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393
defense against pathogens. However, extreme production of ROS can lead to oxidative damage
of lipids, proteins, and DNA. As a result of this, apoptosis or necrosis may eventually cause
cell death [34].
Oxidative stress, which is caused by ROS, has been directly associated with a number of diseases,
including diabetes, asthma, acute ischemic stroke, acute lung or liver injury, acute gastroenteritis,
acute bronchitis, neurodegenerative diseases, IBD, cardiovascular diseases, and RA. When com-
pared to healthy entities that have Helicobacter pylori or IBD, the ROS levels are more than 10–100
times greater [35]. Extracellular H
2
O
2
concentration rose to 100 μM during reperfusion and
ischemia in several neurological disorders. This eventually resulted in the development of
Alzheimer’s and Parkinson’s diseases due to changes in structural elements and neuronal proteins
as well as loss of cognitive function [36]. Respiratory lining cells with inflammatory lung diseases
had 20 times greater H
2
O
2
levels than in healthy tissues [37]. Research carried out on animal mod-
els of colitis, acute lung damage, and alcoholic liver injury demonstrated that the amount of ROS
often follows a parabolic trajectory as different IDs proceed. The kind of illness and whether the
inflammatory stimuli are endogenous or external dictate when the maximal level occurs [38, 39].
Therefore, endogenous biochemical stimuli are treated by oxidative stress at the site of
inflammation.
17.3 The Demand for Advanced Anti-inflammatory Medications
A major healthcare problem worldwide is IDs, which include different types of rheumatic diseases
in which inflammation disorder badly affects human health. There are various agents available to
treat the disorder but they have adverse side effects on human health, in traditional practice there
are two types of drugs either steroidal anti-inflammatory drugs or NSAIDs are available to manage
the ID. Through the cyclooxygenase (COX) inhibition in the prostaglandins biosynthesis, NSAIDs
can inhibit in the early steps, and these are the main drugs for the reduction of inflammation con-
sequences [40]. The use of NSAIDs has many side effects which are related to renal, gastrointesti-
nal, and toxicities [41]. The use of corticosteroids is central to hypertension, hyperglycemia,
osteoporosis, and growth arrest [42]. The significant challenge associated with presently utilized
synthetic drugs is their potential for toxicity and the recurrence of symptoms upon discontinua-
tion [40]. There is a growing interest in addressing this issue by exploring the advances of safer
anti-inflammatory agents [43]. A rational and productive strategy toward the treatment of inflam-
matory conditions involves the progress of anti-inflammatory drugs consequent from normal
sources [44]. For the treatment of IDs natural products are the biocompatible, safe, and cost-
effective alternatives, efficacious.
Since ancient times, there have been many countries, such as India, Sri Lanka, China, and Brazil
called hubs of natural products used as traditional medicine. Recently, research has been delving
into the pharmacologic and molecular mechanisms that underlie the health benefits and thera-
peutic potential of many compounds. The integration of traditional knowledge and indigenous
resources is deemed essential for advancing the development of new anti-inflammatory leads [41].
Numerous reports focus on traditional plants employed in folk medicine for their anti-inflammatory
properties, providing valuable insights that contribute to the potential use of natural products as
anti-inflammatory drugs [45]. The impact of phytoconstituents is manifested through their influ-
ence on pivotal regulatory molecules such as cytokines, inducible nitric oxide synthase (iNOS),
and COX [46, 47].
394
17.4 Natural Products Used for Anti-inflammatory Drug
Development: Systematic Approach in Use of Different Animal
Models for Evaluations
Pharmacology plays an essential role in modern medicine in the search for new drugs with the
use of appropriate models and identifying the mechanism of the selected molecules. For the
prediction of clinically and physiologically suitable models the trial models are used, based on
pharmacological ethics, the model is selected based on their results which should be matched
with the clinical results, for the preclinical assessment of drugs Vogel et al. [48] designated vari-
ous methods, i.e., in vivo and in vitro. For the screening of anti-inflammatory agents, many mod-
els are used they have used different mechanisms for the screening of activity, some examples
are enlisted in Table 17.1.
Before beginning any experimental technique, a number of preparatory criteria such as
medication dosage, sample size, toxicity, and others should be taken into account [60]. There are
several research on the anti-inflammatory properties of phytoconstituents that demonstrate their
safety, toxicity, and mode of action. During the drug discovery process, improper work planning
leads to the rejection of phytoconstituents; thus, program selection must be done carefully. The
main cause of the failure of phytoconstituents-based drug development programs appears to be
program selection.
17.5 Rational Design of Anti-inflammatory Agents
17.5.1 Creating Anti-inflammatory Polymers Through Phosphoramidite Chemistry
Inspired by Apoptotic Processes
The polymers are designed with immunosuppressive effects for anti-inflammatory therapies,
which results in the modification of the morphology of immune cells. The researcher used the
phosphoramidite method in which phosphoramidite chemistry was utilized to synthesize
the apoptotic cell-membrane-inspired polymers. The macrophages employed in the in vitro cell
viability assays of PS-modified polymers demonstrated their nontoxicity at concentrations of
1 × 10
5
μg/mL. The expression of NF–κB has been decreased, which showed that the macrophages
are protected from lipopolysaccharide-induced inflammation [72].
17.5.2 New Anti-inflammatory Agent with Indoyl-imidazole Hybrids
For designing new agents researchers used in vivo analgesic and anti-inflammatory activity as well
as ulcerogenicity of the prepared hybrids were evaluated in experimental animals. COX-2 enzyme
was employed in the computational studies, which produced two new hybrid compounds with the
lowest binding energy [73].
17.5.3 Rational Design of Novel Aminopiperidinyl Amide
In this study, the C-X-C chemokine receptor type 4 has been used as a targeted enzyme for ID. In
this study, the ZINC chemical database has been screened, and after molecular dynamic simula-
tion, the Z7R was identified as a novel compound with nanomolar affinity and 78.5% chemotaxis
inhibition which shows potent anti-inflammatory activity [74].
Table 17.1 Methods for evaluating anti-inflammatory activity in animal models.
S. no. Inflammation Model Mechanism Advantage Disadvantage References
1. Acute-
inflammation
Carrageenan-
induced paw
edema
Initiate the inflammation phase from the
beginning; cyclooxygenase pathway activation
dilates post-capillary venules
Inflammation is reproducible,
acute and nonimmune
Susceptible to inhibitors of
cyclooxygenase
Adequate for NSAIDs evaluation
The researcher was
instructed in recording
the consistent and
dependable paw
volume
[49, 50]
Histamine/5-
HT-induced
paw edema
It causes an increase in lymph flow, which
causes edema to occur
Histamine injected subplantarly stimulates
the release of fluid and plasma proteins from
the cell
Used as a secondary model
5-HT inhibitor drugs assessed
Prostaglandin inhibitor
drugs cannot be
checked
[51, 52]
Paw edema
induced by
bradykinin
Bradykinin-stimulated human endothelial cell
cultures produce metabolites of arachidonic
acid
Drugs suppressing
prostaglandins are successful in
this model
It only causes
moderate, temporary
edema
[53]
Paw edema
induced by
dextran
Increased permeability of blood vessels,
activation of kinin, and release of mediators,
including histamine and serotonin, which
produce osmotic edema with insufficient
neutrophils and proteins
This can be used to bolster the
results of the paw model caused
by carrageenan
Unsuitable for drugs
acting through
mechanisms other
than antiserotonin or
antihistamine
[53–55]
LPS-induced
paw edema
TNF-α-mediated inflammation drugs assisted The simultaneous assessment of
anti-inflammatory and analgesic
can be done
NA [54, 56]
Arachidonic
acid-induced
ear edema
Fast transformation into lipoxygenase and
cyclooxygenase products
Anti-inflammatory for eicosanoid
inhibition recognized
Animals are sacrificed [57]
Croton oil/
TPA-induced
ear edema
Topical administration of croton oil causes
stimulates neutrophil influx, vascular
permeability, synthesis of eicosanoids,
vasodilatation, and liberation of serotonin and
histamine
Most suitable for steroidal and
NSAID
Animals are sacrificed [58, 59, 60, 61]
(Continued )
Table 17.1 (Continued)
S. no. Inflammation Model Mechanism Advantage Disadvantage References
Oxazolone-
induced ear
edema
Oxazolone dramatically raises the levels of
IFN-γ while having a negligible effect on
IL-4 levels
Interferon-γ can cause the activation of various
inflammatory cell
Recognize the model of
delayed-type hypersensitivity
Animals are sacrificed [62, 63]
Acetic acid/
Compound
48/80-induced
vascular
permeability
Compound 48/80 is an activator of histamine
release and mast cell degranulation
Appropriate model for evaluating
the acute-inflammatory effect
Severe irritation [64]
Pleurisy model Exudes, the overall protein composition and
the inhibition of leukocyte migration
demonstrate the acute anti-inflammatory effect
This test enables the evaluation
of the inflammatory
phenomenon
Severe pain, animal
sacrifices
[65, 66]
2. Sub-acute
inflammation
Granuloma
pouch model
Carcinogenic and mutagenic tissues grown
Maintain direct contact of a target with the
compounds
Test substances into air pouches Animal sacrifices [67, 68]
3. Chronic
inflammation
Cotton
pellet-induced
granuloma
The transudatory and proliferative elements
evaluated
Give information about
proliferative changes
It needs surgical skills
May cause localized
sepsis
[64, 69]
Formalin-
induced paw
edema
Bradykinin and substance-p mediate the early
neurogenic phase, while histamine, 5-HT,
prostaglandins, and Bradykinin are implicated
in the later inflammatory phase
It resembles human arthritis Irritating and painful
for animals
[64]
Arthritis
induced by
CFA
Leukocyte infiltration, cytokine, and
chemokine levels elevated with TNF-α and
IL-1β destruction of bone and cartilage
accompanied by edema and deformity and the
release of ROS
The best model for arthritis
alteration
It may affect the
severity of arthritis,
and it needs attention
[70, 71]
TNF, tumor necrosis factor; IL, interleukin; IFN, interferon; NSAID, nonsteroidal anti-inflammatory drugs; LPS, lipopolysaccharide; 5-HT, hydroxytryptamine; CFA, complete Freund’s adjuvant.
References 397
17.5.4 Lipid Nanoparticles (LNPs) as Anti-inflammatory Agents
LNPs are the most used as a delivery agent for RNA therapeutics and have the ability to trigger an
innate immune response and cause inflammation. It has been found that Dexamethasone (Dex) is
used as an anti-inflammatory medication which is directly related to cholesterol, which is the main
component of LNPs. In a study, it was found that the expression of TNF-ɑ has been reduced in
in vivo and in vitro experiments after the treatment of Dex-incorporated LNPs [75].
17.6 Conclusion and Future Perspectives
In conclusion, IDs place a significant burden on global health, affecting various organs and sys-
tems within the body. The complex interaction between immune cells and molecular mediators
defines the inflammatory environment, resulting in either acute or chronic responses. The altered
small blood vessels, acidosis, and increased oxidative stress contribute to the complexity of these
conditions. There are drawbacks and possible adverse effects to the available treatments, which
include glucocorticoids and NSAIDs. Although monoclonal antibodies that target proinflamma-
tory cytokines are promising, there are drawbacks as well, including expense, the possibility of
serious infections and cancers, and primary or secondary unresponsiveness. The demand for
advanced anti-inflammatory medications has led to the exploration of natural products as poten-
tial alternatives. Traditional knowledge and resources from indigenous populations play a crucial
role in identifying new leads for the treatment of inflammatory conditions. However, the challenge
lies in overcoming the toxicity and recurrence of symptoms associated with current synthetic
drugs. To achieve effective anti-inflammatory results, it is essential to follow a systematic approach
that incorporates the use of various animal models for evaluation. The rational design of new com-
pounds, including polymers inspired by apoptotic cell death, indoyl-imidazole hybrids, aminopi-
peridinyl amide, and LNPs, offers promising avenues for therapy development. In general, the
development of anti-inflammatory treatments mandates a multidisciplinary approach that incor-
porates insights from pharmacology, natural products, and innovative methods of drug delivery,
also the future of anti-inflammatory drug development lies in a multidisciplinary approach that
leverages technological advancements, novel therapeutic strategies, and a deep understanding of
the complex biology of inflammation. By addressing current limitations and exploring new fron-
tiers, we can develop safer, more effective treatments that significantly improve the quality of life
for individuals affected by IDs. The objective is to overcome the limitations of current treatments
and provide individuals struggling with IDs with safer and more effective options.
Authors’ Contribution
Conceptualization: K.S. and A.G.; writing: original draft preparation, K.S., A.G., I.S., A.S., and U.S.;
manuscript review and editing: K.S., A.G., I.S., A.S., and U.S.; Supervision: K.S. and A.G.; All the
authors have read and agreed to the published version of the manuscript.
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