Background
Matricaria chamomilla L. (synonym:
Matricaria recutita) commonly known as Chamomile or German Chamomile, belongs to family Asteraceae [
1]. Multiple species of Chamomile are spread over Europe, North-west Asia, North America, North Africa and the temperate regions of Asia [
2,
3]. In Pakistan, it is known as babuna or piunphulli and grows naturally in highlands of Balochistan such as, Hanna valley, Maslakh range, Muslimbagh, Kalat, Nushki, Kharan, Chaman and Ziarat. This plant is widely recognized and is more popular in the western culture for its diverse medicinal uses [
1,
4]. Since ancient times and in accordance with the references written by Hippocrates, Galen and Asclepius, its different parts including flowers, roots and oil have been used to treat variety of ailments [
5].
Chamomile as a whole plant has been used traditionally in different forms for the treatment of multiple medical complaints such as, common cold, bronchitis, gastrointestinal spasms, epilepsy, hypertension, neuralgia, toothache, dysmenorrhea, eczema, impetigo, indigestion, colic and diarrhea [
1,
4-
9]. Its flowers are also used as carminative and antipyretic, while its oil has been used in rheumatism, flatulence and colic [
10]. In addition, this plant had a very long history of its medicinal use in ancient Egypt, Greece and Rome [
11]. Chamomile is also one of the effective ingredients of several traditional formulations in the Unani and Homeopathy systems of medicine [
11-
15].
Phytochemical studies revealed the presence of alpha-bisabolol, cis-spiroethers sesquiterpenes (anthecotulid), cadinene, farnesene, furfural, spathulenol, and proazulene (matricarin and matricin) as plant constituents [
5,
16]. In addition, Chamomile has also been found to possess around 8% of flavone glycosides (apigenin 7-glycoside and its 6’-acetylated derivative) and flavonols (luteolin glucosides, quercetin glycosides, and isohamnetin); 10% of mucilage polysaccharides; 0.3% of choline and 0.1% of coumarins (umbelliferone and its methyl ether, herniarin). The presence of tannin in chamomile has also been detected less than 1% [
17-
19].
Pharmacological investigations showed that
Matricaria chamomilla possesses antiinflammatory [
20], antispasmodic [
21,
22], antibacterial [
23], digestive [
24], antioxidant and antidiabetic [
25,
26] activities. However, there is little evidence available to its medicinal use in diarrhoea. This study has been planned to explore the scientific basis for the medicinal use of
Matricaria chamomilla in hyperactive gut disorders, like diarrhoea and abdominal spasms using different
in vivo and
in vitro assays.
Discussion
To validate the medicinal use of the crude extract of
Matricaria chamomilla in hyperactive gut disorders, like diarrhoea and abdominal colic [
1,
6], this study was designed to determine the antidiarrhoeal, antisecretory and antispasmodic activities of the plant extract using the
in-vivo and
in-vitro assays. To study the insight into mechanisms isolated rabbit jejunum preparations were used.
In castor oil-induced diarrhoea and intestinal fluid accumulation models, Mc. Cr showed antidiarrhoeal and antisecretory activities at 150 and 300 mg/kg, similar to the effects of cromakalim [
38] and loperamide [
39], which are known for their spasmolytic, antidiarrhoeal and antisecretory activities. Castor oil is known to cause increased intestinal fluid contents and promotes diarrhoea indirectly through the effect of its active constituent, ricinoleic acid formed by the hydrolysis of oil [
40], which changes the electrolytes and water transport [
41] and generates massive contractions in transverse and distal colon [
42]. The observed antidiarrhoeal and antisecretory effects of the plant extract appear to be mediated partly through the involvement of potassium channels activation which was evident by partial attenuation of these effects when reproduced in mice pretreated with glibenclamide (GB), an ATP-dependent K
+ channel blocker [
34] or 4-aminopyridine (4-AP), a voltage-dependent K
+ channel blocker [
35], thus, indicating the presence of gut inhibitory constituents in Mc. Cr which might me mediating its observed antidiarrhoeal and antisecretory effects.
The role of multiple types of physiological mediators, such as, acetylcholine, histamine, substance-P, cholecystokinins, prostaglandins and 5-hydroxytryptamine [
43] and some ion channels like, K
+ or Ca
++, is well established in regulatory function of gastrointestinal system. Further, it has also been documented that most of the spasmolytic agents have therapeutic potential in diarrhoea by causing relaxation of the smooth muscle of the gut, in turn retain luminal fluid in the bowl [
38,
44].
It has been observed that most of the plant and plant-based test materials exhibit inhibitory effect through K
+ channel activation or Ca
++ channel blockade like mechanisms [
30-
33,
45,
46]. The use of low K
+ (25 mM) and high K
+ (80 mM)-induced depolarization in the tissues is usually carried out to distinguish K
+ channel opening and Ca
++ channel blocking like activities [
32,
33]. On the basis of presence of K
+ channels and voltage dependent Ca
++ channels in intestinal smooth muscles and epithelial cells [
46], K
+ channel openers (increase in K
+ efflux) and Ca
++ antagonists (inhibition of Ca
++ entry) cause smooth muscle relaxation by decreasing intracellular free Ca
++, through respective mechanisms of membrane hyperpolarization [
38,
44].
To assess whether the inhibitory effect of Mc. Cr was also mediated via similar mechanisms, it was tested on low and high K
+-induced contractions in isolated rabbit jejunum, where it caused complete relaxation of low and high K
+-induced contractions, being more potent against low K
+. Cromakalim, a known ATP-dependent K
+-channel opener [
38], inhibited only low K
+-induced contractions, while verapamil, a known Ca
++ antagonist [
44], was found equipotent against both low and high K
+-induced contractions. These data show that the presence of spasmolytic constituents in
Matricaria chamomilla, is likely to be responsible for its observed antidiarrhoeal and antisecretory activities in mice, mediating their effect primarily through K
+ channel opening (KCO) along with weak Ca
++ channel blockade (CCB) component.
To know the nature of K
+ channels involved in KCO activity of Mc. Cr, the inhibitory CRCs of plant extract against low K
+ were constructed in the absence and presence of GB or 4-AP. Interestingly, in line with
in vivo findings in mice, the inhibitory effect of Mc. Cr was potently inhibited in the presence 4-AP compared to GB. This indicates that the KCO activity of plant extract predominantly involves voltage-dependent K
+ channels along with ATP-sensitive K
+ channels, which are abundantly present in intestinal smooth muscles and are also known for their inhibitory influence in hypermotile gut [
47].
The concentration of K
+ > 30 mM, regarded as high K
+, is known to cause smooth muscle contractions through opening of voltage-dependent Ca
++ channels [
36]. Thus, a substance that inhibits high K
+-provoked contractions is considered a blocker of Ca
++ influx [
48]. The Ca
++ antagonist effect was confirmed when Mc. Cr, at slightly higher concentrations, shifted the CRCs of Ca
++ to the right with suppression of the maximum effect, a typical characteristic of Ca
++ antagonists [
37], which are known for their antispasmodic, antisecretory and antidiarrhoeal activities [
43,
44]. These findings attest the presence of CCB-like spasmolytic continents in
Matricaria chamomilla in addition to its primary effect as K
+ channel opener. This study are not only provides an evidence to the medicinal use of
Matricaria chemomilla in diarrhoea but also highlights the potential of this popular medicinal plant for the development of newer therapeutic options to treat hyperactive gut disorders, such as gut spasms and diarrhoea.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
MHM designed the project, supervised the study and drafted final manuscript. SM and UAK carried out literature search, experimental work and data acquisition. AHG contributed in study design and review of the manuscript. MA identified and procured the plant material and reviewed the manuscript for publication. All authors read and approved the final manuscript for publication.
MHM is an Assistant Professor at Natural Product Research Division,Department of Biological and Biomedical Sciences, Faculty of Health Sciences, Medical College, The Aga Khan University, Stadium Road, P.O. Box 3500, Karachi 74800, Pakistan. SM and UAK are undergraduate medical students at Medical College, The Aga Khan University, Stadium Road, P.O. Box 3500, Karachi 74800, Pakistan. AHG is a Professor of Pharmacology at Natural Product Research Unit, Department of Biological and Biomedical Sciences, The Aga Khan University Medical College, Karachi-74800, Pakistan. MA is Professor at Department of Botany, University of Balochistan, Quetta.