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48 Asian Pacific Journal of Tropical Medicine 2018; 11(1): 48-52

IF: 0.925
Asian Pacific Journal of Tropical Medicine
journal homepage: www.apjtm.org

doi: 10.4103/1995-7645.223533 ©2018 by the Asian Pacific Journal of Tropical Medicine. All rights reserved.

Effects of aqueous extract of Notobasis syriaca on lipopolysaccharide-

induced inflammation in rats
Abdullatif Azab1,2#, Ahmad Nassar3#, Jacob Kaplanski3, Reem Mahajneh3, Galila Agam3, Abed N.
Azab3,4
1
Triangle Research & Development Center, Kfar-Qari, 30026 Israel
2
Formerly: Institute of applied Research, Box 437, Shefa-Amr, 20200 Israel
3
Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
4
Department of Nursing, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel

A RT I C L E I N F O A B S T R AC T

Article history: Objective: To investigate the effects of a dry aqueous extract of Notobasis syriaca (N. syriaca)
Received 12 October 2017 on lipopolysaccharide (LPS)-induced inflammation in rats. Methods: Rats were fed the dried
Received in revised form 20 November 2017
extract [500 mg/(kg•d)] for three consecutive days and then were intraperitoneally injected
Accepted 3 December 2017
Available online 2 January 2018 with LPS (1 mg/kg). Two hours after LPS injection, rats were sacrificed and blood and brain
regions were collected. Inflammatory mediators' levels in plasma and homogenates of brain
Keywords: regions were determined by ELISA. Results: Pretreatment with the N. syriaca extract resulted
Bacterial endotoxin in significant anti-inflammatory effects (P<0.05), including: i) attenuated LPS-induced
Brain hypothermia; ii) decreased hypothalamus and hippocampus prostaglandin E2 levels in the LPS-
Cytokines treated rats; and, iii) reduced hypothalamus and hippocampus interleukin-6 and tumor necrosis
Hypothermia
Natural products factor-毩levels in the LPS-treated rats. Conclusions: These results suggest that N. syriaca
Plants possesses anti-inflammatory properties. Thus, it is possible that long-term consumption of this
plant may result in beneficial pharmacological effects.

1. Introduction sylvestris[6] are well established. Another notable difference can be

easily observed between N. syriaca and Silybum marianum, a very
Notobasis syriaca (L.) Cass. (N. syriaca) is single species in the closely related plant which mostly grows in the same habitats. The
plant genus Notobasis of the Asteraceae family[1]. It is one of the activities of Silybum marianum-medicinal, anti-inflammatory and
most widespread plants in the eastern part of the Mediterranean, others – were extensively studied and its chemical composition is
with spiny, beautiful flowers. In many regions it was used by completely known[7,8]. The anti-inflammatory properties of many
humans and animals as nutritious food since antiquity. Archeological other plants were summarized in a recently published review[9].
findings indicate the use of N. syriaca as a food source by N. syriaca is a well-known plant to traditional medicine. In the
humans as early as 23 000 years ago[2]. Many of the medicinal Arab society, it has been used for treating headaches, plague,
and other activities of this plant are unknown, as compared to canker sores, vertigo and jaundice, and sometimes it is used to
similarly common plants in Euroasia. For example, the chemical enhance lactation. It is also a component in some bitters formulas
compositions and almost all medicinal properties of Micromeria and an antioxidant. Fresh stem and leaf base are edible[10]. In many
fruticosa[3], Origanum majorana[4], Salvia officinalis[5] and Malva countries N. syriaca is used as a food[11]. For example, in Italy, the

#
These authors contributed equally to this work, This is an open access article distributed under the terms of the Creative Commons
First author: Abdullatif Azab, Triangle Research & Development Center, Kfar-Qari, Attribution-NonCommercial-Share Alike 3.0 License, which allows others to remix, tweak
30026 Israel. and build upon the work non-commercially, as long as the author is credited and the new
creations are licensed under the identical terms.
E-mail: abedazab@gmail.com

Corresponding author: Abed N. Azab, Ph.D., School for Community Health For reprints contact: reprints@medknow.com
Professions, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B ©2018 Asian Pacific Journal of Tropical Medicine Produced by Wolters Kluwer- Medknow
653, Beer-Sheva 84105, Israel.
Tel: (972) 8-6479880 How to cite this article: Abdullatif Azab, Ahmad Nassar, Jacob Kaplanski, Reem
Fax: (972) 8-6477683 Mahajneh, Galila Agam, Abed N. Azab. Effects of aqueous extract of Notobasis syriaca on
E-mail: azab@bgu.ac.il lipopolysaccharide-induced inflammation in rats. Asian Pac J Trop Med 2018; 11(1): 48-52.
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Abdullatif Azab et al./Asian Pacific Journal of Tropical Medicine 2018; 11(1): 48-52
49
plant is used as a food with wide variety of forms: boiled, fried as 2. Material and methods
vegetables with eggs and in omelets[12].
As mentioned above, N. syriaca was partially investigated by 2.1. Extraction of plant material
modern research. Antimicrobial activity of some extracts of the plant
was reported by Ali-Shtayeh et al.[13] but they did not indicate the Aerial parts of N. syriaca were air dried and ground to fine powder,
extraction solvents and methods. On the contrary, total phenolic and 500 g of the powder was soaked in distilled water for 24 h at
content and antioxidant activity of the plant were investigated 50 曟. Then, it was filtered (Whatman 44) and the clear solution was
by other groups that reported detailed extraction methods and concentrated by a rotary evaporator (50 曟), yielding about 17 g of
dry extract which was stored in deep freeze.
solvents[14,15]. In the study by Alali et al.[14] only aqueous extract
was used, while in the study of El-Hela et al.[15], methanolic and
aqueous extracts were reported. Expectedly, the aqueous extract 2.2. Animals
was more active with higher phenolic content. Aqueous extract of
Male Sprague-Dawley rats were used all through the studies.
N. syriaca was found to have prominent antifungal activity[16], and
Animals (weighing 225–250 g at experiments commencement)
natural products with antimicrobial activity were isolated from were housed three per cage and maintained under controlled
Phomopsis sp. fungi that lived on the plant[17]. environmental conditions (ambient temperature of (22±1) 曟, humidity
The purpose of the present study was to examine the effects 55%–60%, photoperiod cycle 12 h light: 12 h dark), fed regular Lab
of an aqueous extract of N. syriaca on bacterial endotoxin Chow and water ad libitum. Only animals with no signs of sickness
(lipopolysaccharide, LPS)-induced inflammation in rats. were included in the studies. The procedures of the study were in
Systemic administration of LPS to animals results in an intense accordance with the guidelines of the institutional Committee for the
inflammatory response including prominent secretion of Use and Care of Laboratory Animals.
inflammatory constituents, abnormal changes in body temperature
(BT), cardiovascular complications (such as reduced myocardial 2.3. Measurement of body temperature
contractility and a decrease in blood pressure), organs failure (e.g.,
acute kidney injury), among other pathological findings[18-24]. In Rectal BT was measured with a plastic-coated thermometer
mice and rats intraperitoneal (ip) administration of LPS induces (Anristu Meter Co., Japan). Rats were accustomed to BT
a biphasic change in BT – an early decrease in BT (hypothermia) measurement during three days before the beginning of the
followed by elevation in BT (fever)[18,21,24-26]. The mechanism experiments.
underlying the hypothermia caused by LPS is not fully understood.
Many inflammatory components are thought to contribute to this 2.4. Treatment with N. syriaca extract
intricate process; a central one of which is prostaglandin (PG)
After a week of acclimation to housing conditions and BT
E2[18,21,24-26]. LPS-induced variations in BT are accompanied by
measurements, rats were orally treated with the dry extract of N.
increased levels of PGE2 in the hypothalamus[18,21,24-26]. Of note,
syriaca for three successive days. On the evenings before each day
the thermoregulation zone is located in the hypothalamus in the
of extract treatment, rats were deprived of food from 20:00 pm to
anteroventral periventricular nucleus. Anti-inflammatory drugs that
08:00 am. At 08:00, rats were allowed access to special containers
decrease hypothalamic production of PGE2 attenuate LPS-induced containing either 2.5 g per rat of regular food, or, a total of 2.5 g per
hypothermia[27]. Moreover, it was found that psychotropic drugs rat of regular food + dry extract of N. syriaca (Extract). The extract
(which are not classic anti-inflammatory drugs) significantly reduced was calculated per animal weight to give a dose of 500 mg/kg. Thus,
LPS-induced hypothermia in rats, probably due to reduction of each extract-treated rat received 500 mg/kg extract per day for 3
hypothalamic PGE2 levels[24]. consecutive days. Rats were allowed access to the regular food
The present study tested the effects of pretreatment with an aqueous or extract-containing containers for 2 h during which the animals
extract of N. syriaca on plasma and brain levels of PGE2, interleukin consumed all amount of the food in the containers. Thereafter, all
(IL)-6 and tumor necrosis factor (TNF)-毩 in LPS-treated rats. In animals were allowed free access to regular food again. During the
particular, we examined the levels of PGE2, IL-6 and TNF-毩 in entire experimental procedure rats had free access to water.
three brain regions: hypothalamus (HT), hippocampus (HC) and
frontal cortex (FC). PGE2 affects various crucial physiological 2.5. Induction of inflammation by LPS
functions, including: endocrine system activity, cardiovascular
and kidney function, excretion of neurotransmitters, immune- LPS from Escherichia coli was dissolved in sterile NaCl 0.9%
inflammatory activity, regulation of BT, among others[24,28-32]. IL-6 solution. Rats were administered (ip) with LPS 1 mg/kg to induce an
is a cytokine that exerts both anti-and pro-inflammatory activities; inflammatory response as described previously[24]. Control rats were
injected ip with 0.2 mL NaCl 0.9%. LPS was administered at 2 h
it regulates many physiological and pathological processes [33].
after food/extract consumption.
TNF-毩 is a potent pro-inflammatory cytokine but it also confers
some anti-inflammatory functions[34-36]. It is involved in numerous
physiological as well as pathological conditions in humans and is
2.6. Blood collection and preparation of brain regions
homogenates
thus a target for multiple therapeutic interventions[34-36]. In the brain,
TNF-毩 affects the expression of many genes that are crucial for BT was evaluated immediately before LPS injection (time zero)
neurons function and survival[34].
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50 Abdullatif Azabet al./Asian Pacific Journal of Tropical Medicine 2018; 11(1): 48-52

and at about 90 min thereafter. Then, rats were briefly anesthetized in plasma of control and extract-treated animals (Table 1) and
(with a mixture of 4% isoflurane in 100% oxygen) and immediately pretreatment with N. syriaca did not significantly alter LPS-induced
executed by decapitation. Blood was collected for plasma separation elevation in plasma TNF-毩 levels (Table 1). As for PGE2, its levels
and brain regions (HT, HC and FC) were extracted and immediately did not differ significantly between control animals and those treated
frozen (–80 曟 ). Thereafter, brain regions were weighed and with N. syriaca extract alone (Table 1). LPS significantly increased its
homogenized in a homogenizing buffer (cold phosphate-buffered plasma levels (P<0.05) and pretreatment with N. syriaca led to a non-
saline solution containing a cocktail of phosphatase and protease significant decrease in PGE2 levels in LPS-treated rats (Table 1).
inhibitors purchased from Sigma) and centrifuged at 10 000 g, 4 曟
for 10 min. Supernatants and pellets were separated, collected and Table 1
immediately transferred to –80 曟. Effects of N. syriaca on plasma IL-6, TNF-毩 and PGE2 levels rats (pg/mL).
Group IL-6 TNF-毩 PGE2
2.7. Determination of IL-6, PGE2 and TNF-毩 levels Control UD UD 1 591.0±179.0
Extract UD UD 1 442.0±8.0
Levels of IL-6, PGE2 and TNF-毩 in plasma and brain samples LPS 2 419.8±632.4* 615.5±181.3* 2 074.0±143.0*
LPS + Extract 1 331.0±349.4* 795.7±170.6* 1 771.0±150.0
(supernatants of homogenates) were measured using rat DuoSet
ELISA kits (R&D Systems; Minneapolis, MN, USA) according to LPS, lipopolysaccharide; IL-6, interleukin 6; TNF-毩, tumor necrosis factor-
manufacturer's instruction. The detection limits of the assays were as 毩; PGE2, prostaglandin E2. Rats were fed with regular food or with food
follows: 39–2 500 pg/mL for PGE2; 62.5–4 000 pg/mL for TNF-毩; and, containing N. syriaca [500 mg/(kg•d)] for 3 consecutive days. On day 3, at 2 h
125–8 000 pg/mL for IL-6. For determining plasma PGE2 levels, after N. syriaca consumption, rats were injected LPS (1 mg/kg, ip). Rats were
samples were diluted 100 times to fit the standard curve of the assay. sacrificed at about 2 h post LPS injection and blood was collected for plasma
In all ELISA experiments, when the level of the tested inflammatory separation. Plasma IL-6, TNF-毩, and PGE2 levels were determined by
constituent was under the lower detection limit of the assay, results ELISA. Values are means±SEM of 12 rats. *P<0.05 vs. Control. UD denotes
were marked as "undetectable" and calculated as zero. undetectable.

2.8. Statistical analysis and presentation of the data

3.3. Effects of N. syriaca on IL-6, TNF-毩 and PGE2 levels
Statistical evaluations were carried out using two-tailed Student’s in the hypothalamus of LPS-treated rats
t-test. Results are presented as mean±SEM for the sample size as
indicated in each table. Values of P<0.05 were considered statistically Administration of LPS and pretreatment with N. syriaca alone
significant. The data express the results of one experiment out of did not significantly alter IL-6 and TNF-毩 levels in the HT (Table
three independent experiments with similar results. Results of 2). On the other hand, pretreatment with N. syriaca significantly
plasma IL-6, TNF-毩 and PGE2 levels are presented as pg/mL decreased IL-6 and TNF-毩 levels in HT of LPS-treated rats
according to ELISA results. Results of IL-6, TNF-毩 and PGE2 (P<0.05) (Table 2). Consistent with previous studies, administration
levels (homogenates of brain samples) were calculated as follows: of LPS led to a significant increase in HT PGE2 levels (P<0.05)
ELISA result (pg/mL) divided by weight of each brain sample; data (Table 2). Pretreatment with N. syriaca alone did not alter PGE2
are presented as pg/(mL•mg wet weight of brain sample). levels in this brain region, whereas pretreatment with N. syriaca
significantly decreased HT PGE2 levels in LPS-treated rats (P<0.05)
(Table 2).
3. Results
3.4. Effects of N. syriaca on IL-6, TNF-毩 and PGE2 levels
3.1. Effects of N. syriaca on LPS-induced hypothermia in in the hippocampus of LPS-treated rats
rats
Administration of LPS did not significantly alter IL-6 and PGE2
Administration of LPS led to a significant hypothermia in rats. The levels in the HC (Table 2). In contrast, LPS significantly decreased
BT of the control rats, extract-treated rats, LPS-treated rats and LPS + HC TNF-毩 levels (P<0.05) (Table 2). Pretreatment with N. syriaca
Extract-treated rats was (0.08±0.13), (0.24±0.14), (-1.16±0.26), significantly reduced IL-6 and TNF-毩 levels in the HC of control as
and (-0.61±0.12) 曟, respectively. Pretreatment with N. syriaca well as LPS-treated rats (P<0.05) (Table 2). Similarly, pretreatment
extract alone slightly but significantly increased BT of treated with N. syriaca significantly decreased HC PGE2 levels in LPS-
animals (P<0.05). Moreover, pretreatment with N. syriaca extract treated rats (P<0.05) (Table 2).
significantly attenuated LPS-induced hypothermia in rats (P<0.05).
3.5. Effects of N. syriaca on IL-6, TNF-毩 and PGE2 levels
3.2. Effects of N. syriaca on IL-6, TNF-毩 and PGE2 levels in the frontal cortex of LPS-treated rats
in the plasma of LPS-treated rats
Neither administration of LPS nor pretreatment with N. syriaca
As seen in Table 1, IL-6 was undetectable in plasma of control and alone did not affect IL-6, TNF-毩 and PGE2 levels in the FC (Table
extract (alone)-treated animals. On the other hand, LPS led to a 2). Unexpectedly, pretreatment with N. syriaca significantly elevated
significant elevation in plasma IL-6 levels (P<0.05). Pretreatment IL-6 and TNF-毩 levels in the FC of LPS-treated rats (P<0.05)
with N. syriaca extract did not significantly decrease LPS-induced (Table 2) and pretreatment with N. syriaca led to a non-significant
elevation in IL-6 levels. Similarly TNF-毩 was undetectable increase in PGE2 levels in the FC of LPS-treated rats (Table 2).
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Abdullatif Azab et al./Asian Pacific Journal of Tropical Medicine 2018; 11(1): 48-52
51
Table 2
Effect of N. syriaca on hypothalamus IL-6, TNF-毩 and PGE2 levels in rats [pg/(mL•mg wet weight of brain sample)].
Hypothalamus Hippocampus Frontal cortex
Group
IL-6 TNF-毩 PGE2 IL-6 TNF-毩 PGE2 IL-6 TNF-毩 PGE2
Control 100.9±9.8 86.5±6.4 36.9±4.0 300.5±20.8 113.3±8.0 75.5±8.0 180.3±27.8 138.0±16.8 55.4±4.6
Extract 83.7±8.0 94.3±3.7 39.0±5.5 233.2±18.2* 64.5±9.0* 78.8±6.0 189.0±29.0 131.4±13.6 66.4±5.8
LPS 94.9±9.0 106.4±7.2 74.7±13.9* 264.4±18.7 68.9±7.4* 64.7±6.4 202.0±32.0 140.7±11.2 67.1±5.7
LPS + Extract 39.2±10.0*# 83.7±3.8# 26.2±2.1*# 182.8±15.3*#
40.1±4.2*# 46.9±8.5* 300.1±35.0*# 194.8±13.7*# 79.7±15.1
LPS, lipopolysaccharide; IL-6, interleukin 6; TNF-毩, tumor necrosis factor-毩; PGE2, prostaglandin E2. Rats were fed with regular food or with food
containing N. syriaca [500 mg/(kg•d)] for 3 consecutive days. On day 3, at 2 h after N. syriaca consumption, rats were injected LPS (1 mg/kg, ip). Rats were
sacrificed at about 2 h post LPS injection immediately after which hypothalamus was removed and further processed as described under “Materials and
Methods”. Hypothalamic IL-6, TNF-毩, and PGE2 levels were determined by ELISA. Values are means±SEM of 12 rats. *P<0.05 vs. Control; #P<0.05 vs. LPS.

4. Discussion featured by reduction in social activity or decrease in food and water

consumption, weight loss or diarrhea), this result was seen in two of
To the best of our knowledge, the present study is the first to the three experiments that we performed.
demonstrate that N. syriaca exerts protective effects against LPS- The precise mechanism underlying the protective effects of
induced inflammation. We found that oral pretreatment with a dry N. syriaca against LPS-induced inflammation is currently not
extract of N. syriaca for 3 d resulted in significant anti-inflammatory known. We speculated that N. syriaca may alter the activity of the
effects in LPS-treated rats (P<0.05), including: i) Attenuation transcription factor nuclear factor kappa B (NF-毷B), as was reported
of LPS-induced hypothermia; ii) reduction of hypothalamic and for other plant products with anti-inflammatory activities[9]. NF-毷
hippocampal PGE2 levels in LPS-treated rats; and, iii) decrease B regulates the activity of numerous cellular pathways such as those
of IL-6 and TNF-毩 levels in HT and HC of LPS-treated rats. involved immune and inflammatory responses, cancer pathophysiology,
Nevertheless, pretreatment with N. syriaca also led to some pro- among others[37-40]. The mammalian NF-毷B pathway involves the
inflammatory effects such as elevation of IL-6 and TNF-毩 in FC of activity of a number of proteins such as p50, p65, and RelB, which
LPS-treated rats. contribute to various physiological and pathological processes[37-39].
In general, the results of the present study suggest that N. syriaca Different stimuli activate the NF-毷B pathway including infectious
confers anti-inflammatory effects, and that chronic consumption of microorganisms, LPS, cytokines, tissue damage, neurodegeneration
the plant may be associated with anti-inflammatory and probably and ischemia[37-39]. These stimuli activate the pathway by inducing
other protective properties. It is worth noting that this study utilized phosphorylation and subsequent degradation of NF-毷B inhibitor
a sub-chronic treatment protocol – animals were treated with the proteins (e.g., I毷B毩 and I毷B毬) which inhibit the translocation
extract once daily for 3 consecutive days. It is possible that a longer of NF-毷B proteins to the nucleus. After dissociation of NF-毷B
treatment-duration would have resulted in more profound anti- proteins from I毷B, they undergo phosphorylation by other kinases
inflammatory effects. However, this assumption remains to be and then translocate to the nucleus and facilitate transcription of
confirmed or alternatively refuted. Further study is also necessary target genes. Therefore, it is recognized that elevated levels of
to determine the dose-dependent effect of N. syriaca on the phosphorylated NF-毷B proteins (such as p65) in the nucleus
inflammatory parameters that were examined in this study. Moreover, represent increased activity of the pathway[24,37,39]. In this regard,
the choice of oral (in the food) administration of the extract was we conducted a preliminary experiment in which we examined the
done purposely to resemble a naturally occurring consumption of the effect of N. syriaca on levels of nuclear phosphorylated-p65, as we
plant materials. We decided against administering the extract through described previously[24]. We found that pretreatment with N. syriaca
oral lavage or parenteral administration because these routes would for 3 d did not at all affect nuclear phosphorylated-p65 levels in HT
not have mimicked a natural consumption of the plant. and HC of LPS-treated rats (data not shown). These preliminary
The protective effect of N. syriaca against LPS-induced hypothermia results suggest that the anti-inflammatory effects of N. syriaca
resembles that of classic anti-inflammatory drugs such non-steroidal probably derive from a non-NF-毷B-associated mechanism.
anti-inflammatory drugs[27]. These drugs attenuate LPS-induced This study demonstrated that an aqueous extract of N. syriaca
hypothermia primarily due to inhibition of PGE2 production in the exhibited anti-inflammatory effects in LPS-treated rats. Further
HT[27]. Consistently, psychotropic drugs, that are not classic anti- study is necessary to elucidate the mechanism underlying the anti-
inflammatory compounds, were also capable of reducing LPS- inflammatory effects of N. syriaca and the appropriate treatment
induced hypothermia in rats, probably due to decreasing HT PGE2 regimen, including determination of the most efficacious dose
levels[24]. Therefore, we speculate that N. syriaca also attenuated and treatment duration. Moreover, further research is warranted to
LPS-induced hypothermia due to inhibition of PGE2 production in determine the chemical composition of the extract and reveal its
the HT. Importantly, the protective effect of N. syriaca against LPS- most biologically active chemical constituents.
induced hypothermia was observed in all three experiments that we
performed. On the other hand, currently we do not understand the
reason for the slight elevation in BT which was seen in rats that were Conflict of interest statement
treated only with N. syriaca. Although these animals did not show
any visible pathological characteristic (anhedonia – as could be We declare that we have no conflict of interest.
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52 Abdullatif Azabet al./Asian Pacific Journal of Tropical Medicine 2018; 11(1): 48-52

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