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Role of Vacha (Acorus calamus Linn.) in Neurological and Metabolic Disorders: Evidence from Ethnopharmacology, Phytochemistry, Pharmacology and Clinical Study

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Vacha (Acorus calamus Linn. (Acoraceae)) is a traditional Indian medicinal herb, which is practiced to treat a wide range of health ailments, including neurological, gastrointestinal, respiratory, metabolic, kidney, and liver disorders. The purpose of this paper is to provide a comprehensive up-to-date report on its ethnomedicinal use, phytochemistry, and pharmacotherapeutic potential, while identifying potential areas for further research. To date, 145 constituents have been isolated from this herb and identified, including phenylpropanoids, sesquiterpenoids, and monoterpenes. Compelling evidence is suggestive of the biopotential of its various extracts and active constituents in several metabolic and neurological disorders, such as anticonvulsant, antidepressant, antihypertensive, anti-inflammatory, immunomodulatory, neuroprotective, cardioprotective, and anti-obesity effects. The present extensive literature survey is expected to provide insights into the involvement of several signaling pathways and oxidative mechanisms that can mitigate oxidative stress, and other indirect mechanisms modulated by active biomolecules of A. calamus to improve neurological and metabolic disorders.
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Journal of
Clinical Medicine
Review
Role of Vacha (Acorus calamus Linn.) in Neurological
and Metabolic Disorders: Evidence from
Ethnopharmacology, Phytochemistry, Pharmacology
and Clinical Study
Vineet Sharma 1, Rohit Sharma 1,* , DevNath Singh Gautam 1, Kamil Kuca 2, * ,
Eugenie Nepovimova 2and Natália Martins 3, 4, *
1Department of Rasa Shastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences,
BHU, Varanasi, Uttar Pradesh 221005, India; vinitbhu93@gmail.com (V.S.); drdnsgautam@gmail.com (D.S.G.)
2Department of Chemistry, Faculty of Science, University of Hradec Králové, Rokitanskeho 62,
50003 Hradec Králové, Czech Republic; eugenie.nepovimova@uhk.cz
3Faculty of Medicine, University of Porto, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal
4Institute for research and Innovation in Heath (i3S), University of Porto, Rua Alfredo Allen,
4200-135 Porto, Portugal
*Correspondence: rohitsharma@bhu.ac.in or dhanvantari86@gmail.com (R.S.); kamil.kuca@uhk.cz (K.K.);
ncmartins@med.up.pt (N.M.)
Received: 23 March 2020; Accepted: 14 April 2020; Published: 19 April 2020


Abstract:
Vacha (Acorus calamus Linn. (Acoraceae)) is a traditional Indian medicinal herb, which is
practiced to treat a wide range of health ailments, including neurological, gastrointestinal, respiratory,
metabolic, kidney, and liver disorders. The purpose of this paper is to provide a comprehensive
up-to-date report on its ethnomedicinal use, phytochemistry, and pharmacotherapeutic potential,
while identifying potential areas for further research. To date, 145 constituents have been isolated
from this herb and identified, including phenylpropanoids, sesquiterpenoids, and monoterpenes.
Compelling evidence is suggestive of the biopotential of its various extracts and active constituents in
several metabolic and neurological disorders, such as anticonvulsant, antidepressant, antihypertensive,
anti-inflammatory, immunomodulatory, neuroprotective, cardioprotective, and anti-obesity eects.
The present extensive literature survey is expected to provide insights into the involvement of
several signaling pathways and oxidative mechanisms that can mitigate oxidative stress, and other
indirect mechanisms modulated by active biomolecules of A. calamus to improve neurological and
metabolic disorders.
Keywords:
Acorus calamus; ethnomedicinal; phytochemistry; toxicity; pharmacological action;
clinical trial; neuroprotective; neurological; metabolic application
1. Introduction
Globally, an estimated 450 million people are suering from mental disorders and about 425 million
are known diabetics [
1
,
2
]. In 2016, 650 million adults were obese and about 23.6 million people were
estimated to die of cardiovascular diseases (CVDs) by the year 2030 [
3
]. Metabolic disorders are
characterized by hypertension, hyperglycemia, abdominal obesity, and hyperlipidemia, which may
worsen the neurological disease risk. Improper diet (high calorie intake), lifestyle (e.g., smoking,
chronic alcohol consumption, sedentary habits), and/or low level of nitrosamines (through processed
food, tobacco smoke, and nitrate-containing fertilizers) affect the liver and can further lead to fatty liver
disease [
4
,
5
]. In this condition, fatty changes may be due to increased production or decreased use of fatty
J. Clin. Med. 2020,9, 1176; doi:10.3390/jcm9041176 www.mdpi.com/journal/jcm
J. Clin. Med. 2020,9, 1176 2 of 45
acids, which may lead to inflammatory injury of hepatocytes, where inflammatory mediators, such as
cytokines and interleukins, are released, which, along with lower adipokines, may eventually develop
hepatic insulin resistance [
6
]. The same pathology also mediates diabetes, obesity, and peripheral insulin
resistance. Insulin resistance also promotes the release of ceramides and other toxic lipids which enter the
circulation and cross the blood–brain barrier leading to brain insulin resistance, inflammatory changes,
and further progression to neurodegeneration and neurological disorders (Figure 1) [7].
J. Clin. Med. 2020, 9, 1176 2 of 46
liver disease [4,5]. In this condition, fatty changes may be due to increased production or decreased
use of fatty acids, which may lead to inflammatory injury of hepatocytes, where inflammatory
mediators, such as cytokines and interleukins, are released, which, along with lower adipokines, may
eventually develop hepatic insulin resistance [6]. The same pathology also mediates diabetes, obesity,
and peripheral insulin resistance. Insulin resistance also promotes the release of ceramides and other
toxic lipids which enter the circulation and cross the blood–brain barrier leading to brain insulin
resistance, inflammatory changes, and further progression to neurodegeneration and neurological
disorders (Figure 1) [7].
Figure 1. Pathophysiology of insulin resistance, metabolic malfunction, and progression to a
neurological disorder. TNF, tumor necrosis factor; IL, interleukin.
Acorus calamus Linn. (Acoraceae), also known as Vacha in Sanskrit, is a mid-term, perennial,
fragrant herb which is practiced in the Ayurvedic (Indian traditional) and the Chinese system of
medicine. The plant’s rhizomes are brown in color, twisted, cylindrical, curved, and shortly nodded.
The leaves are radiant green, with a sword-like structure, which is thicker in the middle and has
curvy margins (Figure 2) [8]. Several reports ascertained a wide range of biological activities
involving its myriad of active phytoconstituents. In this sense, the intent of this review is to assemble
and summarize the geographical distribution, ethnopharmacology, phytochemistry, mechanism of
action of A. calamus along with preclinical and clinical claims that are relevant to manage neurological
and metabolic disorders. To the best of our knowledge, so far, none of the published reviews has
described all the characteristics of this medicinal plant [9–11]. The present report is expected to
produce a better understanding of the characteristics, bioactivities, and mechanistic aspects of this
plant and to provide new leads for future research.
Figure 1.
Pathophysiology of insulin resistance, metabolic malfunction, and progression to a neurological
disorder. TNF, tumor necrosis factor; IL, interleukin.
Acorus calamus Linn. (Acoraceae), also known as Vacha in Sanskrit, is a mid-term, perennial,
fragrant herb which is practiced in the Ayurvedic (Indian traditional) and the Chinese system of
medicine. The plant’s rhizomes are brown in color, twisted, cylindrical, curved, and shortly nodded.
The leaves are radiant green, with a sword-like structure, which is thicker in the middle and has curvy
margins (Figure 2) [
8
]. Several reports ascertained a wide range of biological activities involving
its myriad of active phytoconstituents. In this sense, the intent of this review is to assemble and
summarize the geographical distribution, ethnopharmacology, phytochemistry, mechanism of action
of A. calamus along with preclinical and clinical claims that are relevant to manage neurological and
metabolic disorders. To the best of our knowledge, so far, none of the published reviews has described
all the characteristics of this medicinal plant [
9
11
]. The present report is expected to produce a better
understanding of the characteristics, bioactivities, and mechanistic aspects of this plant and to provide
new leads for future research.
J. Clin. Med. 2020,9, 1176 3 of 45
J. Clin. Med. 2020, 9, 1176 3 of 46
(A) (B) (C)
Figure 2. Photographs of Acorus calamus: (A) Natural habitat; (B) Fresh rhizome; (C) Dried rhizome.
2. Methodology
The literature available in the Ayurvedic classical texts, technical reports, online scientific
records such as SciFinder, Google Scholar, MEDLINE, EMBASE, Scopus directory were explored for
ethnomedicinal uses, geographical distribution, phytochemistry, pharmacology, and biomedicine by
applying the following keywords: “Acorus calamus”, “Vacha”, “Medhya”, “neuroprotective”,
“phytochemistry”, “obesity”, “oxidative stress”, “anticonvulsant”, “antidepressant”,
“antihypertensive”, “anti-inflammatory”, “immunomodulator”, “antioxidant”, “diabetes”,
“mechanism of action” with their corresponding medical subject headings (MeSH) terms using
conjunctions OR/AND. The search was focused on identifying Ayurvedic claims in the available
ethnomedicinal, phytochemical, preclinical, clinical, and toxicity reports to understand the role of A.
calamus in neurological and metabolic disorders. This search was undertaken between January 2018
and January 2020. Searches were restricted to the English language. The search methodology as per
the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) is stipulated in
the flowchart in Figure 3.
Figure 3. Flowchart of the selection process.
Figure 2. Photographs of Acorus calamus: (A) Natural habitat; (B) Fresh rhizome; (C) Dried rhizome.
2. Methodology
The literature available in the Ayurvedic classical texts, technical reports, online scientific records
such as SciFinder, Google Scholar, MEDLINE, EMBASE,Scopus directory wereexplored for ethnomedicinal
uses, geographical distribution, phytochemistry, pharmacology, and biomedicine by applying the
following keywords: Acorus calamus”, “Vacha”, “Medhya”, “neuroprotective”, “phytochemistry”,
“obesity”, “oxidative stress”, “anticonvulsant”, “antidepressant”, “antihypertensive”, “anti-inflammatory”,
“immunomodulator”, “antioxidant”, “diabetes”, “mechanism of action” with their corresponding medical
subject headings (MeSH) terms using conjunctions OR/AND. The search was focused on identifying
Ayurvedic claims in the available ethnomedicinal, phytochemical, preclinical, clinical, and toxicity
reports to understand the role of A. calamus in neurological and metabolic disorders. This search
was undertaken between January 2018 and January 2020. Searches were restricted to the English
language. The search methodology as per the Preferred Reporting Items for Systematic Reviews and
Meta-Analysis (PRISMA) is stipulated in the flowchart in Figure 3.
J. Clin. Med. 2020, 9, 1176 3 of 46
(A) (B) (C)
Figure 2. Photographs of Acorus calamus: (A) Natural habitat; (B) Fresh rhizome; (C) Dried rhizome.
2. Methodology
The literature available in the Ayurvedic classical texts, technical reports, online scientific
records such as SciFinder, Google Scholar, MEDLINE, EMBASE, Scopus directory were explored for
ethnomedicinal uses, geographical distribution, phytochemistry, pharmacology, and biomedicine by
applying the following keywords: “Acorus calamus”, “Vacha”, “Medhya”, “neuroprotective”,
“phytochemistry”, “obesity”, “oxidative stress”, “anticonvulsant”, “antidepressant”,
“antihypertensive”, “anti-inflammatory”, “immunomodulator”, “antioxidant”, “diabetes”,
“mechanism of action” with their corresponding medical subject headings (MeSH) terms using
conjunctions OR/AND. The search was focused on identifying Ayurvedic claims in the available
ethnomedicinal, phytochemical, preclinical, clinical, and toxicity reports to understand the role of A.
calamus in neurological and metabolic disorders. This search was undertaken between January 2018
and January 2020. Searches were restricted to the English language. The search methodology as per
the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) is stipulated in
the flowchart in Figure 3.
Figure 3. Flowchart of the selection process.
Figure 3. Flowchart of the selection process.
J. Clin. Med. 2020,9, 1176 4 of 45
3. Geographical Distribution
A. calamus grows in high (1800 m) and low (900 m) altitudes and it is found to be geographically
available in 42 countries [
8
]. Furthermore, as per the Global Biodiversity Information Facility
records [
12
], the distribution of this plant in several parts of the world, as well as in India, is highlighted
in Figure 4.
Figure 4. Distribution of A. calamus worldwide and in India.
4. Ethnomedicinal Use
This plant is being practiced traditionally in the Indian Ayurvedic tradition, as well as in the
Chinese system of medicine for analgesic, antipyretic, tonic, anti-obesity, and healing purposes; it is
highly eective for skin diseases, along with neurological, gastrointestinal, respiratory, and several
other health disorders. Rhizomes and leaves are found to be profusely practiced in the form of infusion,
powder, paste, or decoction [
13
72
]. The ethnomedicinal uses of the A. calamus are detailed in Table 1.
A. calamus rhizomes and leaves are also used as an active pharmaceutical ingredient in various
Ayurvedic formulations (Table 2).
J. Clin. Med. 2020,9, 1176 5 of 45
Table 1. Ethnomedicinal use of A. calamus in various countries.
Country Ailment/Use Part Used/Dosage Form Route of Administration References
India
Eczema The paste of A. calamus rhizomes are given with the paste of
Curcuma aromatica rhizomes and Azadirachta indica leaves
Oral
[13]
Skin diseases
Rhizomes paste A. calamus and C. aromatica are applied with the
seed paste of Argemone Mexicana
Cough, stuttering, ulcer, fever,
dermatitis, scab, sores Rhizomes [14]
Cold, cough, and fever
Rhizomes paste of A. calamus is given to children with mother’s
milk, Myristica fragrance, and Calunarejan spinosa fruits [15]
Two teaspoonfuls of herbal powder containing A. calamus
rhizomes, Boerhaavia diusa roots, Calonyction muricutum flower
pedicles, Ipomoea muricate seeds, Senna leaves, Cassia fistula fruits
pulp, Curcuma longa rhizomes, Helicteres isora fruits, and Mentha
arvensis leaves, black pepper is taken with lukewarm water
[16]
Gastric disorders A. calamus rhizomes paste is given with cow milk [17]
Carminative, flavoring, tonic,
and head lice infestation
Infusion of a dried rhizomes (collected and stored in the
autumn season) [1719]
Epilepsy, dysentery, mental
illnesses, diarrhea, kidney and
liver disorders
A. calamus rhizomes paste is given with honey [20]
Wounds, fever, body pain Rhizomes [21,22]
Dysentery Fresh ground rhizomes is mixed with hot water
and given for 3 days [23]
Stimulant Dry powder of A. calamus is given with honey [24]
Injuries External application of the A. calamus rhizomes paste
Dermal
[25]
Stomachache Ash of the A. calamus rhizomes paste [26]
Otitis externa A. calamus roots paste is given with coconut husk juice [27]
Lotion Fresh leaves of A. calamus [28]
Cough, cancer, and fever A. calamus roots juice is given with honey and
MyristicaDactyloides [29]
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Table 1. Cont.
Country Ailment/Use Part Used/Dosage Form Route of Administration References
Analgesic A. calamus rhizomes are given with cinchona bark
[30]
Gastrointestinal, respiratory,
emmenagogue, antihelmintic Rhizomes
Prolonged labor Rhizomes is applied with saron and horse milk
Paralysis, arthritis Rhizomes ash is applied with castor oil
Neurological disorder,
gastrointestinal, respiratory,
increases menstrual flow,
analgesic, contraceptive Rhizomes
Oral
[3133]
Herpangina, analgesic,
neurological disorder,
gastrointestinal, respiratory
[34]
Pakistan Colic and diarrhea Whole plant [35]
Nepal
Blood pressure Roots infusion of A. calamus [36]
Cough, headache, snake bite,
sore throat, and pain Rhizomes
[37]
Dysentery Rhizomes juice is given with hot water
Neurological, respiratory Rhizomes [38]
Malaysia Rheumatism, diarrhea,
dyspepsia, and hair loss Whole plant [39]
Tibet Fever, gastrointestinal
Dried rhizomes is given with Saussurea lappa,Ferula foetida,
Terminalia chebula,Cuminum cyminum,Inula racemosa,
and Zingiber ocinale
[40]
Cancer Rhizomes [41]
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Table 1. Cont.
Country Ailment/Use Part Used/Dosage Form Route of Administration References
China
Gastrointestinal, respiratory,
neuroprotective, analgesic,
contraceptive, cancer
Rhizomes [4244]
Antipyretic and
ear-related disease
Rhizomes given with squeezed Coccinia cordifolia stems along
with water
[45]
Detoxification Rhizomes with vinegar, Alpinia galanga,Zingiber purpureum
Analgesic Herbal baths of the rhizome External
Hemorrhage Rhizomes paste [46]
Aphrodisiac Rhizomes
Oral
[47]
Hallucination Rhizomesare mixed with Indian hemp and
Podophyllum pleianthum [48]
Fair skin Leaves of A. calamus are given with Artemisia vulgaris Dermal [49]
Indonesia Gastrointestinal Rhizomes
Oral
[50]
England
Rhizomes blended with chalk and magnesium oxide [51]
Gastrointestinal, antibacterial,
analgesic Rhizomes
[52]
Neurological, dysentery, and
chronic catarrh Rhizomesare given with Gentiana campestris L.
Malaria
Rhizomes
[53]
Europe Obesity, influenza,
gastrointestinal, respiratory [54,55]
Republic of
South Africa
Tooth powder, gastrointestinal,
tonic, aphrodisiac [56]
Sweden Liquor [57]
Germany Increases menstrual flow,
gastrointestinal [58,59]
Java Lactation [60]
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Table 1. Cont.
Country Ailment/Use Part Used/Dosage Form Route of Administration References
Lithuania Chest pain, diarrhea Rhizomes and leaves are taken with sugar [52]
Relieves pain, gout, rheumatism
Leaves decoction External [61]
New Guinea Miscarriage
Rhizomes
Oral
[62]
Philippines Gastrointestinal, rheumatism [56]
Russia Typhoid, syphilis, baldness,
fever, cholera [63]
Thailand Blood purifier, fever [64]
Turkey
Wound healing, cough,
tuberculosis External and oral [61]
Gastrointestinal
Oral
[65,66]
Arab
countries Gastrointestinal, tuberculosis [67,68]
Brazil Destroys parasitic worms [68]
Argentina Dysmenorrhea [69]
United States
Gastrointestinal, abortifacient,
stimulant, tonic,
respiratory disorder Rhizomes [70]
Korea
Improves memory and life span
[71]
Sri Lanka Cough, worm infestation Rhizomes paste are given with milk [72]
J. Clin. Med. 2020,9, 1176 9 of 45
Table 2. Pharmaceutical products of A. calamus available in the market.
Medicine/Formulations Indications/Use Manufacturers
Pilochek tablets Hemorrhoids
Dabur India Limited
Brahm Rasayan Nervine tonic
Mahasudarsan Churna Malaria
Janma Ghunti Honey Babies growth, Constipation, Diarrhea
Brahmi Pearls capsules Brain Nourisher
Kerala Ayurveda
GT capsules Osteoarthritis, osteoporosis, hyperlipidemia
Histantin tablets Anti-allergic
Santhwanam oil Antioxidant, rejuvenate
Mahathikthaka Ghrita capsules Skin disease, malabsorption syndrome
Calamus root tincture Stimulates the digestive system Florida Herbal Pharmacy
Vacha capsules Food supplements DR Wakde’s Natural Health Care, London
Mentat tablets and syrup Nervine tonic
Himalaya Herbal Healthcare
Abana
Cardiovascular disorders, hyperlipidemia, dyslipidemia
Mentat tablets and Syrup Anxiety, depression, insomnia
Muscle & Joint Rub Backaches, muscular sprains, pain
Anxocare Anxiety
Erina-EP Ectoparasites
Himpyrin, Himpyrin Vet Analgesic and anti-inflammatory
Scavon Vet Anti-bacterial, anti-fungal
Vacha powder Brain tonic, improves digestion, and prevents nausea Bixa Botanical
Amalth Herbal supplements Mcnow Biocare Private Limited
Sunarin capsules Anal fissures, piles, rectal inflammation, congestion SG Phyto Pharma
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Table 2. Cont.
Medicine/Formulations Indications/Use Manufacturers
Dr Willmar Schwabe India Acorus calamus
mother tincture Intestinal worms and stomach disorders, fever, nausea Dr Willmar Schwabe India Pvt Ltd.
Himalayan calamus root essential oil Pain relief and calm mind Naturalis Essence of Nature
Calamus oil Body, skin care, hair growth Kazima Perfumers
Calamus root powder Mental health problems Heilen Biopharm
Winton tablets and syrup Reduce tension, stress, and anxiety Scortis Healthcare
Chesol syrup Muscular aches and pains, chest colds, and bronchitis J & J Dechane Laboratories Private Limited
Enzo Fast Acidity, gastritis, flatulence, indigestion Naturava
Dark Forest Vekhand powder Abdomen pain, worms (infants) Simandhar Herbal Pvt. Ltd.
Nervocare Insomnia Deep Ayurveda
Antress tablets Anxiety and stress disorders Ayursun Pharma
Grapzone syrup Mental wellness Alna Biotech Pvt Ltd.
Memoctive syrup Improves memory power Aayursh Herbal India
Smrutihills capsules Stress, anxiety, adaptogenic Ayush Arogyam
Gastrin capsules Gastritis, dyspepsia Sarvana Marundhagam
Pigmento tablets Leukoderma or vitiligo Charak Pharma
Paedritone drops Digestive functions
Vacha Churna Brain tonic, digestion, nausea Sadvaidyasala
Alert capsules Immunomodulator, anxiety Vasu Healthcare
Brento tablets Increasing cognitive functions
Zandu Realty Limited
Livotrit Forte Hepatitis, jaundice
Zanduzyme Indigestion and dyspepsia
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Table 2. Cont.
Medicine/Formulations Indications/Use Manufacturers
Vedic Slim Anti-obesity Vedic Bio-Labs Pvt. Ltd.
Hinguvachaadi Gulika Anorexia, indigestion, appetite loss Nagarajuna Pvt. Ltd.
Nilsin capsules Sinusitis and allergic rhinitis Phytomarketing
Norbeepee tablet Hypertension AVN Formulations
Sooktyn tablet Antacid, antispasmodic Alarsin Pharma Pvt. Ltd.
Deonac oil Pain reliving oil Doux Healthcare Pvt. Ltd.
Smrutisagar Rasa Memory enhancer Shree Dhootpapeshwar Limited
Yogaraj Guggul Vitiligo, anorexia, indigestion, loss of appetite
Kankayan Bati Gastritis, flatulence, dyspepsia Baidyanath Pvt. Ltd.
Brahmi Ghrita Insanity and memory issues
Fat Go Controls high cholesterol level Jolly Healthcare
Divya Medha Vati Improves memory power Patanjali Ayurveda
Divya Mukta Vati High blood pressure
J. Clin. Med. 2020,9, 1176 12 of 45
5. Phytochemistry
The phytochemical investigation of this plant has been ongoing since the year 1957 [
73
,
74
]. To date,
about 145 compounds were isolated from A. calamus rhizomes and leaves, viz. phenylpropanoids,
sterols, triterpene glycosides, triterpenoid saponins, sesquiterpenoids, monoterpenes, and alkaloids
(Table 3). Amongst those, phenylpropanoids (chiefly, asarone and eugenol) and sesquiterpenoids
have been considered the principal eective compounds of A. calamus. Chemical structures of isolated
compounds from A. calamus are illustrated in Figure 5.
J. Clin. Med. 2020, 9, 1176 16 of 46
Figure 5. Cont.
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Figure 5. Cont.
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Figure 5. Chemical structures of isolated compounds from A. calamus.
6. Pharmacological Properties
Diverse bioactivities of A. calamus extracts are evident from preclinical (in vitro and in vivo) and
clinical reports, such as antidiabetic, anti-obesity, antihypertensive, antioxidant, anti-inflammatory,
immunomodulatory, anticonvulsant, and neuroprotective [105–173]. The summarized information
on A. calamus botanical parts, extract type, and their bioactivities in neurological and metabolic
disorders is stipulated in Table 4.
6.1. Antidiabetic Effect
The antidiabetic effect of A. calamus ethyl acetate fraction was evaluated in streptozotocin (STZ)-
induced and diabetic (db/db) mice. Glucagon-like peptide-1 (GLP-1) levels, plasma insulin, “and
related gene expression were evaluated. The fraction (100 mg/kg, intragastric (i.g.)) indicated a
significant reduction in blood glucose levels. For in vitro, at the concentration of 12.5 μg/mL, a
significant increment in GLP-1 levels was found in the insulin-secreting L-cell culture medium [108].
The ethyl acetate radix fraction exhibited a significant effect on the HIT-T15 cell line and α-
glucosidase enzyme. The ethyl acetate fraction also enhanced insulin secretion in HIT-T15 cells and
blocked the α-glucosidase in vitro activity with 0.41 μg/mL of inhibitory concentration (IC50) [109].”
6.2. Anti-Obesity Effect
The β-asarone compound isolated from the rhizome was investigated against high-fat diet
(HFD)-induced obesity in animals. β-Asarone-treated adipose rats showed weight loss, but also
inhibited metabolic transformations, as well as glucose intolerance, elevated cholesterol, and
adipokine variance [143]. The in vitro investigation on the A. calamus aqueous extract showed lipid-
lowering activity through inhibition of the pancreatic lipase percentage (28.73%) [144].
6.3. Antihypertensive Effect
The antihypertensive effects of A. calamus were studied on their own, in isolation, and in
combination with Gymnema sylvestre in the HFD-induced hypertension in rats. The HFD was given
for 4 weeks, which significantly increased the average systolic blood pressure (SBP). At a 200 mg/kg
Figure 5. Chemical structures of isolated compounds from A. calamus.
5.1. Phenylpropanoids
Phenylpropanoids have an aromatic ring with a structurally diverse group of phenylalanine-
derived secondary plant metabolites (C
6
–C
3
), like
α
-asarone,
β
-asarone, eugenol, isoeugenol, etc. [
75
].
A number of phenylpropanoids have been identified from A. calamus rhizome and leaves
(1-45)
.
α
and
β
-asarone isolated from the rhizome are the predominant compounds present in this plant. A series of
aromatic oils from the rhizome with diverse structures are also reported [7498].
J. Clin. Med. 2020,9, 1176 15 of 45
Table 3. Chemical compounds isolated from dierent botanical parts of A. calamus.
Classification Compound No. Chemical Ingredient Methods of
Characterization Parts/Extract References
Phenylpropanoids
1α-Asarone
GC-FID, GC-MS Rhizomes/n-hexane, aqueous,
methanol, ethanol [74,78,84,8991]
2β-Asarone
3γ-Asarone
4Eugenyl acetate
GC-MS
Rhizomes/aqueous extract [74,78,91]
5Eugenol
6Isoeugenol
7Methyl eugenol Rhizomes/n-hexane,
ethyl acetate [92]
8Methyl isoeugenol Rhizomes/hexane [74,78,91,94]
9Calamol
Rhizomes/aqueous extract
[74,78,91]
10 Azulene
11 Eugenol methyl ether
12 Dipentene
13 Asaronaldehyde
14 Terpinolene
15 1,8-cineole
16 (E)-isoeugenol acetate
GC-FID, GC-MS
[89]
17 (E)-methyl isoeugenol
18 Cis-methyl isoeugenol
Rhizomes/n-hexane, ethyl acetate [92]
19 Euasarone
20 Cinnamaldehyde
21 Cyclohexanone GC-MS Rhizomes/hexane [94]
22 Acorin
NMR Rhizomes/chloroform [95]
23 Isoasarone
24 Safrole
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Table 3. Cont.
Classification Compound No. Chemical Ingredient Methods of
Characterization Parts/Extract References
Phenylpropanoids
24 Safrole
25 Z-3-(2,4,5-trimethoxyphenyl)-2-propenal
FTIR, NMR Rhizomes/ethanol [96]
26 2,3-dihydro-4,5,7-trimethoxy-1-ethyl-2-methyl-3
(2,4,5-trimethoxyphenyl) indene
27 (Z)-asarone
GC-MS
Leaves/n-hexane [97]
28 (E)-caryophyllene
29 Estragole
Rhizomes/aqueous [98]
30 Carvacrol
31 2-cyclohexane-1-one
32 Naphthalene
33 γ-Cadinene
34 Aristolene
35 1(5),3-aromadenedradiene
36 5-n-butyltetraline
37 4,5-dehydro-isolongifolene
38 Calarene
39 Isohomogenol
40 Zingiberene
41 α-Calacorene
42 5,8-dimethyl isoquinoline
43 Cyclohexane methanol
44 Longifolene
45 Isoelemicin
J. Clin. Med. 2020,9, 1176 17 of 45
Table 3. Cont.
Classification Compound No. Chemical Ingredient Methods of
Characterization Parts/Extract References
Sesquiterpenoids
46 Calamene
Rhizomes/aqueous
[74,78,91]
47 Calamenenol
48 Calameone
49 Preisocalamendiol
50 1,4-(trans)1,7(trans)-acorenone
[93]
51 1,4-(cis)-1,7-(trans)-acorenone
52 2,6 diepishyobunone
53 α-Gurjunene
54 β-Gurjunene
55 α-Cedrene [98]
56 β-Elemene
57 β-Cedrene
[93]
58 β-Caryophyllene
59 Valencene
60 Viridiflorene
61 α-Selinene GC-FID, GC-MS [89,93]
62 δ-Cadinene
GC-MS
[93]
63 α-Curcumene
64 Shyobunone [84,93,99,100]
65 Isoshyobunone [93,99,101]
66 Caryophyllene oxide [93]
67 Humulene oxide II GC-FID, GC-MS [89,93]
68 Elemol
GC-MS [93]
69 Cedrol
70 Spathulenol
71 Acorenone
72 α-Cadinol
73 Humulene epoxide II GC-FID, GC-MS [89]
74 α-Bisabolol
J. Clin. Med. 2020,9, 1176 18 of 45
Table 3. Cont.
Classification Compound No. Chemical Ingredient Methods of
Characterization Parts/Extract References
Sesquiterpenoids
75 Asaronaldehyde NMR Rhizomes/chloroform [95]
76 Calamusenone
GLC, IR, NMR Rhizomes/petroleum ether [99]
77 Isocalamendiol
78 Dehydroxyiso-calamendiol
79 Epishyobunone
80 Acorone
NMR
Rhizomes/hydro alcoholic [100]
81 Neo-acorane A
Rhizomes/ethanol [102]
82 Acoric acid
83 Calamusin D
84 1β,5α-Guaiane-4β,10α-diol-6-one [103]
85 Dioxosarcoguaiacol HPLC Rhizomes/petroleum ether [101]
86 7-tetracycloundecanol,4,4,11,11-tetramethyl
GC-MS
Rhizomes/ethanol [84]
87 4α,7-Methano-4α-naphth[1,8a-b] oxirene,
88 Spathulenol Rhizomes/aqueous [98]
89 Vulgarol B
90 Tatanan A
HPLC, NMR Rhizomes/95% ethanol [104]
91 Acoramone
92 2-hydroxyacorenone
93 4-(2-formyl-5-methoxymethyl
pyrrol-1-yl) butyric acid methyl ester
94 2-acetoxyacorenone
95 Acoramol
96 N-transferuloyl
tyramine
97 Tatarinoid A
98 Tatarinoid B
99 Acortatarin A
J. Clin. Med. 2020,9, 1176 19 of 45
Table 3. Cont.
Classification Compound No. Chemical Ingredient Methods of
Characterization Parts/Extract References
Monoterpenes
100 α-Pinene
GC-MS
Rhizomes, roots/aqueous
[74,78,91,93]
101 β-Pinene
102 Camphene [74,78,91,93,98]
103 o-Cymol [98]
104 p-Cymene GC-FID, GC-MS [89,93,98]
105 γ-Terpinene
GC-MS
[98]
106 α-Terpinolene
107 Anethole
108 Thymol
109 Isoaromadendrene epoxide
110 Camphor Rhizome, leaves, roots/aqueous,
hexane [93,97]
111 Sabinene
Roots/aqueous
[93]
112 2-hexenal
113 Limonene [93,98]
114 Cis-linaloloxide
[93]
115 Cis-sabinene hydrate
116 Trans-linalol oxide
117 Linalool [93,97]
118 Terpinen-4-ol
[93]
119 α-Acoradiene
120 β-Acoradiene
121 α-Terpineol
122 Isoborneol Leaves/hexane [97]
J. Clin. Med. 2020,9, 1176 20 of 45
Table 3. Cont.
Classification Compound No. Chemical Ingredient Methods of
Characterization Parts/Extract References
Xanthone glycosides
123
4,5,8-trimethoxy-xanthone-2-O-
β
-D-glucopyranosyl
(1-2)-O-β-D-galactopyranoside
NMR
Rhizome/ethanol
[83]
Triterpenoid
saponins
124
1β,2α,3β, 19α-Tetrahydroxyurs-12-en-28-oic
acid-28-O- {(β-D-glucopyranosyl (1-2)}-β-D
galactopyranoside
[82]
125
3-β,
22-
α
-24,29-Tetrahydroxyolean-12-en-3-O-(
β
-Darabinosyl
(1,3)}-β-D-arabinopyranoside
Alkaloids
126 Trimethoxyamphetamine,2,3,5
GC-MS [84]
127 Pyrimidin-2-one,4-[N-methylureido]-1-[4methyl
amino carbonloxy methy]
Triterpene glycoside 128 22-[(6-deoxy-α-L-rhamnopyranosyl)
oxy]-3,23-dihydroxy-, methyl ester, (3
β
,4
β
,20
α
,22
β
)
NMR Root, Rhizomes/ethyl acetate [85]
Steroids/Sterols 129 β-daucosterol
Amino acids
130 Arginine
HPLC Roots/ethanol [86,87]
131 Lysine
132 Phenylalanine
133 Threonine
134 Tryptophan
135 α-alanine
136 Asparagine
137 Aspartic acid
138 Norvaline
139 Proline
140 Tyrosine
141 Glutamic acid
Fatty acids
142 Palmitic acid
GLC Rhizome/petroleum ether [88]
143 Myristic acid
144 Palmitoleic acid
145 Stearic acid
GC-FID, gas chromatography – flame ionization detector; GC-MS, gas chromatography – mass spectrometry; NMR, nuclear magnetic resonance; FTIR, Fourier-transform infrared
spectroscopy; GLC, gas liquid chromatography; IR, infrared spectroscopy; HPLC, high-performance liquid chromatography.
J. Clin. Med. 2020,9, 1176 21 of 45
5.2. Sesquiterpenoids
About 44 sesquiterpenes, including lactones, were characterized and identified in A. calamus
rhizomes. Sesquiterpene lactones are produced of 3 isoprene units and composed of lactone rings.
α
β
unsaturated
γ
-lactonic ring in sesquiterpene lactones is believed to be responsible for pharmacological
activity (46-99) [74,78,89,91,93,98104].
5.3. Monoterpenes
Monoterpenes (C-10) are the simplest class of the terpene series that belongs to two isoprene units
(tricyclic, bicyclic, monocyclic, etc.). Monoterpenes can have dierent functional groups, like aldehydes,
ketones, esters, ethers, phenols, and alcohols [
80
]. These organic compounds emit the characteristic
flavor and fragrance of A. calamus leaves and rhizomes (100-122) [74,78,89,91,93,97,98].
5.4. Triterpenoid Saponins
Triterpenoid saponins are made up of a pentacyclic C-30 terpene skeleton as a pillar. Limited
reports studying triterpenoid saponins in A. calamus are available, and only two triterpenoid saponins
(124, 125) have been isolated from A. calamus rhizomes (Table 3) [85].
5.5. Other Compounds
To date, one xanthone glycoside (123) [
82
,
83
], two alkaloids (126-127) [
84
], one triterpene glycoside
(128), one steroid (129) [
85
], 12 amino acids (130-141) [
86
,
87
], and 4 fatty acids (142-145) [
88
] have been
identified in A. calamus rhizomes [8388].
6. Pharmacological Properties
Diverse bioactivities of A. calamus extracts are evident from preclinical (
in vitro
and
in vivo
) and
clinical reports, such as antidiabetic, anti-obesity, antihypertensive, antioxidant, anti-inflammatory,
immunomodulatory, anticonvulsant, and neuroprotective [
105
173
]. The summarized information on
A. calamus botanical parts, extract type, and their bioactivities in neurological and metabolic disorders
is stipulated in Table 4.
J. Clin. Med. 2020,9, 1176 22 of 45
Table 4. Preclinical claims of A. calamus in neurological and metabolic disorders.
Action Parts of Plant Extract/Compound Animal Model Dosage Results References
Antidiabetic eects
Rhizomes
Methanol STZ-induced 50, 100, and 200 mg/kg, p.o. to rats
Lipid profile and blood glucose,
while levels of plasma insulin,
tissue glycogen, and G6PD
[105]
Alloxan-induced 150 and 200 mg/kg, p.o. to rat Blood glucose level [106]
Ethyl acetate
Genetically obese diabetic
C57BL/Ks db/db mice 100 mg/kg, p.o. Levels of triglycerides and
serum glucose [107]
GLP-1 expression and secretion
with STZ-induced 100 mg/kg, i.g. Secretion of GLP-1 and blood
glucose levels [108]
In vitro HIT-T15 cell line and
alpha-glucosidase enzyme 6.25, 12.5, and 25 µg/mL
Insulin secretion in HIT-T15 cells
[109]
Glucose tolerance 400 and 800 mg/kg, p.o. to mice
Serum glucose, and abolished the
level of blood glucose
Anti-obesity eects
Ethanol and aqueous HFD-induced 100 and 200 mg/kg to rats Levels of serum cholesterol and
triglycerides,
lipoprotein fraction
[110]
Diethyl ether HFD-induced 20 and 40 mg/kg, p.o. to rats
Total cholesterol and low-density
lipoprotein levels, plasma
fibrinogen levels
[111]
Methanol
Triton-X-100-induced
hyperlipidemic 250 and 500 mg/kg to rats Dose-dependent
anti-hyperlipidemic eect [112]
HFD-induced 250 and 500 mg/kg, p.o. to rats
Level of total cholesterol,
triglycerides, and LDL,
HDL cholesterol
[113]
Aqueous HFD-induced 100, 200, and 300 mg/kg, p.o. to rats
Levels of serum glucose, leptin,
and insulin along with
triglyceride, low-density
lipoprotein, very LDL cholesterol,
total cholesterol, phospholipids,
and free fatty acid increased levels
[114]
Antihypertensive eects Ethyl acetate Clamping the left kidney
artery for 4 h 250 mg/kg, p.o. to rats
SBP and DBP, blood urea nitrogen,
creatinine and LPO,
level of nitric
oxide, SOD, CAT, GPX
[115]
Crude extract, ethyl acetate and
n-hexane
Blood pressure lowering eect in
normotensive
10, 30, and 50 mg/kg to
anesthetized rats
Relaxant eects mediated through
Ca+2antagonism
and NO pathways
[116]
Ethanol and α-asarone Dimethyl sulfoxide-induced noise
stress to rats 100 and 9 mg/kg, p.o. to rats
Destructive eect of stress
enlightening the morphological
changes of hippocampus
[117]
Anti-inflammatory eects Leaves Ethanol Carrageenan-induced paw edema 100 and 200 mg/kg to rats Histamine, 5-HT, and kinins [118]
Antioxidant eects
Rhizomes α-asarone Noise stress induced to rats 3, 6, and 9 mg/kg, i.p. to rats
SOD and LPO, decreased CAT,
GPX, GSH, vitamins C and E,
and protein thiol levels
[119]
Leaves and rhizomes Ethyl acetate and methanol DPPH radical scavenging
chelating ferrous ions, FRAP
200, 100, 80, 60, 40, 20, 10, and 5
µ
g/mL
Prominent DPPH scavenging
activity, chelating ferrous ions, and
reducingpower
[120,121]
Rhizomes Ethanol Acetaminophen-induced 250, 500 mg/kg, p.o. to rats MDA and SOD, CAT, GPX,
GSH levels [122]
J. Clin. Med. 2020,9, 1176 23 of 45
Table 4. Cont.
Action Parts of Plant Extract/Compound Animal Model Dosage Results References
Anticonvulsant eects
Roots Ethanol and β-asarone Kainic acid-induced convulsion 35 and 20 mg/kg
Epileptic seizure,
neuroprotective,
and regenerative ability
[123]
Methanol PTZ-induced convulsion 100 and 200 mg/kg, p.o. to mice Latency period and
PTZ-induced seizure time [124]
Rhizomes
Calamus oil MES, PTZ, and MCS model 30, 100, and 300 mg/kg, p.o. to mice Calamus oil is found stable [125]
Ethanol MES and PTZ-induced convulsion 250, 500 mg/kg, p.o. to mice Hind limb extension and tonic
flexion of forelimbs [126]
Methanol
MES and PTZ-induced 250 and 150 mg/kg, p.o. to rats Immobility time at 250 mg/kg;
however, ineective at 150 mg/kg [127]
Antidepressant eects
TST and FST 50 and 100 mg/kg, i.p. to mice Immobility time in a
dose-dependent manner [128]
Leaves TST and FST 50 and 100 mg/kg Immobility time [129]
Roots Aqueous TST and FST 100, 150, 200 mg/kg, p.o. to mice Immobility time [130]
Rhizomes
Hydro-alcoholic extract TST and FST 75 and 150 mg/kg, p.o. to mice Corticosteroid levels [131]
Ethanol OFB and HPM test 72 mg/kg, p.o. No stimulation of postsynaptic
5-HT1A receptors [132]
Methanol and acetone Behavioral despair test 5, 20, and 50 mg/kg, p.o. Spontaneous locomotor activity [133]
β-asarone EPM and FST 25, 50, and 100 mg/kg, p.o. Immobility time [134]
Neuroprotective eects
Hydro-alcoholic CCI of sciatic nerve-induced
neuropathic pain 10 mg/kg to rats Significantly ameliorated
CCI-induced nociceptive pain [135]
CCI of sciatic nerve-induced
peripheral neuropathy 100 and 200 mg/kg to rats
Prevented CCI-induced
neuropathy through oxidation
and inflammation
[136]
Leaves Methanol and acetone Apomorphine-induced stereotypy
and haloperidol-induced catalepsy
20 and 50 mg/kg to mice
Reversed stereotypy induced by
apomorphine and significantly
potentiated catalepsy
induced by haloperidol
[137]
Rhizomes
Ethanol
Spontaneous electrical activity and
monoamine levels of the brain 200 and 300 mg/kg to rats
Depressive response by altering
electrical activity, including
changing brain monoamine levels
[138]
Hydro-alcoholic MCAo-produced brain ischemia 25 mg/kg to rats
Improvement in neurobehavioral
performance,
levels of GSH, SOD,
and LPO level
[139]
Ethanol Methotrexate-induced stress 5, 10, 15, 20, 25 ppm concentration to
fruit flies
Elevated ROS, SOD, CAT, and
GPX levels [140]
Cardioprotective eects Whole plant DOX-induced myocardial toxicity 100 and 200 mg/kg to rats
Serum enzyme levels and
protected the myocardium from
the toxic eect of DOX
[141]
Rhizomes Crude, n-hexane, ethyl acetate Guinea pig tracheal segments 0.01 mg/mL Force and rate of contractions at
higher concentrations [142]
CAT, catalase; CCI, chronic constriction injury; COX, cyclooxygenase; DBP, diastolic blood pressure; DOX, doxorubicin; DPPH, 2,2-diphenyl-1-picrylhydrazyl radical; EPM, elevated
plus maze; FRAP, ferric reducing antioxidant power; FST, forced swim test; GLP-1, glucagon-like peptide-1; GPX, glutathione peroxidase; GR, glutathione reductase; GSH, reduced
glutathione; HDL, high-density lipoproteins; HFD, high-fat diet; HPM, high plus maze; i.g., intragastric; i.p., intraperitoneal; LDL, low-density lipoprotein; LPO, lipid peroxides; MCAo,
middle cerebral artery occlusion; MCS, minimal clonic seizure; MDA, malondialdehyde; MES, maximal electroshock; NO, nitric oxide; OFB, open field behavior; p.o., per oral; PTZ,
pentylenetetrazol; ROS, reactive oxygen species; SBP, systolic blood pressure; SOD, superoxide dismutase; STZ, streptozotocin; TST, tail suspension test.
J. Clin. Med. 2020,9, 1176 24 of 45
6.1. Antidiabetic Eect
The antidiabetic eect of A. calamus ethyl acetate fraction was evaluated in streptozotocin
(STZ)-induced and diabetic (db/db) mice. Glucagon-like peptide-1 (GLP-1) levels, plasma insulin,
“and related gene expression were evaluated. The fraction (100 mg/kg, intragastric (i.g.)) indicated
a significant reduction in blood glucose levels. For
in vitro
, at the concentration of 12.5
µ
g/mL,
a significant increment in GLP-1 levels was found in the insulin-secreting L-cell culture medium [
108
].
The ethyl acetate radix fraction exhibited a significant eect on the HIT-T15 cell line and
α
-glucosidase
enzyme. The ethyl acetate fraction also enhanced insulin secretion in HIT-T15 cells and blocked the
α-glucosidase in vitro activity with 0.41 µg/mL of inhibitory concentration (IC50) [109].”
6.2. Anti-Obesity Eect
The
β
-asarone compound isolated from the rhizome was investigated against high-fat diet
(HFD)-induced obesity in animals.
β
-Asarone-treated adipose rats showed weight loss, but also
inhibited metabolic transformations, as well as glucose intolerance, elevated cholesterol, and adipokine
variance [
143
]. The
in vitro
investigation on the A. calamus aqueous extract showed lipid-lowering
activity through inhibition of the pancreatic lipase percentage (28.73%) [144].
6.3. Antihypertensive Eect
The antihypertensive eects of A. calamus were studied on their own, in isolation, and in
combination with Gymnema sylvestre in the HFD-induced hypertension in rats. The HFD was given for
4 weeks, which significantly increased the average systolic blood pressure (SBP). At a 200 mg/kg dose,
A. calamus in combination with G. sylvestre reduced the SBP and heart rate significantly. A. calamus
with G. sylvestre exhibited synergistic eect as compared with individual herbs [145].
6.4. Anti-Inflammatory and Immunomodulatory Eect
The methanolic A. calamus rhizome extract (12.5
µ
g/mL) prevented the VCAP-1 and intercellular
expression on the surface of mouse myeloid leukemia cells and murine endothelial cells, respectively [
146
].
In an
in vitro
anti-inflammatory study (Red blood cell membrane stabilization method), the A. calamus
aqueous rhizome extract at the highest concentration of 10 mg/mL showed insignificant activity against
hemolysis inhibition and the RBC membrane stabilization percentage [
144
]. Aqueous A. calamus leave
extract was studied on HaCaT cells and restricted the characteristics of interleukin (IL)-8, IL-6 RNA
protein levels alongside interferon regulatory factor 3 (IRF3) and nuclear factor kB (NF-
κ
B) activation [
147
].
N-hexane, butanolic, and aqueous fractions of A. calamus were evaluated against cyclooxygenase (COX)
and lipoxygenase (LOX)-mediated eicosanoid production by arachidonic acid. The butanolic fraction
inhibited the COX-mediated production of thromboxane B2 (TXB2) and lipoxygenase product 1 (LP1).
Investigation of the underlying signaling pathways revealed that the butanolic fraction inhibited
phospholipase C (PLC) pathway in platelets, presumably acting on protein kinase C (PKC) [
148
].
The essential oil isolated from A. calamus was evaluated by protein denaturation assay, where at the
concentration level of 300 µg/mL, 69.56% of the inhibition level was observed [149].
6.5. Antioxidant Eect
The
in vitro
antioxidant activity of acetone, acetonitrile, alcoholic, and aqueous extracts of A. calamus
rhizomes exhibited free radical scavenging activity on the [2,2
0
-azinobis (3-ethylbenzothiazoline-
6-sulphonic acid)] free radical scavenging activity assay (ABTS), the (1, 1-diphenyl-2-picrylhydrazyl) free
radical scavenging activity assay (DPPH), and the ferric ion reducing antioxidant power assay (FRAP).
Strong antioxidant effect was noticed in the acetone extract, followed by acetonitrile and methanol, while
in the aqueous extract, poor antioxidant activity was found [
150
]. The aqueous extract exhibited superior
antioxidant eects in metal ion chelation, lipid peroxidation (LPO), and DPPH assays [
144
,
151
].
The
in vitro
antioxidant activity of ethanol, hydro-ethanol, and aqueous whole plant extracts of
J. Clin. Med. 2020,9, 1176 25 of 45
A. calamus was investigated using FRAP, DPPH, nitric oxide, hydroxyl radical, reductive ability,
and superoxide radical scavenging activity. The existence of phenolics and flavonoids in A. calamus
are believed to contribute to the promising antioxidant eect. IC
50
values of the ethanol extract were
found to be 54.82, 109.85, 38.3, 118.802
µ
g/mL for the scavenging activities of DPPH, hydroxyl radical,
superoxide radical, and nitric oxide, respectively. The irreversible potential of the above results and
the FRAP values of the extracts were found to augment in a concentration-dependent manner [
152
].
“Ethanol and hydro-alcoholic extracts of A. calamus roots and rhizomes were studied for antioxidant
potential against DPPH compared with butylated hydroxyanisole (BHA) and silymarin. Ethanol and
hydro-alcoholic extracts showed free radical scavenging activity of 59.13
±
18.95 and 56.71
±
19.54,
respectively [
153
155
]. The essential oil isolated from A. calamus showed strong antioxidant ecacy
against the
β
-carotene/linoleic acid bleaching test and DPPH free radicals [
156
]. The methanol extract
of the A. calamus rhizome was evaluated against the free radical scavenging activity, and the reported
IC
50
value was 704
µ
g/mL [
157
]. The IC
50
of the essential oil was 1.68
µ
g/mL, which showed virtuous
free radical scavenging activity in the DPPH test [149].”
6.6. Anticonvulsant Eect
The methanol extract shows anticonvulsant eects feasibly through potentiating the action of
gamma-aminobutyric acid (GABA) pathway in the central nervous system [
124
]. When it comes to the
purification of A. calamus rhizome in cow urine, it is advocated in the Ayurvedic pharmacopoeia of
India (API) before its therapeutic use. The purified rhizome was investigated in a maximal electroshock
(MES) seizure model, and phenytoin was used as the standard drug. The raw and processed rhizome
(11 mg/kg, p.o.) exhibited notable anticonvulsant activity by minimizing the span of the tonic extensor
period in rats, whereas the processed rhizome showed better therapeutic activity than when it was
raw [
158
]. The calamus oil isolated from the A. calamus rhizome was evaluated at varying dose levels
of 30, 100, and 300 mg/kg, p.o., body weight (b.w.), against MES, pentylenetetrazol (PTZ), and minimal
clonic seizure (MCS) models. The calamus oil was found to be neurotoxic at 300 mg/kg, though it was
eective in the MCS test at 6 Hz. The protective index value of calamus oil was found to be 4.65 [
125
].
6.7. Antidepressant Eect
Interaction of the methanolic A. calamus rhizome extract with the adrenergic, dopaminergic,
serotonergic, and GABAergic system was found responsible for the expression of antidepressant
activity [
128
]. In another study, the methanolic A. calamus leave extract showed significant activity
through a reduction in the immobility period in the TST and FST [129]. Through interaction with the
adrenergic and dopaminergic system, the hydro-alcoholic extract was normalized to the over-activity
of the hypothalamic pituitary adrenal (HPA) axis [
131
]. Sobers capsules (a herbo-mineral formulation
containing A. calamus) were evaluated by tail suspension and forced swimming tests in mice. At the
oral dose of 50 mg/kg for 14 days, capsules exhibited insignificant impact on locomotor activity,
and caused antidepressant eects in experimental animals [
159
]. Tensarin (the traditional medicine
of Nepal containing A. calamus) was evaluated for the anxiolytic eect in mice using the open field
test (OFT), activity monitoring along with the passive avoidance test. At all three dose levels (50, 100,
200 mg/kg), Tensarin produced an anxiolytic eect in a dose-dependent way by an improvement in
rearing, number of passages, and duration of the period employed by mice [160].
6.8. Neuroprotective Eect
The ethanolic extract was studied (25, 50, and 100 mg/kg doses, oral and intraperitoneal routes)
for learning and memory-enhancing activity. The subjects used consisted of male rates, through Y
maze and shuttle box tests models. The findings showed an increase in acquisition–recalling and
spatial recognition data [
161
]. The ethanolic A. calamus rhizome extract (0.5 mL/kg, i.p.) potentiated
pentobarbitone-created sleep periods, which caused significant inhibition of conditioned avoidance
response in rats and marked (40–60%) protection against PTZ-induced convulsions, although it did
J. Clin. Med. 2020,9, 1176 26 of 45
not show any spontaneous motor activity and impact the aggressive or fighting behavior response in
male rat pairs [162].
6.9. Cardioprotective Eect
The alcoholic A. calamus rhizome extract (100 and 200 mg/kg) considerably attenuated
isoproterenol-led cardiomyopathy in rats and showed a significant reduction in the heart/body
weight ratio, level of serum calcineurin, serum nitric oxide, serum lactate dehydrogenase (LDH),
and thiobarbituric acid reactive substances (TBARS) level. However, the level of the antioxidant
enzyme was found increased at the 100 mg/kg extract dose level [
163
]. The crude extract and its
fractions (0.01–10 mg/mL) were investigated in an isolated rabbit heart, which showed mild reduction
in the force of forced vital capacity (FVC), hazard ratio (HR), and cystic fibrosis (CF), while the ethyl
acetate extract exhibited complete suppression, and the n-hexane fraction showed the same eect on
FVC and HR, but enhanced CF. The extract and its fractions exhibited controlled coronary vasodilator
eect, interceded maybe by an endothelial-derived hyperpolarizing factor [
164
]. The cardioprotective
potential of the whole plant’s ethanolic extract (100 and 200 mg/kg) reduced serum enzyme levels and
shielded the myocardium from the lethal eect of DOX [141].
6.10. Cytochrome Inhibitory Activities
Cytochromes P450 (CYPs) are the prime enzymes that catalyze the oxidative metabolism of a
wide variety of xenobiotics. It is known that 2,4,5-trimethoxycinnamic acid is the main metabolite of
α
-
or
β
- asarone [
165
]. The metabolism rate of
α
- and
β
-asarone was shown to be directly proportional to
the CYPs concentration in rat hepatocytes and liver microsomes [
166
,
167
]. CYP3A4 (CYP isoforms) has
been reported for bioactivation of
α
-asarone [
168
]. The hydro-alcoholic A. calamus extract and
α
-asarone
were evaluated by the CYPs-carbon monoxide complex method. The extract exhibited moderate
potential interaction in CYP3A4 (IC
50
=46.84
µ
g/mL) and CYP2D6 (IC
50
=36.81
µ
g/mL), while
α
-asarone
showed higher interaction in CYP3A4 (IC
50
=65.16
µ
g/mL) and CYP2D6 (
IC50 =55.17 µg/mL
) [
169
].
These outcomes indicated that both extracts and
α
-asarone interacted quite well in drug metabolism
and also had an inhibitory eect on CYP3A4 and CYP2D6. The drug-drug interaction eect of the A.
calamus extract and its main chemical constituent (
α
and
β
-asarone) needs to be studied in more CYPs
isomers, like CYP2C9 and CYP2E1.
6.11. Toxicity and Safety Concerns
In acute and sub-acute toxicity of the hydro-alcoholic extract of A. calamus in rats, at the highest
dose level of 10 gm/kg, no severe changes were observed, and the lethal dose (LD
50
) was found to be
5 g/kg [
170
]. The petroleum ether extracts (obtained by cold rolling, water distillation, and Soxhlet
extraction methods) of the A. calamus rhizome showed mild toxicity in two-day-old oriental fruit flies [
171
].
The ethanolic extract of the A. calamus rhizome at oral dosage of 175, 550, 1750,
and 5000 mg/kg b.w.
was
given for 14 days within an acute toxicity study, while at the dose level of 0, 200, 400, and 600 mg/kg, p.o.,
the extract was given for 90 days within a chronic toxicity study. At the doses of 1750 and 5000 mg/kg,
piloerection, tremors, and abdominal breathing were found for 30 min [
172
]. In that study, A. calamus
was purified for 3 h in cow urine, decoction of Sphaeranthus indicus, and decoction of leaves of Mangifera
indica,Eugenia jambolana,Feronia limonia,Citrus medica, and Aegle marmelos, followed by fomentation with
Gandhodaka (decoction of six aromatic herbs) for 1 h. The acute oral toxicity test of raw and purified
A. calamus was performed in albino rats at 2000 mg/kg for 2 weeks. At the 2000 mg/kg dose, A. calamus
did not produce any toxic symptoms within 14 days [173].
The
β
-asarone compound isolated from A. calamus was found to be carcinogenic and toxic [
174
].
The LD
50
value of
β
-asarone by oral and intraperitoneal route was found to be 1010 and 184 mg/kg,
respectively, in mice and rats [
175
]. The LD
50
of calamus oil was found to be 8.88 gm/kg b.w. [
176
],
while in the calamus oil obtained from Jammu, India, the LD
50
was 777 mg/kg b.w. [
177
]. Overall,
J. Clin. Med. 2020,9, 1176 27 of 45
several investigations have been carried out on A. calamus regarding its toxicity; however, no noticeable
data on toxicity have been found so far.
7. Clinical Reports
A. calamus has also been clinically investigated as a monotherapy as well as in combination with
other medicinal herbs in healthy subjects and suerers of various metabolic and neurological ailments.
Most clinical research has looked at the A. calamus eect on obesity, depression, neuroprotection,
and cardiovascular disease [178191]. The data obtained so far can be found in Table 5. Furthermore,
a systematic review reveals that A. calamus (alone or in combination therapy) exhibits anti-obesity,
antidepressant, and cardioprotective eects, as well as helps physical and mental performance.
J. Clin. Med. 2020,9, 1176 28 of 45
Table 5. Clinical claims of A. calamus in neurological and metabolic disorders.
Formulations/Dosage forms
A. calamus Subjects Study Design Intervention Primary Endpoint Outcome Evidence Quality Reference
A. calamus rhizome powder
24 patients of both sexes
with hyperlipidemia
Randomized
single-blind
controlled study
500 mg twice daily after meal
for 1 month
BMI, body perimeter,
skinfold depth
Significant reduction in
skinfold depth, fatigue,
and excessive hunger
III [178]
Davaie Loban capsules (A. calamus,
nut grass, incense, ginger,
and black pepper)
24 patients of both
sexes with Alzheimer’s
disease
Double-blind
randomized clinical
study
500 mg capsule thrice daily for
3 months
ADAS-cog and CDR-SOB
scores
At 4 weeks and 12 weeks:
significant reduction in the
ADAS-cog and CDR-SOB scores
III [179]
70% hydro-alcoholic extract of
A. calamus
33 patients of both sexes
(20 male and 13 female)
with anxiety disorder
Non-randomized,
open-label, single-arm
study
500 mg extract of one capsule
twice daily after meal for
2 months
BPRS score Significant reduction of anxiety
and stress-related disorder III [180]
Vachadi Churna (A. calamus,Cyperus
rotundus,Cedrus deodara, ginger,
Aconitum Heterophyllum,T. chebula)
30 obese patients of both
sexes aged 14–50 years
Non-randomized,
open-label,
single-arm study
3 g powder twice daily with
lukewarm water before meal
for 1 month
BMI, girth measurements of
mid-thigh, abdomen, hip, chest
Significant improvement in
extreme sleep, body heaviness,
fatigue, and excessive hunger
III [181]
Guduchyadi Medhya Rasayana,
(A. calamus,Tinospora cordifolia,
Achyranthes aspera,Embelia ribes,
Convolvulus pluricaulis,T. chebula,
S. lappa,Asparagus racemosus,
cow ghee, and sugar)
138 patients of both
sexes aged 55–75 years
with senile memory
impairment
Randomized,
two-parallel-group
study
3 g granule thrice daily after
meal for 3 months
Mini–Mental State Examination,
BPRS score, and estimation of
serum acetylcholinesterase
Significant improvement in
terms of recall memory,
cognitive impairment, amnesia,
concentration ability,
depression, and stress
III [182]
Dried aqueous extract of A. calamus
40 healthy volunteers,
both sexes aged 18–50
years with a
premedicant for
anesthesia
Open-label randomized,
two- parallel-group
study
90 min before anesthesia;
In the control group:
0.2 mg intramuscular (IM)
glycopyrrolate and a 0.2 mg IM
50 mg tablet of promethazine
hydrochloride with water;
In the second group: 0.2 mg IM
glycopyrrolate and 100 mg
A. calamus extract
Pulse rate, blood pressure,
respiratory rate,
body temperature
The dried aqueous extract
exhibited anti-hyperthermic
and sedative eect without
producing
any respiratory depression
III [183]
Shankhapushpyadi Ghana Vati
(A. calamus,C. pluricaulis,Bacopa
monnieri,T. cordifolia,C. fistula,
A. indica,S. lappa,Tribulus terrestris)
20 hypertensive patients
of both sexes
Randomized
single-blind controlled
study
1 g twice daily after meal for
2 months SBP and DBP Significant relief in raised SBP
and DBP III [184]
Brahmyadiyoga (A. calamus,Centella
asiatica,Rauvolfia serpentina,Saussurea
lappa,Nardostachys jatamansi)
10 schizophrenia
patients of both sexes
aged 18–40 years
Non-randomized,
open-label, single-
arm study
4 tablets thrice daily for three
months after meal Symptoms rating scale
Significant eect as a brain
tonic, tranquillizer, hypnotic,
and sedative
III [185]
Bala compound (A. calamus,
Emblica ocinalis,E. ribes,T. cordifolia,
Piper longum,Glycyrrhiza glabra,
C. rotundus,A. heterophyllum)
24 neonates, both sexes,
2.5–3 kg body weight
Randomized
single-blind controlled
study
5 oral drops twice daily for
6 months
Change in serum
immunoglobulins (IgG, IgM,
and IgA) levels
Significant improvement in
immunoglobulin levels after
6 months
Ib [186]
Vachadi Ghrita (A. calamus,
T. cordifolia,Hedychium spicatum,
C. pluricaulis,E. ribes, ginger, A. aspera,
T. chebula, and cow ghee)
90 healthy individuals
of both sexes aged 40–50
years for assessment
of cognition
Non-randomized
positive-controlled
study
10 g twice daily for 1 month
with lukewarm water
Post Graduate Institute
Memory Scale (PGIMS) test
Significant change in the mental
balance score, holding
of like and dierent pairs,
late-immediate memory,
and also improved digestion
III [187]
J. Clin. Med. 2020,9, 1176 29 of 45
Table 5. Cont.
Formulations/Dosage forms
A. calamus Subjects Study Design Intervention Primary Endpoint Outcome Evidence Quality Reference
Bramhi Vati (A. calamus,B. monnieri,
C. pluricaulis,Onosma bracteatum,
copper pyrite, iron pyrite, mercuric
sulphide, Piper nigrum,N. jatamansi)
68 essential
hypertension patients of
both sexes
aged 20–70 years
Randomized,
double-blind,
parallel-group
comparative study
500 mg tablets twice daily for
1 month
Hamilton anxiety rating scale,
SBP and DBP, and MAP
Significant improvement in the
Hamilton anxiety rating scale,
SBP and DBP, and MAP
III [188]
Tagaradi Yoga (A. calamus,
Valeriana wallichii,N. jatamansi)
24 insomnia patients of
both sexes
aged 18–75 years
Non-randomized
positive-controlled
study
500 mg hydro-alcoholic extract
capsule twice daily after meal
for 15 days
Sleep duration, initiating time
of sleep, quality of sleep
Significant improvement in
sleep duration, in the initiating
time of sleep,
and in quality of sleep
III [189]
Acorus calamus rhizome powder
20 obese patients of both
sexes
Randomized
single-blind study
250 mg rhizome powder twice
daily for 1 month
Body weight, height according
to age, waist-hip ratio, and BMI
Significant improvement in
extreme sleep, body heaviness,
fatigue, and excessive hunger
III [190]
Acorus calamus rhizome powder 45 ischemic heart
disease patients
Non-randomized
positive-controlled
study
3 gm rhizome powder twice
daily for 3 months ECG, serum cholesterol level
Improvement of chest pain,
dyspnea on eort, reduction of
the body mass index, improved
ECG: reduced serum
cholesterol, reduced serum
LDL, and increased serum HDL
Ib [191]
ADAS-cog, alzheimer’s disease assessment scale–cognitive subscale; BMI, body mass index; BPRS, brief psychiatric rating scale; CDR-SOB, clinical dementia rating scale sum of boxes; DBP,
diastolic blood pressure; ECG, electrocardiogram; Ib, evidence from at least one randomized study with control; HDL, high-density lipoprotein; Ig, immunoglobulin; III, evidence from
well-performed nonexperimental descriptive studies, as well as from comparative studies, correlation studies, and case studies; LDL, low-density lipoprotein; MAP, mean arterial pressure;
SBP, systolic blood pressure.
J. Clin. Med. 2020,9, 1176 30 of 45
8. Mechanistic Role
The proposed mechanism of action of A. calamus in neurological and metabolic disorders includes a
synergic integration of antioxidant defense, GABAergic transmission, brain stress hormones modulation,
pro-inflammatory cytokines, leptin and resistin levels, adipocytes inhibition, calcium channel blocker
eect, protein synthesis, oxidative stress, acetylcholinesterase (AChE) inhibition, and anti-dopaminergic
properties. A compendium of mechanisms of action of A. calamus in neurological and metabolic
protection is illustrated in Figure 6and Table 6.A. calamus significantly aects fasting blood sugar, insulin
resistance, HbA1c, and the adipogenic transcription expression factor through various mechanisms, viz.
antioxidant, anti-inflammatory,
β
-cells regeneration, improving insulin sensitivity, gluconeogenesis,
nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and glucose transporter type 4
(GLUT-4)-mediated transport inhibition.
J. Clin. Med. 2020, 9, 1176 26 of 46
of leaves of Mangifera indica, Eugenia jambolana, Feronia limonia, Citrus medica, and Aegle marmelos,
followed by fomentation with Gandhodaka (decoction of six aromatic herbs) for 1 h. The acute oral
toxicity test of raw and purified A. calamus was performed in albino rats at 2000 mg/kg for 2 weeks.
At the 2000 mg/kg dose, A. calamus did not produce any toxic symptoms within 14 days [173].
The β-asarone compound isolated from A. calamus was found to be carcinogenic and toxic [174].
The LD50 value of β-asarone by oral and intraperitoneal route was found to be 1010 and 184 mg/kg,
respectively, in mice and rats [175]. The LD50 of calamus oil was found to be 8.88 gm/kg b.w. [176],
while in the calamus oil obtained from Jammu, India, the LD50 was 777 mg/kg b.w. [177]. Overall,
several investigations have been carried out on A. calamus regarding its toxicity; however, no
noticeable data on toxicity have been found so far.
7. Clinical Reports
A. calamus has also been clinically investigated as a monotherapy as well as in combination with
other medicinal herbs in healthy subjects and sufferers of various metabolic and neurological
ailments. Most clinical research has looked at the A. calamus effect on obesity, depression,
neuroprotection, and cardiovascular disease [178–191]. The data obtained so far can be found in Table
5. Furthermore, a systematic review reveals that A. calamus (alone or in combination therapy) exhibits
anti-obesity, antidepressant, and cardioprotective effects, as well as helps physical and mental
performance.
8. Mechanistic Role
The proposed mechanism of action of A. calamus in neurological and metabolic disorders
includes a synergic integration of antioxidant defense, GABAergic transmission, brain stress
hormones modulation, pro-inflammatory cytokines, leptin and resistin levels, adipocytes inhibition,
calcium channel blocker effect, protein synthesis, oxidative stress, acetylcholinesterase (AChE)
inhibition, and anti-dopaminergic properties. A compendium of mechanisms of action of A. calamus
in neurological and metabolic protection is illustrated in Figure 6 and Table 6. A. calamus significantly
affects fasting blood sugar, insulin resistance, HbA1c, and the adipogenic transcription expression
factor through various mechanisms, viz. antioxidant, anti-inflammatory, β-cells regeneration,
improving insulin sensitivity, gluconeogenesis, nicotinamide adenine dinucleotide phosphate
(NADPH) oxidase, and glucose transporter type 4 (GLUT-4)-mediated transport inhibition.
Figure 6. Illustration of role of A. calamus mechanisms in the treatment of neurological and metabolic
disorders. AChE, acetylcholinesterase; APP, amyloid precursor protein; Bcl-2, B-cell lymphoma 2;
CHOP, C/EBP homologous protein; CCAAT (cytosine-cytosine-adenosine-adenosine-thymidine)-
enhancer-binding protein homologous protein; C/EBP, CCAAT enhancer-binding protein; GABAA,
γ-Aminobutyric acid type A; GRP78, 78-kDa glucose-regulated protein; HMG-CoA, 3-hydroxy-3-
methylglutaryl coenzyme A; iNOS, inducible nitric oxide synthase; JNK, c-Jun NH2-terminal kinase;
LC3b, microtubule-associated proteins 1A/1B light chain 3B; MCP, modified citrus pectin; MDA,
malondialdehyde; MIP, macrophage inflammatory protein; p-PERK, phospho-protein kinase RNA-
like ER kinase; PPARγ, peroxisome proliferator-activated receptor gamma; ERK1/2, extracellular
signal-regulated protein kinase.
Figure 6.
Illustration of role of A. calamus mechanisms in the treatment of neurological
and metabolic disorders. AChE, acetylcholinesterase; APP, amyloid precursor protein; Bcl-2,
B-cell lymphoma 2; CHOP, C/EBP homologous protein; CCAAT (cytosine-cytosine-adenosine-
adenosine-thymidine)-enhancer-binding protein homologous protein; C/EBP, CCAAT enhancer-binding
protein; GABAA,
γ
-Aminobutyric acid type A; GRP78, 78-kDa glucose-regulated protein; HMG-CoA,
3-hydroxy-3-methylglutaryl coenzyme A; iNOS, inducible nitric oxide synthase; JNK, c-Jun
NH2-terminal kinase; LC3b, microtubule-associated proteins 1A/1B light chain 3B; MCP, modified citrus
pectin; MDA, malondialdehyde; MIP, macrophage inflammatory protein; p-PERK, phospho-protein
kinase RNA-like ER kinase; PPAR
γ
, peroxisome proliferator-activated receptor gamma; ERK1/2,
extracellular signal-regulated protein kinase.
J. Clin. Med. 2020,9, 1176 31 of 45
Table 6. Mechanistic role of phytochemicals of A. calamus in the treatment of neurological and metabolic disorders.
Study Compound Model Increased Level Decreased Level References
Anti-Parkinson
β-Asarone
6-OHDA parkinsonian Bcl-2 expression GRP78, p-PERK, CHOP, and
Beclin-1 expression [192]
6-OHDA parkinsonian - mRNA levels of GRP78 and CHOP
and p-IRE1and XBP1 [193]
Dopamine in the striatum
TH plasma concentrations
Striatal COMT levels [194]
6-OHDA parkinsonian L-DOPA, DA, DOPAC,
and HVA levels
P-gp, ZO-1, occludin, actin,
and claudin-5 [195]
Alzheimer’s
Aβ25-35-induced
inflammation Bcl-2 level TNF-α, IL-1β, IL-6, Beclin-1,
and LC3B level [196]
NG108 cells - Upregulated SYP and
GluR1 expression [197]
PC12 cells -
Aβ-induced JNK activation, Bcl-w
and Bcl-xL levels, cytochrome c
release, and caspase-3 activation
[198]
Aβ-induced cytotoxicity Cell viability, p-Akt and
p-mTOR NSE levels, Beclin-1 expression [199]
Neuroprotective
Pb-induced impairments
NR2B protein expression
along with Arc/Arg3.1
and Wnt7a mRNA levels
- [200]
β-Asarone, eugenol Scopolamine-induced
Improvement of neuron
organelles and
synaptic structure
APP expression [201]
Neotatarine MTT reduction assay - Aβ25-35–induced PC12 cell death [202]
β-asarone, paeonol MCAo model Cholecystokinin and
NF-κB signaling TNF-α, IL-1β, IL-6 production [203]
J. Clin. Med. 2020,9, 1176 32 of 45
Table 6. Cont.
Study Compound Model Increased Level Decreased Level References
Neuroprotective
β-Asarone Cultured rat astrocytes NGF, BDNF, and GDNF
expression - [204]
SN4741 cells p62, Bcl-2 expression JNK, p-JNK and Beclin-1
expressions [205]
Tatarinolactone hSERT-HEK293 cell line - SERTs activity [206]
β-Asarone
RSC96 Schwann cells GDNF, BDNF, and CNTF
expression - [207]
Aβ-induced p-mTOR and p62
expression
AChE and Aβ42 levels, p-Akt,
Beclin-1, and LC3B expression, APP
mRNA and Beclin-1 mRNA levels
[208]
Aβ1–42-induced injury - GFAP, AQP4, IL-1β, and TNF-α
expression [209]
Anti-depression
Chronic unpredictable
mild stress BDNF expression Blocked ERK1/2-CREB signaling [210]
α-Asarone
Noradrenergic and
serotonergic
neuromodulators in TST
α1and α2adrenoceptors
and 5-HT1A receptors - [211]
Anticonvulsant and
sedative Eudesmin MES and PTZ
GABA contents,
expressions of GAD65,
GABAA, and Bcl-2
Glu contents and ratio of
Glu/GABA, caspase-3 [212]
Anti-anxiety
α-Asarone
BLA or CFA-induced Down-regulation of
GABAAreceptors
Up-regulation of GluR1-containing
AMPA, NMDA receptors [213]
Anti-epilepsy
Temporal lobe epilepsy
Levels of GABA, GAD67,
and GABAAR-mRNA
expression
GABA-T [214]
Mitral cells Down-regulation of
GABAAreceptors Na+channel blockade [215]
β-Asarone KA-induced GABA Glu [216]
J. Clin. Med. 2020,9, 1176 33 of 45
Table 6. Cont.
Study Compound Model Increased Level Decreased Level References
Anti-inflammatory α-Asarone Spinal cord injury IL-4, IL-10, and arginase
1 levels
TNF-α, IL-1β, IL-6, MCP-1, MIP-2,
iNOS levels [217]
Cytoprotective
β-Asarone
tBHP-induced
astrocyte injury
GST, GCLM, GCLC,
NQO1, Akt
phosphorylation
- [218]
Cardioprotective Cultured neonate rat
cardiac myocytes
Viability of cardiac
myocytes Pulse frequency [219]
Arteriosclerosis ECV304 cell strain Apoptotic rate of
ECV304 cells
Apoptotic rate of MMP, stabilized
MMP and VSMC proliferation [220]
Anti-adipogenic 3T3-L1 preadipocytes -
C/EBPβ, C/EBPα, and PPARγ
expression levels, ERK1/2
phosphorylation
[89]
Antioxidant Cerebral artery occlusion Antioxidant activity Focal cerebral ischemic/
reperfusion injury [221]
Anti-diabetic
α-Asarone +β-asarone +
metformin HCl STZ-induced Insulin level
Glucose, glycosylated hemoglobin
level, liver dysfunction, and tumor
biomarkers
[222]
Asarone 3T3-L1 preadipocytes Hormone-sensitive lipase
phosphorylation
Intracellular triglyceride levels,
down-regulation of PPARγ
and C/EBPα
[223]
6-OHDA, 6-hydroxydopamine; Ox-LDL, oxidized low-density lipoprotein; BDNF, brain-derived neurotrophic factor; NGF, nerve growth factor; GDNF, glial derived neurotrophic
factor; SERTs, serotonin transporters; MCAo, middle cerebral artery occlusion; A
β
,
β
-amyloid; NSE, neuron specific enolase; AMPA,
α
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid; NMDA, NR2A-containing N-methyl-D-aspartate; GABA
A
,
γ
-aminobutyric acid A; BLA, basolateral amygdala; CFA, complete Freund’s adjuvant; CNTF, ciliary neurotrophic
factor; COMT, catechol-O-methyltransferase; TH, tyrosine hydroxylase; DA, dopamine; DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanillic acid; P-gp, P-glycoprotein; ZO-1,
zonula occludens-1; SYP, synaptophysin; GluR1, glutamatergic receptor 1; GABA-T, GABA transaminase; TST, tail suspension test; KA, kainic acid; MCP-1, monocyte chemoattractant
protein 1; MIP-2, macrophage inflammatory protein 2; iNOS, inducible nitric oxide synthase; GST, glutathione S-transferase; GCLM, glutamate-cysteine ligase modulatory subunit;
GCLC, glutamate-cysteine ligase catalytic subunit; NQO1, NAD(P)H quinone oxidoreductase; GFAP, glial fibrillary acidic protein; AQP, aquaporin; VSMC, vascular smooth muscle cells;
MMP, mitochondrial membrane potential; C/EBP, CCAAT enhancer-binding protein; PPAR
γ
, peroxisome proliferator-activated receptor gamma; ERK1/2, extracellular signal-regulated
protein kinase; XBP1, x-box binding protein; IRE1, inositol-requiring enzyme 1; A
β
1-42, amyloid
β
peptide; mTOR, mammalian target of rapamycin; MTT, 3-(4,5-dimethythiazol-.
2-yl)-2,5-diphenyl tetrazolium bromide; CREB, cAMP response element-binding protein; GABAAR, gamma-aminobutyric acid type-A receptor, tBHP, t-butyl hydroperoxide.
J. Clin. Med. 2020,9, 1176 34 of 45
The antihypertensive eect of A. calamus may be explained by Ca
2+
antagonists that aect the
nitric oxide pathway. The chemical constituents of A. calamus upregulate the antioxidant eect,
suppress pro-inflammatory cytokines, and act as detoxifying enzymes through the NF-
κ
B and nuclear
factor erythroid 2-related factor 2 (Nrf2) signaling pathways. The Nrf2 pathway may be activated by
phenylpropanoids, sesquiterpenoids, and monoterpenes by interaction of active phytoconstituents
with nitric oxide derivatives react with thiol groups between KEAP1 and Nrf2, along with Nrf2
phosphorylation. “When Nrf2 is released from the Kelch-like erythroid-derived CNC (cap’n’collar)
homology protein (ECH)-associated protein 1 (KEAP1), it transfers into the nucleus, where it induces
the genes encoding protein expression impenetrable in glutathione (GSH) synthesis, antioxidant, and
detoxifying phase 2 enzymes. Oxidative stress and ligands for tumor necrosis factor receptors (TNFRs)
and toll-like receptors (TLRs) activate upstream Ik-B kinases (IKKs), ensuing phosphorylation of IkB
that is generally bound to the inactive NF-kB dimer in the cytoplasm. After that, IkB is targeted for
proteasomal degradation and NF-kB, then it moves into the nucleus where it induces inflammatory
cytokine expression in addition to the genes encoding proteins like superoxide dismutase (SOD) 2 and
B cell chronic lymphocytic leukemia (CLL)/lymphoma 2 (Bcl2) involved in adaptive stress response
(Figure 7). The bioactive molecules of A. calamus can inhibit NF-kB in inflammatory immune cells, while
other phytoconstituents may activate NF-kB in neuronal cells to improve stress resistance.” A. calamus
phytoconstituents regulate NF-kB, LOX, and COX-2 activity. These compounds dose-dependently
suppress the production of inflammatory factors like NO, TNF-
α
, IL-6, IL-1
β
, and JNK signaling, acting
as anti-inflammatory agents. In addition, it was also noted that the inflammation induced by various
chemicals was inhibited by bioactive constituents through suppression of IkB/NF-kB and JNK/AP-1
signaling pathways. Thus, over several studies, it has been reported that asarone compounds have a
potential against neurodegenerative diseases.
PPAR gene and C/EBP are involved in the dierentiation process. PPAR-δand PPAR-γpromote
adipogenesis. In the same way, amino acids and glucose react with C/EBP-
δ
and C/EBP-
β
. If low
levels of glucose induce gadd153, the inactive dimer is formed, with C/EBP-βinhibiting the progress
of adipocyte development. C/EBP delta activates C/EBP-
α
. This is mainly involved in the formation
of mature adipocytes and lipid accumulation in adipose tissue. In 3T3-L1 preadipocytes,
α
-asarone
and
β
-asarone inhibited adipocyte dierentiation and reduced the intracellular lipid accumulation,
and also decreased the expression levels of adipogenic transcription factors (PPAR
γ
and C/EBP
α
).
These phytochemicals significantly promoted adenosine monophosphate-activated protein kinase
(AMPK), which is known to suppress adipogenesis. It was also found that pretreatment with
α
-asarone
and
β
-asarone, a typical inhibitor of AMPK, attenuated the inhibitory eect of asarone on AMPK
phosphorylation. The asarone-induced AMPK activation leads to a decrease in adipogenic transcription
factor expression, and suppresses adipogenesis.
J. Clin. Med. 2020,9, 1176 35 of 45
J. Clin. Med. 2020, 9, 1176 5 of 47
4. Ethnomedicinal Use
This plant is being practiced traditionally in the Indian Ayurvedic tradition, as well as in the
Chinese system of medicine for analgesic, antipyretic, tonic, anti-obesity, and healing purposes; it is
highly effective for skin diseases, along with neurological, gastrointestinal, respiratory, and several
other health disorders. Rhizomes and leaves are found to be profusely practiced in the form of
infusion, powder, paste, or decoction [13–72]. The ethnomedicinal uses of the A. calamus are detailed
in Table 1.
A. calamus rhizomes and leaves are also used as an active pharmaceutical ingredient in various
Ayurvedic formulations (Table 2).
Figure 7.
The role of the Nrf-2, NF-
κ
B, PI3K/AKT, Ras/MAPK, and PPAR
γ
signaling pathways as aected
by phytoconstituents of Acorus calamus to upregulate antioxidant, neuroprotective, detoxifying enzymes
and suppress inflammation. Ub, ubiquitin; NEMO, NF-kB essential modulator; ARE, antioxidant
response element; Maf, musculoaponeurotic fibrosarcoma oncogene homolog; NLS, nuclear localization
signal; CAT, catalase; GPX, glutathione peroxidase; Trk, tyrosine kinase receptor; LPS, lipopolysaccharide;
TLRs, toll-like receptors; PI3K, phosphatidylinsoitol-3-kinase; MAPK, mitogen-activated protein kinase;
mTOR, mammalian target of rapamycin; ERK, extracellular signal-regulated kinases; Nrf2, nuclear factor
e2-related factor 2; Keap-1, kelch-like ECH-associated protein-1; MEK, mitogen-activated protein kinase;
JNK, c-Jun N-terminal kinase;NADPH, nicotinamide adenine dinucleotide phosphate; NF-
κ
B, nuclear
factor-kappa B; IkB, inhibitor of kB; IKK, inhibitor of kB kinases.
9. Perspectives and Future Directions
The present review provides a plethora of information apropos ethnomedicinal uses, marketed
formulations, geographical distribution, chemical constituents, pharmacological activities of crude,
n-hexane, ethyl acetate, methanolic, ethanolic, hydro-alcoholic, aqueous extracts along with pure
compounds, and clinical trials related to A. calamus.
Investigations on extracts and compounds of A. calamus suggested antidiabetic, anti-obesity,
antihypertensive, anti-inflammatory, antioxidant, anticonvulsant, antidepressant, neuroprotective,
and cardioprotective potentials with distinct underlying signaling pathways. The biological potential
and mechanisms of action of some of the chemical constituents (
α
-asarone,
β
-asarone, eugenol) are
known. However, other compounds need to be scientifically explored for their bioactivities and
molecular modes of action, which could provide a lead for further development into therapeutics.
More systematic, well-designed, and multi-center clinical studies are warranted to evaluate
standardized extracts of A. calamus therapeutically and to identify the pharmacokinetic-dynamic
roles of pharmacologically active biomolecules. There is scarce data from experimental and clinical
reports on hypertension, diabetes, and atherosclerosis, and less supporting evidence is available on
the use of A. calamus to treat hypertension and diabetes. Based on the available data, it is suggested
that this plant could be used as an adjuvant to the established targeted drugs for neurological and
metabolic disorders.
In 1974, United States food & drug administration (USFDA) banned A. calamus due to its
carcinogenic eects following animal studies. They reported
β
-asarone as a carcinogenic agent, but the
study was conducted on the calamus oil which consists of
β
-asarone in about 80%, while its dierent
genotype in Europe and India contains
β
-asarone in lower concentrations. A. calamus cultivated
J. Clin. Med. 2020,9, 1176 36 of 45
in various geographical regions may have dierent chemical compositions along with therapeutic
properties challenging quality control, toxicity, and safety concerns of A. calamus. In addition, the heavy
metal, mycotoxin, and pesticide concentrations are required to be addressed in all toxicity studies.
10. Conclusions
Compelling
in vitro
,
in vivo
and clinical evidence suggests that the potential role of A. calamus
rhizomes for modulating metabolic and neurological disorders could be due to their richness in several
classes of active phytoconstituents. The predominant compounds present in rhizomes and leaves
responsible for expression of potent bioactivities include
α
-asarone,
β
-asarone, eugenol, and calamine.
The present report is expected to fill the gaps in the existing knowledge and could provide a lead for
researchers working in the areas of phytomedicine, ethnopharmacology, and clinical research.
Author Contributions:
R.S. and V.S. conceived the idea and wrote the manuscript. D.S.G., K.K., E.N., and N.M.
edited and proofread the document. The entire team approved the submission of the final manuscript. All authors
have read and agreed to the published version of the manuscript.
Funding: This paper was supported by the UHK Excellence project.
Acknowledgments:
The authors express their sincere gratitude to Bharat Ratna Mahamana Pandit Madan Mohan
Malviya, the founder of the Banaras Hindu University, Varanasi, for his services to humanity, great vision, and
blessings. This work was also supported by Universityof Hradec Kralove (Faculty of Science, VT2019-2021) [KK, EN].
Conflicts of Interest: The authors declare no conflict of interest.
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