28 and Phellodendron amurense. 29 The intestine and liver play a significant role in the metabolism of berberine. ...
In the last few decades, traditional natural products have been the center of attention for the scientific community and exploration of their therapeutic abilities is proceeding perpetually. Berberine, with remarkable therapeutic diversity, is a plant derived isoquinoline alkaloid which is widely used as a traditional medicine in China. Berberine has been tackled as a fascinating pharmacophore to make great contributions to the discovery and development of new therapeutic agents against variegated diseases. Despite its tremendous therapeutic potential, clinical utility of this alkaloid was significantly compromised due to undesirable pharmacokinetic properties. To overcome this limitation, several structural modifications were performed on this scaffold to improve its therapeutic efficacy. The collective efforts of the community have achieved the tremendous advancements, bringing berberine to clinical use and discovering new therapeutic opportunities by structural modifications on the berberine scaffold. In this review, recent advancements in the medicinal chemistry of berberine and its derivatives in the last few years (2016-2020) have been compiled to represent inclusive data associated with various biological activities of this alkaloid. The comprehensive structure-activity relationship studies along with molecular modelling and mechanistic studies have also been summarized. This article would be highly helpful for the scientific community to get better insight into medicinal research of berberine and become a compelling guide for the rational design of berberine based compounds.
... Berberin, diyare durumunda geleneksel Çin tıbbında uzun yıllardır kullanılan, Berberis cinsinin türlerinin saflaştırılmasıyla elde edilen doğal bir bileşendir (Chen ve ark, 2014). Berberin; B. aristata (Potdar, Hirwani ve Dhulap, 2012; Amritpal ve ark, 2010), B. darwinii (Habtemariam, 2011;Habtemariam, 2013), B. Petiolaris (Singh ve ark, 2015) ve B. vulgaris (Suau ve ark, 1998) dahil Berberis türlerinin saplarından ve köklerinden izole edilen doğal kaynaklı bir alkaloiddir. Berberinin antibakteriyel (Jamshaid, Dai ve Yang, 2020), antienflamatuar (Habtemariam, 2016), antidiyabetik (Liang ve ark, 2019) ve antiobezite (Tabeshpour, Imenshahidi ve Hosseinzadeh, 2017) gibi çeşitli farmakolojik özellikleri bulunmaktadır. ...
... Berberine is an alkaloid with therapeutic properties like an antimicrobial, antioxidant, antidepressant, antidiabetic, anticancer, antihypertensive, anti-inflammatory, anti-diarrhea. It also has hypolipidemic activity and therapeutic effects on Alzheimer's disease and reduces total cholesterol [14][15][16][17]. Berberine can be found in different parts of barberry especially roots and stems. ...
BACKGROUND:Barberry is a valuable plant, which is useful in the treatment of different diseases. There are valuable compounds in different parts of barberry that are pruned per year and discarded as waste. OBJECTIVE:In this study, the amount of berberine, phenolic compounds and antioxidant activity of barberry fruits, leaves, and stems of different barberry species (B.integerrima and B.thunbergii) were investigated. METHODS:Central composite design of response surface methodology (RSM) were used in this study to investigate the extraction variables (time: 2–24 h, temperature: 24–70°C and ethanol concentration: 50–90%) in the extraction of berberine from the stem of B.integrrima. The responses used as criteria were the amount of berberine, scavenging radical DPPH, and polyphenol. Also, pulsed electric field-assisted (PEF) was applied as a pretreatment (Pulse strengths of 250, 1000 and 1250 Vcm–1; Pulse numbers (n) of 50 and 100; frequency (f) of 1 Hz) and then the extraction was conducted in optimum condition. PEF increased significantly the amount of berberine. RESULTS:The stem of B.integrrima had the most amounts of antioxidant activity and berberine content, and it was selected for more investigation. The optimum condition in the maceration method was: 90% of ethanol, 70°C, and 3.36 h (141.6 min). According to the result of PEF method, the best condition for extraction of berberine from barberry stems was 1000 Vcm–1 and n = 100. CONCLUSIONS:The results demonstrated that the extract of B.integrrima stem is a good source of berberine, antioxidant, and has the potential to be applied in various industries.
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Neurodegenerative diseases refer to a group of neurological disorders as a consequence of various destructive illnesses, that predominantly impact neurons in the central nervous system, resulting in impairments in certain brain functions. Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and other neurodegenerative disorders represent a major risk to human health. In order to optimize structural and functional recovery, reconstructive methods integrate many approaches now, to address the complex and multivariate pathophysiology of neurodegenerative disorders. Stem cells, with their unique property of regeneration, offer new possibilities in regenerative and reconstructive medicine. Concurrently, there is an important role for natural products in controlling many health sufferings and they can delay or even prevent the onset of various diseases. In addition, due to their therapeutic properties, they have been used as neuroprotective agents to treat neurodegenerative disorders. After decades of intensive research, scientists made advances in treating these disorders so far, but current therapies are still not capable of preventing the illnesses from progressing. Therefore, in this review, we focused on a new perspective combining stem cells and natural products as an innovative therapy option in the management of neurodegenerative diseases.
Berberis darwinii Hook. has its natural origin in both slopes of the Andes Mountains, in Southern Chile and Argentina, but the species has been naturalized also in other continents. In traditional medicine, it is used by the Mapuche ethnic group for the treatment of inflammatory processes, feverish states and stomach pain. The secondary metabolites in B. darwinii, primarily alkaloids and polyphenols, show a great diversity. There are several scientific reports and ethnographic antecedents about the traditional uses. From a medicinal point of view, this seems to be a promising plant species.
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The increased incidence of metabolic diseases (e.g., diabetes and obesity) has seriously affected human health and life safety worldwide. It is of great significance to find effective drugs from natural compounds to treat metabolic diseases. Berberine (BBR), an important quaternary benzylisoquinoline alkaloid, exists in many traditional medicinal plants. In recent years, BBR has received widespread attention due to its good potential in the treatment of metabolic diseases. In order to promote the basic research and clinical application of BBR, this review provides a timely and comprehensive summary of the pharmacological and clinical advances of BBR in the treatment of five metabolic diseases, including type 2 diabetes mellitus, obesity, non-alcoholic fatty liver disease, hyperlipidemia, and gout. Both animal and clinical studies have proved that BBR has good therapeutic effects on these five metabolic diseases. The therapeutic effects of BBR are based on regulating various metabolic aspects and pathophysiological procedures. For example, it can promote insulin secretion, improve insulin resistance, inhibit lipogenesis, alleviate adipose tissue fibrosis, reduce hepatic steatosis, and improve gut microbiota disorders. Collectively, BBR may be a good and promising drug candidate for the treatment of metabolic diseases. More studies, especially clinical trials, are needed to further confirm its molecular mechanisms and targets. In addition, large-scale, long-term and multi-center clinical trials are necessary to evaluate the efficacy and safety of BBR in the treatment of these metabolic diseases.
Background: Genus Berberis (family Berberidaceae), which contains about 650 species and 17 genera worldwide, has been used in folklore and various traditional medicine systems. Berberis Linn. is the most established group among genera with around 450-500 species across the world. This comprehensive review will not only help researchers for further evaluation but also provide substantial information for future exploitation of species to develop novel herbal formulations. Objective: The present review is focussed to summarize and collect the updated review of information of Genus Berberis species reported to date regarding their ethnomedicinal information, chemical constituents, traditional/folklore use, and reported pharmacological activities on more than 40 species of Berberis. Conclusion: A comprehensive survey of the literature reveals that various species of the genus possess various phytoconstituents mainly alkaloids, flavonoid based compounds isolated from different parts of a plant with a wide range of pharmacological activities. So far, many pharmacological activities like anti-cancer, anti-hyperlipidemic, hepatoprotective, immunomodulatory, anti-inflammatory both in vitro & in vivo and clinical study of different extracts/isolated compounds of different species of Berberis have been reported, proving their importance as a medicinal plant and claiming their traditional use.
A photometric method for determining acetylcholinesterase activity of tissue extracts, homogenates, cell suspensions, etc., has been described. The enzyme activity is measured by following the increase of yellow color produced from thiocholine when it reacts with dithiobisnitrobenzoate ion. It is based on coupling of these reactions: The latter reaction is rapid and the assay is sensitive (i.e. a 10 μ1 sample of blood is adequate). The use of a recorder has been most helpful, but is not essential. The method has been used to study the enzyme in human erythrocytes and homogenates of rat brain, kidney, lungs, liver and muscle tissue. Kinetic constants determined by this system for erythrocyte eholinesterase are presented. The data obtained with acetylthiocholine as substrate are similar to those with acetylcholine.
Seasonal variations in biomass and alkaloid contents of goldenseal (Hydrastis canadensis) were investigated. Five-year-old plants gave 5x the yield of roots and rhizomes of two-year-old plants, and summer growth gave significant increases in root biomass but not rhizomes. Berberine contents of roots plus rhizomes did not vary significantly and were >3.4% in all samples. Hydrastine contents of 5 y roots plus rhizomes showed significant seasonal variation. These variations were due to significant changes in the hydrastine contents of the roots (1.3-1.9%), but not the rhizomes (2.2-2.8%). Goldenseal leaves plus stems had lower contents of hydrastine (0.4-0.8%) and berberine (1.0-1.5%).
A series of novel berberine derivatives were designed, synthesized, and biologically evaluated as inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among these derivatives, compound 48a, berberine linked with 3-methylpyridinium by a 2-carbon spacer, was found to be a potent inhibitor of AChE, with an IC(50) value of 0.048 microM and compound 40c, berberine linked with 2-thionaphthol by a 4-carbon spacer, acted as the most potent inhibitor for BuChE with an IC(50) value of 0.078 microM. Kinetic studies and molecular modeling simulations of the AChE-inhibitor complex indicated that a mixed-competitive binding mode existed for these berberine derivatives.
Coptidis rhizoma (huanglian) and its major component, berberine, have drawn extensive attention toward their antineoplastic effects in the recent years. The antineoplastic effects are related to the Chinese Medicine (CM) properties of huanglian in treating diseases by removing damp-heat and purging fire and counteracting toxicity. To trace the long history of the traditional use of huanglian from folk medicines, especially from Chinese medicine, to recent pharmacological studies of huanglian and berberine, with an emphasis on their antineoplastic effects and the promise as novel antineoplastic agents. A total of seven databases were extensively searched for literature research. The terms and keywords for searching included huanglian, berberine, Coptis, Coptidis rhizoma, anticancer, anti-invasion, antimatastasis and mechanism. The papers including ours with studies on anticancer and mechanism, pharmacology and toxicology of huanglian and/or berberine were focused. In view of traditional use, the anticancer effects of huanglian can be ascribed to its CM trait by removing damp-heat, fire and toxicity. From modern biomedical studies, anticancer effects have been demonstrated in both huanglian and berberine. The underlying molecular mechanisms involve cell-cycle arrest, apoptosis induction and anti-inflammation. Berberine is an essential anticancer compound in huanglian. In some studies, the use of huanglian was shown to be more effective and beneficial than the use of berberine alone. The presence of other protoberberine-type alkaloids in huanglian might give synergistic effects for the anticancer effects. Berberine also demonstrates effects of antiangiogenesis, anti-invasion and anti-metastasis in some cancer cell lines, however, more investigations are required to unravel the underlying mechanisms involved. The modern evidences of treating cancer with huanglian and berberine have a strong linkage with traditional concept and rules of using huanglian in CM practice. As anticancer candidates with low toxicity, berberine and its altered structure, as well as huanglian and its formulae, will attract scientists to pursue the potential anticancer effects and the mechanisms by using technologies of genomics, proteomics and other advanced approaches. On the other hand, relatively few in vivo studies have been conducted on anticancer effects of huanglian and berberine. The clinical application of berberine or huanglian as novel cancer therapeutic agents requires in vivo validations and further investigations of their anticancer mechanisms.
Berberine is an alkaloid derived from herb medicine Coptidis Rhizom. Although there are increasing evidences that berberine exhibits neuroprotective effects against ischemic brain damage, little is known about the mechanism. In this study, we investigated the effect of berberine on ischemic injury in a middle cerebral artery occlusion (MCAO) model. We found that berberine improved neurological outcome and reduced ischemia/reperfusion (I/R)-induced cerebral infarction 48h after MCAO. The protective effect of berberine was confirmed in in vitro study. Berberine protected PC12 cells against oxygen-glucose deprivation (OGD)-induced injury. The results showed that berberine inhibited reactive oxygen species (ROS) generation, and subsequent release of pro-apoptotic factor cytochrome c and apoptosis-inducing factors (AIFs) evoked by OGD. Findings of this study suggest that berberine protects against ischemic brain injury by decreasing the intracellular ROS level and subsequently inhibiting mitochondrial apoptotic pathway.
Over the past several years, experiments with synthetic amyloid-beta peptide (Abeta) and animal models have strongly suggested that pathogenesis of Alzheimer's disease (AD) involves soluble assemblies of Abeta peptides (Trends Neurosci. 24 (2001) 219). These soluble neurotoxins (known as ADDLs and protofibrils) seem likely to account for the imperfect correlation between insoluble fibrillar amyloid deposits and AD progression. Recent experiments have detected the presence of ADDLs in AD-afflicted brain tissue and in transgenic-mice models of AD. The presence of high affinity ADDL binding proteins in hippocampus and frontal cortex but not cerebellum parallels the regional specificity of AD pathology and suggests involvement of a toxin receptor-mediated mechanism. The properties of ADDLs and their presence in AD-afflicted brain are consistent with their putative role even in the earliest stages of AD, including forms of mild cognitive impairment.
The therapeutic approach for improving the cognitive function in patients with Alzheimer's disease (AD) is mainly based on the potentiation of central cholinergic activity and is achieved clinically by the use of acetylcholinesterase (AChE) inhibitors such as tacrine, donepezil, rivastigmine, galantamine and other drugs currently in clinical trials. These are, by their pharmacology, only symptomatic drugs yet recently these molecules have shown some potential also in the modulation of amyloid precursor protein (APP) processing. We explore in this review the experimental evidence that suggests a role for AChEIs in APP processing and point to multiple complex mechanisms involving either a cholinergic agonist effect, coupled to multiple signal transduction pathways, or post-transcriptional effects that modulate the expression of cellular APP.
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.
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.