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CHAPTER 2
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Herbal Anti-Arthritic Drug Discovery
Tool Based on Inflammatory Biomarkers
MAHFOOZUR RAHMAN,1 ANKIT SAHOO,1 and SARWAR BEG
1
Shalom Institute of Health and Allied Sciences, Sam Higginbottom
University of Agriculture, Technology, and Sciences (SHUATS),
Allahabad – 211007, India
2
Department of Pharmaceutics, School of Pharmaceutical Education and
Research, Jamia Hamdard (Hamdard University), New Delhi – 110062,
India
ABSTRACT
According to the American College of Rheumatology, conventional medicines have limited effectiveness and are highly toxic. Therefore, 60%–90%
concentrate on complementary and alternative medicine and people are
dissatisfied with the available therapies. Herbs have enormous potential that
are not often seen in synthetic drugs of large structural complexity. Different
plant constituents, including terpenoids, flavonoids, fatty acids, steroids,
have investigated the anti-rheumatic action. These all target different inflammatory mediators such as nitric oxide (NO), cytokines, chemical substances,
conformity molecules, NF-kβ, LLOX, and arachidonic acid (AA). They
often target various inflammatory mediators. The text presented details on
the phytoconstituents based on targeted action on inflammatory biomarkers.
2
Rheumatoid arthritis (RA) is an immune-based joint inflammatory disorder
that starts when the immune system attacks its own body tissue or bone, which
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Biomarkers as Targeted Herbal Drug Discovery
affects almost 1% of the world population. The most evince pathogenesis is
T-cell activation which associated with the increase of different inflammatory bio-marks and a bunch of variation (CD) in the T-cells. These involve
cytokines, NF-Kβ, arachidonic, nitric oxide (NO), chemokines, lipoxygenase
(LOX), adhesion molecules, and matrix metalloproteinase (MMP) (Anderson
et al., 1985). Finally, these all damage bone and cartilage by degeneration and
alteration. On the basis of this interaction of bioactive such as thymoquinone,
curcumin, hesperidin, gambogic acid (GA), polyphenols, celastrol, and resveratrol display high anti-arthritic activity against RA which is dependent on the
concentration of dose via targeting inflammatory bio-marks.
RA is afliated with synovial tissue polyarticular inammation, which
leads to damage the articular cartilage and bones (Anderson et al., 1985).
Factors that inuence the progression of RA are the change in the shape of
an immunological phenomenon, environmental, and genetic and can change
the shape of the immunological phenomenon (Scrivo et al., 2007). RA may
appear due to abnormal immune response leads to synovial inammation
and joint destructions, but still, its etiology is not clear (Rahman et al., 2015).
T cell activation causes CD and simultaneously enhances the secretion of
cytokines including TNF-a, IL-1, IL-3, IL-6, inhibitory factors, and macro-
phage migration (Ismail et al., 2015). These inammatory biomarkers are
involving in the proliferation, secretion of PGs, chemokines, and adhesion
molecules (Rahman et al., 2015; Ismail et al., 2015). Whereas adhesion
molecule expression causes T-cells excessive binding to synovial type B
cells, results to produce a large quantity of MMP (Araki et al., 2016). For
angiogenesis in aggravation of RA, there are many factors involving such
as cyclooxygenase, neutral proteases, NO synthase, and group of antibodies
including IgG, IgM, and IgA respectively (Firestein, 2003; Araki et al., 2016).
These all play a role in xing complements, screen macrophages, cytokines,
lymphocytes by ligating the macrophages Fc-c receptors which abnormally
lead to inammation in RA (Smolen et al., 2016; Rahman et al., 2016).
Furthermore, the IgA immune complex also involving in the production of
higher intraarticular tissue growth factor-β secretion as well as bone erosion,
results to RA symptoms (Song et al., 2014). Overall, the pathogenesis of
RA involves angiogenesis, synovial cell proliferation, cellular immune
system activation by B and T-cells, macrophages, and pannus formation, all
these results to produces cartilage deformation and bone erosion. Thus, all
these factors are actively involving in the pathogenesis of RA (Song et al.,
2014). For the management of RA, there are several drug molecules such
as glucocorticoids (GCs), non-steroidal anti-inammatory drugs (NSAIDs),
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disease-modifying anti-rheumatic drugs (DMARDs), and biological agents
including IL-1 receptor antagonist (IL-1Ra) and TNF-a blockers, reduce
inammation and pain in RA (Smolen et al., 2016). However, there is a
need to develop to improve the antirheumatic drugs with the safety and
efcacy in the management of RA with fewer side effects. In the current
treatment approaches, many of the drugs are withdrawn from the market due
to cardiotoxicity associated with cyclooxygenase-2 inhibitors and DMARDs
associated with fungal infections, tuberculosis, liver injury, lymphomas,
and myelosuppression with long term use (Cannon et al., 2004). Biologic
agents act by inhibiting IL-6, IL-1ß, and TNF-a immune mediators. Despite
their availability and the high cost of injectables, patients are often unable to
continue biological therapy or they discontinue their medication after shortterm use (Cannon et al., 2004).
According to the American College of Rheumatology, conventional medication has limited efficacy and high toxicity. Nowadays people are dissatisfied with the available conventional therapies and 60–90% of people are
dependent on complementary and alternative medicines (Tamhane et al.,
2014). But herbs have great potential and no side effects with wide structural
diversity which is not commonly seen with synthetic drug molecules. The
various phytoconstituents such as flavonoids, terpenoids, steroids, and fatty
acids have anti-RA action which has been explored (Kumar et al., 2015).
These all phytoconstituents act on inflammatory mediators such as cytokines,
chemokines, NO, NF-ҡB, adhesion molecules, LOX, and arachidonic acid
(AA) (Kumar et al., 2015). It is also illustrated in Figure 2.1.
Pomegranate extracts (PE) are obtained from the fruit of Punica granatum,
which contains polyphenols, ellagitannins, quercetin, gallic, and ellagic acid.
The oral administration of PE prevents cartilage destruction in the arthritic
rat models (Rasheed et al., 2010).
Thymoquinone (TQ) is a major bioavonoid isolated from Nigella sativa
seeds. In Far and middle-Eastern Countries, it is extensively used as an alternative medicine to treat several diseases. Various literature surveys indicate
the benets of TQ in inammation such as osteoarthritis. RA and inammatory bowel disease (Umar et al., 2015). In a study on adjuvant-induced
arthritis (AIA) conducted by Tekeoglu and Colleagues explored when TQ
is administered by injection into the intraperitoneal (I.P) cavity it exhibits
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Biomarkers as Targeted Herbal Drug Discovery
the same therapeutic value as MTX (Tekeoglu et al., 2007). Another study
conrmed that TQ on oral administration at 5 mg/Kg/day leads to inhibition
of the serum TNF-a and IL-1β level in RA (Ahmed et al., 2013).
Resveratrol is a polyphenolic compound present in the epidermis of grapes
(Vitis vinifera). In various literatures, the medicinal use of resveratrol has
been reported (Elmali et al., 2007). In Japan and China grape epidermis along
with polygonum, cuspidatum roots which are rich in resveratrol are used as
indigenous medicine. In rat models, resveratrol on intra-articular injection is
effective against RA by retarding the level of ROS, IL-1, PGE2, tumor protein
(p53), induced apoptosis, MPPs, and LTB-4 (Baur and Sinclair, 2006).
Citrus avonoid hesperidin is known for its pharmacological activity
and for its therapeutic effect. It has been extensively investigated in arthritis
rat models. Studies showed that hesperidin suppresses the proliferation of
synoviocytes in the model of rat adjuvant arthritis (Umar et al., 2013). When
hesperidin is given an intragastric dose of 80 mg and 160 mg/kg successfully
reduced secondary paw-swelling and decreased the production of TNF-a,
IL-6, and IL-1 in RA (Umar et al., 2013).
Curcumin is a tetraterpenoid isolated from rhizomes of Curcuma longa.
It has a broad range of pharmacological activities such as anticancer, anti-
inammatory, and antioxidant effects (Funk et al., 2006). Due to its lipid
solubility, its bioavailability is low and clinically not administrated orally.
Currently, curcumin is under study for its action against RA. it suppresses
the catabolic and inammatory mediators such as stimulated NO, MMP-3,
MMP-9, IL-b, IL-8, COX-2, PGE2, when given intra-peritoneal in a dose
of 23 mg total curcuminoids per kg, per day. Furthermore, it also inhibits
mediators like JAK/STAT pathways, NF-ҡB, and JNK in human chondrocytes (Zheng et al., 2015).
Camellia (family Theaceae) is a species of evergreen shrub or small tree
whose leaves and leaf buds are used to produce tea. Extract of green tea shows
anti-arthritic potential when given orally at 200 mg/kg. Extract of green tea
contains epigallocatechin-3-gallate (EGCG) as active constituents. Whereas its
administration into the arthritic rats’ results to retards the release of IL-1 induced
glycosaminoglycan via blocking the activity of NF-ҡB in chondrocytes. Furthermore, it also inhibits NO synthase (iNOS) which stimulated by IL-1, JNK action,
and NO. These three inammatory biomarkers induce the destruction of cartilage
(Ahmed, 2010; Datta et al., 2012). Whereas the RA synovial broblasts contain
TNF-a-induced ERK (extracellular signal-regulated kinase), MMP-3, MMP-1,
JNK, p38, and AP-1 are promptly inhibited by EGCG and also TNF-a-induced
ERK (extracellular signal-regulated kinase), MMP-3, MMP-1, JNK, p38, and
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AP-1 and inhibits the expression of oncostatin M stimulated CCL2 chemokines
in human osteoblasts and signicantly lowers the severity of arthritis induced by
collagen (CIA). Therefore, in vitro and in vivo evaluation concluded that EGCG
reduces cartilage degradation, synovial hyperplasia, and bone resorption through
different targets in the affected joints (Min et al., 2015).
Trypterigium wilfordii contains pentacyclic triterpene called celastrol. It
shows anti-inammatory and anti-tumor activity (Salminen et al., 2010). In
China, T. wilfordii has traditionally been used as a treatment of RA. Salminen
et al. reported the I.P administration of xed-dose of celastrol at every day
to AIA rats, which exhibits an anti-inammatory potential via inhibition of
NF-ҡB activation and downregulation of caspase 1 (Salminen et al., 2010;
Astry et al., 2015). Furthermore, it also down-regulated the TNF and IL-1β
secretion in a rat model of AIA. Now, this study reached to clinical trial
phase 1 (Astry et al., 2015).
Sinomenine is an alkaloid isolated from the Sinomenium acutum plant,
which is traditionally used in herbal medicine in Japan and China for RA.
Other compounds isolated from the plant include madecassoside, asiaticoside, Asiatic acid, and centelloside. Sinomenine I.P administration of
sinomenine suppressing MMP-2, MMP-9, and IL-6 in the animal model of
arthritis. A recent study reported that asiaticoside successfully exhibits antiinammatory potential by CIA mice. After oral administration of madecassoside at 10, 20, and 40 mg/kg body weight (BW) dose in CIA mice, the
histopathology revealed that inammatory cells inltration and synovial
hyperplasia helps in providing protection against joint destruction (Tong et
al., 2015).
The seeds of Vitex negundo (Nirgundi) have been widely used as a
traditional Ayurvedic and Chinese herbal medicine which is rich in lignans
metabolites and used in the treatment of rheumatism and joint inammation.
The entire lignans of Vitex negundo (Nirgundi) seeds (TOV) were offered to
play an important role in the treatment of arthritis (Rui et al., 2019).
TOV signicantly inhibited the paw edema and decreased the arthritis
index, with no inuence on the BW and the indices of thymus and spleen
of CIA rats. Meanwhile, TOV dose-dependently reduced the inltration of
inammatory cells, synovial hyperplasia, and attenuated cartilage damage
(Rui et al., 2019). Additionally, the serum levels of IL-1β, IL-6, IL-8, IL-17A,
TNF-α, MMP-3, and MMP-9 were markedly decreased, while the level of
serum IL-10 was increased in TOV-treated rats. The signicant reduction
of the expression of COX-2, iNOS, and p-IκB and the notable increase of
IκB in synovial tissues were also observed in TOV-treated animals (Rui et
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Biomarkers as Targeted Herbal Drug Discovery
al., 2019). TOV also signicantly inhibited acetic acid-induced writhing and
decreased xylene-induced ear edema in mice. Furthermore, due to its high
efcacy and safety, TOV can be regarded as a promising drug candidate for
RA treatment (Rui et al., 2019).
The whole dried M. pentaphylla plants were reux with 70% ethanol for
its extracts. The anti-osteoarthritic effect of MPE was checked in a Sprague-
Dawley rat model of MIA-induced OA and anti-inammatory in in-vitro
lipopolysaccharide (LPS)-treated RAW264.7 cells (Lee et al., 2019). MPE
exhibited anti-inammatory activity via inhibition of the production of NO
(57.8%), PGE2 (97.1%), and IL-6 (93.2%) in LPS-treated RAW264.7 cells
at 200 μg/m L. In addition, MPE suppressed IL-1β (60.9%), TNF-α (37.9%),
and IL-6 (40.9%) production and suppressed the synthesis of MMP-2,
MMP-9, and COX-2 in the MIA-induced OA rat model. Furthermore, the
results suggest that MPE has signicant anti-inammatory activity and
protects cartilage in an OA in the rat model (Lee et al., 2019).
Anoectochilus roxburghii, with rich in the polysaccharide, has been
widely used as Chinese herbal medicine for the treatment of RA, liver
disease, and diabetes. Pharmacological results displayed that ARP signicantly ameliorated the inammatory cell inltration, decrease the arthritis
index, and the synovial tissue destruction in CIA rats (Guo et al., 2019). It
also shows that ARP possessed antioxidant activity and inhibit NO produc-
tion. Further investigation showed that the anti-inammatory mechanism of
ARP signicantly inhibited the activation of nuclear factor-Kβ (NF-Kβ) by
suppressing the phosphorylation of I_B and P65, which subsequently down-
regulate the mRNA expression of IL-1β and IL-6 in LPS stimulated RAW
264.7 cells. Result suggested that ARP has great potential for the treatment
of type II collagen-induced arthritis (CIA) (Guo et al., 2019).
Apigenin (API) is a natural potent compound found in the avone which
is an aglycone part of the glycoside that was suggested as the suppressor of
dendritic cell maturation and migration and protects against CIA. In a study
found that CIA mice, API suppress arthritis development through the modulation of dendritic cell functions (Chang et al., 2015). Bone marrow-derived
dendritic cells (BMDCs) were stimulated in vitro with LPS and treated with
API for 24 hrs; DC functions, including phenotype expressions, cytokine
secretion, phagocytosis, and chemotaxis, were then investigated (Chang et
al., 2015). The effects of API on CIA were examined in vivo, and puried
DCs from the lymph nodes (LNs) of API-treated CIA mice were analyzed for
phenotypes and subsets. In in-vitro, API efciently restrained the phenotypic
and functional maturation of LPS-stimulated BMDCs while maintaining
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phagocytotic capabilities. Moreover, API inhibited the chemotactic responses
of LPS-stimulated BMDCs, which may be related to the depressive effect on
chemokine receptor 4 (CXCR4). In in-vivo, API treatment delayed the onset
and reduced the severity of arthritis in CIA mice, and diminished secretion of
pro-inammatory cytokines in the serum and supernatants from the LN cells
of the CIA mice (Chang et al., 2015). Similar to the in vitro ndings, the API-
treated mice exhibited reduced expression of co-stimulatory molecules and
major histocompatibility complex II on DCs. Furthermore, API treatment
strongly down-regulated the number of Langerhans cells, but not plasmacytoid DCs (pDCs) in LNs, which may be related to the depressive effect of
API on the expression of CXCR4 on DCs of peripheral blood. These data
provide new insight into the mechanism of action of API on arthritis and
indicate that the inhibition of maturation and migration of DCs by API may
contribute to its immunosuppressive effects (Chang et al., 2015). Therefore,
all the above bioactive has also summarized in Table 2.1.
Illustration of bioactive and their mechanisms involved in the management of
rheumatoid arthritis.
In RA patient’s administration of high doses of vitamin E were effective in
reducing pain symptoms. However, in the in-vitro studies show that foods
rich in antioxidants have anti-inflammatory effects to be linked to the down-
regulation of NF-ҡB (Sukkar and Rossi, 2004).
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