https://doi.org/10.52973/rcfcv-e34410
Received: 03/03/2024 Accepted: 04/04/2024 Published: 08/07/2024
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Revista Científica, FCV-LUZ / Vol. XXXIV, rcfcv-e34410
ABSTRACT
This study investigated the inuence of Salvia barrelieri (SBA) methanol
and decocted extracts (ME and DE) on intestinal transit (IT) and
gastric emptying (GE) in mice. Only the doses of ME SBA induced a
strong inhibition of GE at 46.82 ± 4.34, 54.71 ± 3.29 and 48.45 ± 1.33%
(P≤0.0001) for the dosages 100, 200 or 400 mg·kg
-1
respectively. The
extracts by themselves had no effects on intestinal movement (only
a slight, non–signicant increase at 400 mg·kg
-1
). However, blocking
muscarinic receptors resulted in a decrease in IT by 10.34 and 17.53%
with ME and DE extracts, respectively, compared to control. Conversely,
co–administration with L–arginine (Nitric Oxide donor) signicantly
decreased transit (47.31 and 50.80% for ME and DE, respectively), while
inhibiting Nitric Oxide Synthase (NOS) with L–Nω–Nitro–Arginine (L–
NNA) had a smaller effect (12.24 and 17.24% for ME and ED, respectively).
Only ME SBA extracts signicantly inhibited GE (46.82–54.71% decrease
across doses), mimicking atropine’s effect. DE extracts and combining
ME with atropine showed no signicant impact. Interestingly, L–arginine
only affected emptying with DE SBA (27.8% decrease), not ME SBA.
Inhibiting NOS partially blocked the effect of ME SBA. These ndings
suggest that ME SBA extracts primarily target GE through mechanisms
involving both muscarinic and NO pathways, while DE extracts have
minimal effects. This study highlights the intricate interplay of
pathways in gut function and the potential inuence of extract type
and formulation on their effectiveness.
Key words: Salvia barrelieri; intestinal motility; gastric emptying;
muscarinic receptors; NO pathway
RESUMEN
Este estudio evaluó la inuencia de los extractos metanólico (EM) y
decoctado (ED) de Salvia barrelieri (SBA) sobre el tránsito intestinal
(TI) y el vaciamiento gástrico (VG) en ratones. Sólo las dosis de ME
SBA indujeron una fuerte inhibición de GE en 46,82 ± 4,34; 54,71 ± 3,29
y 48,45 ± 1,33 % (P≤0.0001) para las dosis de 100, 200 o 400 mg·kg
-1
respectivamente. Los extractos por sí solos no tuvieron efectos sobre
el movimiento intestinal (sólo un ligero aumento no signicativo a
400 mg·kg
-1
). Sin embargo, el bloqueo de los receptores muscarínicos
resultó en una disminución de TI de 10,34 % y 17,53 % con EM y ED,
respectivamente, en comparación con el control. Por el contrario,
la coadministración con L–arginina (donante de óxido nítrico)
disminuyó signicativamente el tránsito (47,31 % y 50,80 % para EM
y ED, respectivamente), mientras inhibe Oxido Nítrico Sintasa (NOS)
con L–Nω–Nitro–Arginina (L–NNA) tuvo un efecto menor (12,24 % y
17,24 % para EM y ED, respectivamente). Solo los extractos EM de SBA
inhibieron signicativamente el VG (disminución del 46,82–54,71 % en
todas las dosis), imitando el efecto de la atropina. Los extractos ED
y la combinación de EM con atropina no mostraron ningún impacto
signicativo. Curiosamente, la L–arginina solo afectó al vaciamiento
con ED SBA (disminución del 27,8 %), no con EM SBA. La inhibición
del NOS bloqueó parcialmente el efecto de EM SBA. Estos hallazgos
sugieren que los extractos EM de SBA se dirigen principalmente al
VG a través de mecanismos que involucran tanto la vía muscarínica
como la del NO, mientras que los extractos ED tienen efectos mínimos.
Este estudio destaca la compleja interacción de las vías en la función
intestinal y la inuencia potencial del tipo de extracto y su formulación
en su efectividad.
Palabras clave: Salvia barrelieri; motilidad intestinal, vaciamiento
gástrico, receptores muscarínicos, vía del NO
Muscarinic and Nitric oxide Pathway Involvement in the Intestinal Transit
and Gastric Emptying delay of Salvia barrelieri Methanol Extract in Mice
Implicación de la vía muscarínica y del óxido nítrico en el tránsito intestinal y el retraso
del vaciamiento gástrico del extracto metanólico de Salvia barrelieri en ratones
Fatima Benchikh , Hind Amira , Walid Mamache* , Hassiba Benabdallah , Smain Amira
Ferhat Abbas University, Faculty of Natural Life and Sciences, Laboratory of Phytotherapy Applied to Chronic Diseases. Setif, Algeria.
*Corresponding author: mamache_w@univ–setif.dz
Salvia barrelieri extract: Muscarinic and NO Pathways in Gastric Emptying delay / Benchikh et al. _________________________________
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INTRODUCTION
The coordinated contractions of digestive tract, known as intestinal
motility, and the process of moving food from the stomach to the
small intestine, or gastric emptying, are crucial for ecient nutrient
absorption [1]. Disruptions in these processes can lead to various
gastrointestinal issues like pain, bloating, constipation, diarrhea, nausea,
and vomiting [2]. While conventional treatments exist, a growing body of
research highlights the potential of natural remedies, particularly plants
from the Lamiaceae family and the Salvia genus (sage), in promoting
healthy gut function and managing related disorders [3].
Lamiaceae plants boast a diverse range of aromatic and medicinal
properties, thanks to their rich phytochemical prole that includes
terpenoids, avonoids, and phenolic acids [4]. These compounds
hold promise for gut health through various mechanisms. The
antispasmodic effects of extracts from peppermint (Mentha piperita)
and lemon balm (Melissa ocinalis) have been shown to reduce the
intensity and frequency of spasms associated with conditions like
inammatory bowel disease and irritable bowel syndrome, potentially
improving bowel movements and alleviating discomfort [5, 6].
Among Lamiaceae plants, the Salvia genus, including common sage
(Salvia ocinalis), has received particular attention for its potential
gut health benets. Studies have highlighted its antispasmodic
and anti–inammatory properties, potentially valuable in managing
spasmodic gut disorders and protecting gut health. Antioxidant
and anti–inammatory benets studies indicate that Lamiaceae
extracts can scavenge free radicals, reduce inammatory markers,
and protect the gut lining [7, 8]. This protection may contribute to
normalizing intestinal motility and preventing symptoms associated
with motility disorders [9, 10].
In this study, we investigated the effects of Salvia barrelieri (SBA)
extracts on intestinal transit (IT) and gastric emptying (GE) in mice.
Further research remains crucial to fully understand the clinical
implications and optimal use of these natural remedies for managing
gastrointestinal disorders.
MATERIAL AND METHODS
Salvia barrelieri (SBA) plants, identied by voucher number 105 SO
29/6/16 BAT/SA/HL, were harvested in June. To preserve them, the
plants were dried for ten days in shaded conditions. Subsequently,
an electric grinder pulverized the dried material into a ne powder.
Two types of extracts were prepared: methanolic and aqueous
according to Mamache et al. [4]. The methanolic extract was obtained
by immersing the plant powder in 85% methanol at room temperature
for seven days, using a 15 g per 100 mL solvent ratio (w/v). Following
ltration through muslin cloth and lter paper (Whatman paper), the
ltrate was concentrated under vacuum (Buchi Vaccum Controller
V–800, Switzerland) using a rotary evaporator (Buchi rotavap R–205,
Switzerland) at 40°C. Finally, the concentrated extract was completely
dried in an oven at 37°C.
The aqueous extract was prepared by decoction, boiling 30 g of
plant powder in 1L of distilled water until the volume was reduced
to one–eighth of its original volume. After ltration through muslin
cloth and lter paper, the ltrate was dried completely in an oven
(Memmert UM200, Germany) at 37°C.
Animals
This study utilized male Albino Swiss mice (Mus musculus) obtained
from the Pasteur Institute in Kouba, Algiers. The mice weighed 25–30 g,
were acclimatized for one week in a controlled laboratory environment
with standard temperature, humidity, and light/dark cycles. Food
access was restricted 18–20 hours (h) before the experiment, but
water remained freely available until 60 min prior to testing. All animal
procedures adhered to the European Union’s Guidelines for Animal
Experimentation (2007/526/EC) and were approved by the Scientic
Council of the Faculty of Natural Sciences and Life, University Setif–1
(Algeria), ensuring ethical treatment throughout the study.
Assessment of GE and IT
GE and IT measurements adhered to the methodology outlined
by Amira et al. [11]. Three doses (100, 200 and 400 mg·kg
-1
) of the
studied extracts were studied. Each mouse was orally ingested by
125 µL of the extract. One hour later, mice received a 200 µL test
meal consisting of carboxymethyl cellulose (CMC) and red dye (phenol
red) with concentration of 1.5% (w/v) and 0.1% (w/v) respectively as
a visual indicator. After 20 min, animals were euthanized by cervical
dislocation for analysis. Laparotomy was performed to execute a
total gastrectomy and small bowel resection with pyloric and cardiac
ligation. Stomach contents were homogenized in 0.1 N NaOH. An
amount of aliquot of this homogenate was combined with 1 mL of
trichloroacetic acid (33%, w/v) to precipitate proteins at 1600 G
for 30 min at 4°C (Sigma 3–30K, Germany). Absorbance (Abs) was
measured at 560 nm (Shimadzu™ UV 1800 Spectrophotometer,
Japan). To determine the extent of gastric emptying, four animals
were euthanized (by cervical dislocation) immediately following test
meal administration, representing the 0% emptying control group.
GE rate over 20 min was calculated as follows:
(%)GE
Absuntreated
Absuntreated Abstreated
100
#
=
-
cm
Following stomach removal, the entire small bowel was carefully
excised, and a measurement of the length was taken. The progression
of the test meal was marked using a drop of 0.1 N NaOH. The ratio
was determined by dividing the distance travelled by the food by the
total intestinal length.
To investigate pharmacological effects on gastrointestinal motility,
mice received one of the following substances 15 min before the
ingestion of SBA extracts at dose of 400 mg·kg
-1
: atropine (1 mg·kg
-1
),
N
ω
–Nitro–L–Arginine (L–NNA) (20 mg·kg
-1
), or Arginine (300 mg·kg
-1
).
Statistical analysis
GraphPad Prism (V 8.0) was used for the statistical analysis of the in
vivo data, results are expressed as mean ± standard error of the mean
(SEM). One–way ANOVA followed by Tukey’s multiple comparison test
determined differences between groups, and statistical signicance
was set at P<0.05.
RESULTS AND DISCUSSION
Effect of SBA extracts on intestinal transit
Treatment of mice with SBA extracts had no effect on IT (P>0.05).
A slight increase was observed with the 400 mg·kg
-1
dose, but this
increase was not signicant (FIG. 1).
FIGURE 1. Eect of Salvia barrelieri on intestinal transit in mice. CMC: carboxy
methyl cellulose as control, ME: Methanolic Extract, DE: Decocted Extract.
Results are represented in average % ± SEM vs Atropine
FIGURE 2. Mechanism of the effect of Salvia barrelieri on intestinal transit
in mice. 0: No extract used. CMC: Carboxy Methyl Cellulose as Control, ME:
Methanolic Extract, DE: Decocted Extract. The results are represented in average
% ± SEM vs CMC vs. corresponding control
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Blockade of muscarinic receptors induced a decrease in IT in
the presence of the ME or DE extracts of studied plant by 10.34 and
17.53% respectively (P≤0.002). Despite this decrease, the transit
rates in the presence of the extracts and atropine remained high
compared to atropine alone (P≤0.0001). In the presence of Arginine
(Arg), ME and DE induced a strong decrease in IT compared to their
respective controls, the rates recorded in this case were 47.31 ± 4.21
and 50.80 ± 2.08% (P≤0.0002, FIG 2) respectively. In parallel, ME and
DE under NOS inhibition induced a decrease of 12.24 and 17.24%
(P≤0.002) respectively, the transit rates in this case were comparable
to that of L–NNA alone.
Dysfunction of gastrointestinal motility is well known to contribute
to certain physiopathological complications of the gastrointestinal
tract. The regulation of GE and IT function is a complex interplay
between neuronal and myogenic pathways, employing a multitude
of neurotransmitters and mediators.
The present study reveals that ME SBR and DE SBR which induce a
slight increase. The inhibition of muscarinic receptors or the enzyme
NOS suggest that the NO pathway is involved in observed effect. In
contrast of the present study, Demireezer, Gürbüz [12] showed that
methanolic, aqueous and butanol extracts of three species of Salvia
trichoclada, Salvia verticillata and Salvia fruticosa induce inhibition
of ACh–induced contraction of guinea pig ileum strips. The inhibitory
effect of contraction is due to rosmarinic acid which showed the
same effects by inhibiting muscarinic receptors by this compound.
In addition, the ethanolic extract of hyptis macrostachys Benth had an
observed selective spasmolytic effect on the guinea pig ileum, and might
be attributed to its ability to block voltage–gated calcium channels. On
the other hand, a relaxant effect of the same extract is observed on the
guinea pig ileum via the activation of large conductance potassium
channels (BKCa) by Rosmarinic acid [13]. The dichloromethane fraction
of Origanum majoranum induces a relaxation of the smooth muscles
of the rabbit jejunum, an effect independent of several cholinergic,
nitrergic, adrenergic or guanyl cyclase pathways [14].
It has also been shown that the pathological state of the digestive
tract plays a key role in the effect of herbal extracts on intestinal transit.
Indeed, the ethanolic extract of Salvia divinorum does not modify IT in
normal mice, but it decreases it in the case of induced inammation [15].
The stomach’s process of releasing chyme into the duodenum
is pulsatile and controlled by the balance between the strength of
contractions and relaxation of the pylorus and antrum respectively,
and of the duodenum resistance [16]. Muscles in the stomach
(especially the antrum) squeeze and push partially digested food
(called chyme) towards the pyloric valve. This valve relaxes to let the
chyme through, while at the same time, the pylorus itself contracts,
creating a backward ow that mixes the food further and a forward
ow that pushes the chyme into the small intestine (duodenum) [17].
The tone of the pyloric sphincter plays a crucial role in the rate of GE
[18] a contraction mechanism dependent on signals from the duodenum
and stomach [19]. The delaying effect of GE depends essentially on
the release of NO which causes relaxation of the pyloric sphincter, an
opposite effect is observed following the application of L–NAME [18].
Effect of SBA extracts on gastric emptying
Only the doses of ME SBA induced a strong inhibition of GE at
46.82 ± 4.34, 54.71 ± 3.29 and 48.45 ± 1.33% (P≤0.0001) for the dosages
100, 200 or 400 mg·kg
-1
respectively (FIG. 3), this decrease is comparable
to that induced by atropine alone. On the other hand, the doses of the
DE extract had no effect. The coupling of the extracts with atropine
decreased the rate of GE for DE to 60.96% (P≤0.05, Fig.4), however the
rate of GE observed with the mixture of ME and Atr remained unchanged
compared to ME alone. The diminution in the rate of GE induced by
ME SBA persisted after the addition of L–Arg. On the other hand, the
latter had no effect on GE in the presence of DE SBA (P≤0.0001). Oral
administration of 400 mg·kg
-1
of ME and DE of the studied plant under
the effect of L–NNA induced a decrease in the rate of GE of 25 and 27.8%
respectively. On the one hand, the rate of emptying in the presence of
ME and L–NNA is comparable to that of ME SBA alone (Fig. 4). On the
FIGURE 3. Eect of Salvia barrelieri on intestinal transit in mice. CMC: carboxy
methyl cellulose as control, ME: Methanolic Extract, DE: Decocted Extract.
Results are represented in average % ± SEM vs CMC vs Atropine
FIGURE 4. Mechanism of the effect of Salvia barrelieri on gastric emptying
in mice. 0: No extract used. CMC: Carboxy Methyl Cellulose as Control, ME:
methanolic extract, DE: decocted extract. Results are represented on average
% ± SEM vs. CMC vs. corresponding control
Salvia barrelieri extract: Muscarinic and NO Pathways in Gastric Emptying delay / Benchikh et al. _________________________________
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other hand, the rate of GE under L–NNA and DE is high compared to
the rate observed with L–NNA alone (P≤0.0002).
ME SBA decrease gastric emptying. The inhibitory effect of this
extracts was very close to that of atropine as a positive control (1
mg·kg
-1
). This effect is due entirely to the blockade of muscarinic
receptors; this was conrmed after the application of atropine. The
inhibitory effect of ME SBA (for all doses) on GE involves both the
cholinergic and NO pathways. This was conrmed after the inhibition
of muscarinic receptors by atropine and the inhibition of the enzyme
NOS by L–NNA.
A delayed GE effect is observed after the ingestion of the aqueous
extract of Rosmarinus ocinalis, for rats, an effect observed with
the minimum dose, while the methanolic extract accelerated GE
[20]. Supporting this concept, another investigation revealed the
relaxant effect of the aqueous extract of Origanum onite on strips
of fundus, ileum and duodenum, an effect that is little dependent on
muscarinic receptors [21]. However, the methanolic extract (70%) of
Zingiber ocinalis inhibits the contraction of the stomach fundus by
blocking muscarinic receptors [22].
The impact of phenolic and bioactive compounds on GE differs.
Indeed, ferulic acid, what led to the acceleration of GE, is arbitrated
by prostaglandin [23]. Furthermore, Wang, Zhang [24] demonstrated
that the contractile outcome of magnolol (lignans) by inhibiting iNOS.
Flavonoids extracted from Aurantii fructus immaturus have no effect
on the longitudinal muscles of the rat stomach. On the other hand, a
remarkable inhibition of the amplitude of contractions of the strips of
circular muscles of the stomach, an effect dependent on the multiple
pathways NO/cGMP/PKG/Ca
2+
[25]. Intraperitoneal administration
of a avonoid–rich fraction (catechin, epicatechin, quercetin and
kaempferol) of Maytenus ilicifolia induces a strong decrease in
gastric emptying, this inhibition involves muscarinic receptors and
not dopaminergic receptors [26]. The delayed GE effect is probably a
result of rosmarinic acid blocking muscarinic receptors in the rat ileum
[12]. The weak effect of the different extracts on GE can be credited
to the malabsorption of phenolic compounds in the stomach [27].
CONCLUSION
In conclusion, the results of the present study show that the
extracts of Salvia barrelieri (SBA) delay gastric motility through
complex interactions with muscarinic and NO pathways, thus
supporting the traditional use of this plant as a promising therapeutic
agent for digestive disorders. Additionally, the results underscore
the importance of considering the type of extract and its formulation
in determining its effectiveness in modulating gastrointestinal
functions. Further research is warranted to delve into the detailed
mechanisms underlying the action of SBA extracts and to explore
their potential therapeutic applications for digestive disorders. Such
investigations may provide valuable insights into the development of
novel treatments targeting gastrointestinal dysfunctions.
Conict of interest statement
We declare that there is no conict of interest
Ethical approvals
This study was following European Union Guidelines (2010/63/
EU) approved by the Committee of the Algerian Association of
Experimental Animal Sciences (88–08/1988)
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