1.0. Introduction to inflammation -...

Chapter V

Jamia Hamdard Page 280

1.0. Introduction to inflammation

Based on visual observation, the ancients have characterised inflammation by

five cardinal signs, namely redness (rubor), swelling (tumour), heat (calor; only

applicable to the body's extremities), pain (dolor) and loss of function (functio laesa).

The first four of these signs were named by Celsus in ancient Rome (30-38 B.C.) and

the last by Galen (A.D 130-200) [1]. However, beginning with the work of

Metchnikoff and others in the 19th

century, the contribution of inflammation to the

body's defensive and healing process was recognised [1]. More recently,

inflammation was described as "the succession of changes which occurs in a living

tissue when it is injured provided that the injury is not of such a degree as to at once

destroy its structure and vitality" [2], or "the reaction to injury of the living

microcirculation and related tissues [3]. Although, in ancient times inflammation was

recognised as being part of the healing process, up to the end of the 19th century,

inflammation was viewed as being an undesirable response that was harmful to the

host.

Inflammation is a part of the complex biological response of vascular tissues

to harmful stimuli, such as pathogen, damaged cells, or irritants [4]. Inflammation is a

process by which the body deals with insult and injury. Insult may be caused

mechanically (by pressure or foreign bodies), chemically (by toxins, acidity,

alkalinity), physically (by temperature), by internal processes (uremia) and by

mircoorganisms (bacteria, virus and parasites) etc. Inflammation rids the body of

foreign matter and disposes of damaged cells and initiates wound healing.

Furthermore, inflammation is considered as the corner stone of pathology in that the

changes observed are indicative of injury and disease.

During inflammation the sensation of heat is caused by the increased

movement of blood through dilated vessels into the environmentally cooled

extremities resulting in the increased redness. The swelling is the result of increased

passage of fluid from dilated and permeable blood vessels into the surrounding

tissues, infiltration of cells into the damaged area and in prolonged inflammatory

responses deposition of connective tissue. Pain is due to the direct effects of

mediators, either from initial damage or that resulting from the inflammatory response

itself and the stretching of sensory nerves due to oedema. The loss of function refers

Chapter V

Jamia Hamdard 81

to either simple loss of mobility in a joint, due to the oedema and pain, or to the

replacement of functional cells with scar tissue [5].

Inflammation is a diverse phenomenon (Figure1), ranging from the acute

inflammation associated with S. aureus infection of the skin (the humble boil),

through to chronic inflammatory processes resulting in remodelling of the artery wall

in atherosclerosis, the bronchial wall in asthma and chronic bronchitis and the

debilitating destruction of the joints associated with rheumatoid arthritis.

Figure 1. Inflammation - The basic cause of many diseases.

Inflammation is controlled by mast cells that are in close proximity to

autonomic nerves. Mast cells are the constituents of connective tissues containing

large granules that contain heparin, serotonin, bradykinin and histamine. These

substances are released from the mast cell (Figure 2) in response to injury and

infection and by their degranulation, they control most of the processes of

inflammation. Mast cells are responsive to other controls, for example, under the

influence of progesterone they release serotonin and under the influence of estrogen

they release histamine.

Chapter V


Figure 2. Role of the mast cells in inflammation.

Another important pathway is known as the arachidonic acid cascade which is

largely controlled by eicosanoids. Eicosanoids are local “hormones” made from 20-

carbon essential fatty acids; they are short-lived and can affect many aspects of

physiological function at the cellular level. Eicosanoids include all the prostaglandins,

thromboxanes and leukotrienes. Depending on genetic as well as other factors

eicosanoids transform or control prostaglandins, thromboxanes, and leukotrienes all

of which are inflammatory mediators. Eicosanoids can initiate, regulate and terminate

all local inflammatory responses. When inflammation affects a joint (such as in

rheumatoid arthritis), the cartilage can be damaged by neutrophils and lysosomal

enzymes that enter the area. This leads to a vicious cycle of repeated injury and

persistent inflammation. Inflammation may also lead to mental depression which is

commonly seen in chronic pain patients. Indolamine dioxygenase (IDO) is a rate-

limiting enzyme in the degradation of tryptophan and is induced during inflammation

by the cytokines interferon-gamma (IFN-gamma), interferon-alpha (ITN-alpha) and

tumor necrosis factor-alpha (TNF-alpha) in a broad variety of cells. Elevated levels of

IDO can enhance tryptophan degradation and subsequent serotonin depletion which

may cause depression [6].

Chapter V


1.1. Global status of inflammatory diseases

Figure 3. The global map of inflammatory bowel disease: absence of colour indicates

absence of data.

In the west, the incidence and prevalence of inflammatory bowel diseases

(IBD) (Figure 3) has increased in the past 50 years i.e. 120-200/100,000 persons for

ulcerative colitis (UC) and 50-200/100,000 persons for crohn's disease (CD). Studies

of migrant populations and populations of developing countries demonstrated a recent

slow increase in the incidence of UC, whereas that of CD remained low, but CD

incidence eventually increased to the level of UC. CD and UC are incurable; they

begin in young adulthood and continue throughout life. CD begins with ulcers that

develop into strictures or fistulas. Lesions usually arise in a single digestive segment

in CD. Amongst the patients with CD, intestinal surgery is required for as many as

80% and a permanent stoma is required in more than 10% patients. In patients with

UC, the lesions usually remain superficial and extend proximally and colectomy is

required for 10-30% of patients. The mortality of patients with UC is not greater than

that of the CD. It has been proposed that only aggressive therapeutic approaches

based on the treatment of early recurrent lesions in patients may significantly check

the progression of these chronic diseases [7]. Although progress has been made in

understanding these diseases, their etiology is still unknown.

Chapter V


1.2. Role of Natural products in the treatment of inflammatory diseases

Humans have been the most privileged form of life who has dominated the

rest of creatures. This most privileged class suffered from different ailments and

health disorders at different stages of life. For the treatment of illness, humans started

searching for the remedies in its surroundings i.e. the mother nature. The world health

organization (WHO) estimates that 80% of the population living in the developing

countries rely exclusively on traditional medicine for their primary health care needs.

In almost all the traditional medicines, the traditional plants play a major role and

constitute the backbone of the traditional medicine. Indian Materia Medica includes

about 2000 drugs of natural origin almost all of which are derived from different

traditional systems and folklore practices. Out of these drugs, 400 are of mineral and

animal origin while the rest are of vegetable origin. Since less than 10% of the

world’s biodiversity has been evaluated for potential biological activity, many more

useful natural lead compounds await discovery with the challenge being how to

access this natural chemical diversity [8]. The earliest records of natural products

were depicted on clay tablets in cuneiform from Mesopotamia (2600 B.C.) which

documented oils from Cupressus sempervirens (Cypress) and Commiphora species

(myrrh) which are still used today to treat coughs, colds and inflammation [8]. The

Ebers Papyrus (2900 B.C.) is an Egyptian pharmaceutical record, which documents

over 700 plant-based drugs ranging from gargles, pills, infusions, to ointments. The

Chinese Materia Medica (1100 B.C.) (Wu Shi Er Bing Fang, contains 52

prescriptions), Shennong Herbal (~100 B.C., 365 drugs) and the Tang Herbal (659

A.D., 850 drugs) are documented records of the uses of natural products [8].

1.3. Therapeutic potential of natural products

The Greek physician, Dioscorides (100 A.D.) recorded the collection, storage

and the uses of medicinal herbs, whilst the Greek philosopher and natural scientist,

Theophrastus (~300 B.C.) dealt with medicinal herbs. During the dark and middle

ages the monasteries in England, Ireland, France and Germany preserved this western

knowledge whilst the Arabs preserved the Greco-Roman knowledge and expanded the

uses of their own resources, together with Chinese and Indian herbs unfamiliar to the

Greco-Roman world [8]. It was the Arabs who were the first to privately own

pharmacies (8th century) with Avicenna, a Persian pharmacist, physician, philosopher

Chapter V


and poet, contributing much to the sciences of pharmacy and medicine through works

such as the Canon Medicinae [8].

In India Ayurveda originated long back in the pre‐vedic period. The Rigveda

and Atharvaveda (5000 BC), the earliest Indian documents have references on health

and diseases. During the Vedic period the Susruta samhita and the Charaka samhita

were influential works on traditional medicine. The fundamental and applied

principles of “Ayurveda” science of life; got organized and enunciated around 1500

B.C. Ayurveda traces its origins to the Vedas, Atharvaveda in particular, and is

connected to Hindu religion. Atharvaveda (one of the four most ancient books of

Indian knowledge, wisdom and culture) contains 114 hymns or formulations for the

treatment of diseases. Ayurvedic system of medicine was based on nature and its

products. Hundreds of medicinal plants were identified and have been traditionally

used since then. Over the following centuries, Ayurvedic practitioners developed a

number of medicinal preparations and surgical procedures for the treatment of various

ailments and diseases. Ayurvedic medicinal preparations consist mainly of plant

materials in the form of powders, semi‐solid preparations, decoctions, elixirs and

distillates. Many of them also contain inorganic chemical substances, minerals and

animal products. Alcoholic extracts and alcoholic solutions of the ingredients,

tinctures and elixirs are also frequently used in Ayurvedic medicine.

The role of natural products for the treatment of diseases has been recognized

since ancient times. There has been considerable public and scientific interest in the

use of natural products to combat human diseases such as inflammatory disease,

cardiovascular disease, and cancer etc. In spite of major scientific and technological

progress in combinatorial chemistry, drugs derived from natural products still make

an enormous contribution to drug discovery today [9]. Natural products with anti-

inflammatory activity have long been used as a folk remedy for inflammatory

conditions such as fever, pain, migraine and arthritis.

Boswellia serrata is native to India and has been used in traditional Ayurvedic

medicine for the treatment of inflammatory diseases in India [10]. The gum resin of

Boswellia serrata called ‘salai guggul’ or ‘Indian olibanum’ and is obtained from the

bark of Boswellia serrata after injury. Many commercial formulations of salai guggul

in the form of ointments, creams and capsules are available in the market [11]. As a

Chapter V


result of its alleged safety, boswellia was considered superior over mesalazine in

terms of a benefit-risk evaluation [12]. Research has shown that it is perhaps the

triterpenoid boswellic acids in the Boswellia serrata gum resin which exert the anti-

inflammatory action [13]. Boswellic acids inhibit the 5-LOX (Lipoxygenase) enzyme,

thereby reducing the production of the potent inflammatory mediators, the

leukotrienes [14].

Bromelain is a crude aqueous extract which is obtained from both the stem

and fruit of the pineapple plant and contains a number of proteolytic enzymes [15]. A

large body of scientific research shows that bromelain is a potential product for

treatment of osteoarthritis [16]. Bromelain was first reported to be used as an anti-

inflammatory for use in both rheumatoid arthritis and osteoarthritic patients in 1964

[16]. The mechanism of anti-inflammatory action of bromelain is known [16]. They

suggest that bromelain’s anti-inflammatory action is mediated by increasing serum

fibrinolytic activity, reducing plasma fibrinogen levels and decreasing bradykinin

levels (which results in reduced vascular permeability) and hence reducing oedema

and pain; by decreasing levels of PGE2 and thromboxane A2 (TXA2); and by

modulation of certain immune cell surface adhesion molecules.

Lyprinol is a stabilized lipid extract obtained from the New Zealand

green-lipped mussel (NZGLM) and is used to relieve the symptoms of arthritis. The

oil of the NZGLM contains a complex mixture of triglycerides, sterol esters, polar

lipids and free fatty acids [17].

Ternatin, a tetramethoxy flavone (Figure 4) isolated from Egletes viscosa, was

shown to have anti-inflammatory activity in rat carrageenan-induced pleurisy test

[18].

O

O

O

OH O

O

O

OH

Figure 4. Ternatin

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Quercitrin and rutin display beneficial effects in experimental inflammation

which is induced by trinitrobenzene sulfonic acid in the rat model [19]. The

mechanism by which flavonoids exert their anti-inflammatory effects involves the

inhibition of COX and LOX activities, eicosanoid biosynthesis and neutrophil

degranulation. Selective flavonoids such as quercetin inhibit both COX and LOX

activities [20]. Pelzer et al., (1998) investigated the anti-inflammatory activity of 30

flavonoids isolated from several plants of the compositae family and found that all the

flavonoids tested have anti-inflammatory activity depending on both their structure

and the method used for the assay [21].

Just et al., (1998) isolated three saponins (Fruticesaponin A, Fruticesaponin B,

ruticesaponin C) from Bupleurum fruticescens and investigated their anti-

inflammatory effects. All of them exerted anti-inflammatory activity in the mouse

oedema assay; however Fruticesaponin B has the highest anti-inflammatory activity

[22]. Silva et al., (2002) isolated a new steroidal saponin from the leaves of Agave

attenuata and investigated its anti-inflammatory activity using the capillary

permeability assay. It inhibits the increase in vascular permeability caused by acetic

acid [23]. Aescin, the main active constituent of Aesculus hippocastanum, is a

complex mixture of triterpenoid saponin glycosides. It has been shown to have anti-

oedematous, anti-inflammatory and venotonic properties in different animal models

[24]. Two triterpenoid saponins (Figure 5), kalopanaxsaponin A and pictoside A,

have been isolated from the stem bark of Kalopanax pictus and were found to exhibit

significant anti-inflammatory activity at the oral dose of 50 mg/ml [25].

O

COOH

HOH2C R2

R3O

OH

HO

R1O

R1 R2 R3

Kalopanaxsaponin A a-L-rhamnopyranosyl -H -H

a-L-rhamnopyranosyl -H -OHPictoside A

Figure 5. Kalopanaxsaponin A and Pictoside A

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Probably the most famous and well known example to date would be the

synthesis of the anti-inflammatory agent, acetylsalicyclic acid (1) (aspirin) [26]

derived from the natural product, salicin (2) isolated from the bark of the willow tree

Salix alba L. Investigation of Papaver somniferum L. (opium poppy) resulted in the

isolation of several alkaloids including morphine (3) a commercially important drug,

first reported in 1803.

O

HO

O

O CH3

O

OH

HO

HO OH

O

HO

HO

O

HO

H

N CH3

1 2 3

It was in the 1870s that crude morphine derived from the P. somniferum was

boiled in acetic anhydride to yield diacetylmorphine (4) (heroin) which was readily

converted to codeine (5), a painkiller.

O

O

O

H

N CH3

5

O

O

O

O

HO

H

N CH3

H3C

4

Pilocarpine (6) found in Pilocarpus jaborandi (Rutaceae) is a L-histidine-

derived alkaloid, which has been used as a clinical drug for the treatment of chronic

open-angle glaucoma and acute angle-closure glaucoma for over 100 years. In 1998,

its oral preparation was approved for the treatment of Sjogren's syndrome, an

autoimmune disease that damages the salivary and lacrimal glands [27].

OO

N

N

CH3

6

Tripterygium wilfordii (Lei Gong Teng) is a Chinese herb that has been shown

to be quite effective in treating inflammation. It is a toxic herb that should be used

Chapter V


with caution as it can cause internal bleeding, kidney damage, decrease in blood cell

counts, decreased bone mineral density in females, hair loss, immune system dys-

function and even death. PG490-88, a diterpene-diepoxide (7), is a semisynthetic

analogue of triptolide which is isolated from Tripterygium wilfordii. It is used for the

treatment of autoimmune and inflammatory diseases in the People’s Republic of

China [28, 29].

O

OH

O

OO

O

O

O Na

O

7

Grandisines A (8) and B (9) are two indole alkaloids which were isolated from

the leaves of the Australian rainforest tree, Elaeocarpus grandis. Grandisine A (8)

contains a unique tetracyclic skeleton, while Grandisine B (9) possesses an unusual

combination of isoquinuclidinone and indolizidine ring systems. Both 8 and 9 exhibit

binding affinity for the human δ-opioid receptor and are potential leads for analgesic

agents [30].

O

O

N

H

H

HO

NO

N

H

8 9

The first notable discovery of biologically active compounds from marine

sources can be traced back to the reports of Bergmann on the isolation and

identification of C-nucleosides, spongouridine (10) and spongothymidine (11) from

the Caribbean sponge, Cryptotheca crypta in the early 1950s [31]. These compounds

were found to possess antiviral activity and the synthesis of its structural analogues

led to the development of cytosine arabinoside (Ara-C) as a clinical anticancer agent,

together with (Ara-A) as an antiviral agent 15 years later [31].

Chapter V


O

HO OH

N

OH

NH

O

O

O

HO OH

N

OH

NH

O

O

10 11

There are many anti-inflammatory natural products derived from marine

sponges. Eighty four anti-inflammatory compounds dominated by isoprenoid derived

metabolites, especially sesterterpenes (means 2.5 terpenes) have been isolated from

marine sponges [32]. Manoalide (12) is probably the most well-known of all the anti-

inflammatory products from sponge and was originally isolated by de Silva and

Scheuer in 1980 from the sponge Luffariella variabilis [33].

OHO

O

O

OH

12

The global marine pharmaceutical pipeline consists of three Food and Drug

Administration (FDA) approved drugs, one EU registered drug, 13 natural products

(or there derivatives) in different phases of the clinical trial and a large number of

marine chemicals in the pre-clinical pipeline [34]. Some examples include, Ziconotide

(Prialt®, Elan Corporation) a peptide first discovered in a tropical cone snail, which

was approved in December 2004 for the treatment of pain. Plitidepsin (13) (Aplidin®,

PharmaMa), a depsipeptide was isolated from the Mediterranean tunicate Aplidium

albicans [35,36]. Plitidepsin (13) is effective in treating various cancers, including

melanoma, small cell and non-small cell lung, bladder as well as non-hodgkin

lymphoma and acute lymphoblastic leukemia and is currently in Phase II clinical trials

[34,37].

Chapter V


N

O

O

O

N

O

NH

NHO

OH O

O

O

O

NHO

NO

N

O

O

13

Sativex, a mixture of dronabinol 14 and cannabidol 15 obtained from the

cannabis plant, is the world's first pharmaceutical prescription medicine that was

launched in Canada (April 2005) and was later approved by Health Canada (August

2007) as adjunctive analgesic for severe pain in advanced cancer patients [38].

Sativex has been recommended by FDA to enter directly in Phase III trials and as of

November 2009, GW Pharmaceuticals have completed the recruitment for Phase II/III

trial against cancer pain.

O

CH3

H3C

H3C

OH

CH3

14

CH3

OH

OHH2C

CH3

CH3

15

Chapter V


Natural product-derived drugs launched during 2005-2010; lead

compounds, and therapeutic area.

Year Trade name Lead Compound Disease area

2005 Dronabinol / Cannabidol

(Sativex®)

Dronabinol /

cannabidol Pain

2005 Fumagillin (Flisint®) Fumagillin Antiparasitic

2005 Doripenem

(Finibax® / DoribaxTM) Thienamycin Antibacterial

2005 Tigecycline (Tygacil®) Tetracycline Antibacterial

2005 Ziconotide (Prialt®) Ziconotide Pain

2005

Zotarolimus

(EndeavorTM stent)

Sirolimus Cardiovascular

surgery

2006

Anidulafungin

(EraxisTM / EcaltaTM)

Echinocandin B Antifungal

2006 Exenatide (Byetta®) Exenatide-4 Diabetes

2007 Lisdexamfetamine

(VyvanseTM) Amphetamine

Attention deficit-

hyperactivity

disorder (ADHD)

2007

Retapamulin

(AltabaxTM/AltargoTM)

Pleuromutilin Antibacterial

2007 Temsirolimus (ToriselTM) Sirolimus Oncology

2007 Trabectedin (YondelisTM) Trabectedin Oncology

2007 Ixabepilone (IxempraTM) Epothilone B Oncology

2008 Methylnaltrexone (Relistor®) Naltrexone Pain

2009 Everolimus (Afinitor®) Sirolimus Oncology

2009 Telavancin (VibativTM) Vancomycin Antibacterial

2009 Romidepsin (Istodax®) Romidepsin Oncology

2009 Capsaicin (Qutenza®) Capsaicin Pain

2010

Monobactam aztreonam

(CaystonTM)

Aztreonam Antibacterial

Chapter V


Natural products as anti-inflammatory agents

Compound Source Structure Reference

Curcumin

Curcuma longa

OHO

O O

OOH

CH3CH3

[39]

Parthenolide Tanacetum

parthenium

CH3

H3C OO

O

CH2

[40]

Cucurbitacins Wilbrandia

ebracteata

HH

HH

H

Basic structure

[41]

1,8-Cineole Eucalyptus

obliqua O [42]

Pseudopterosins Pseudopterogorgia

elisabethae H

O OHO OH

OH

OH

[43]

Amrubicin

hydrochloride

Streptomyces

peucetius

O

O

OH

OH O

OH

OHOH

O

NH2

[44]

Chapter V


The natural products discovered so far have played a vital role in improving

the human health and have been the drugs of choice despite facing a tough

competition from their synthetic counterparts, due to their safe and long lasting

effects. Current interest leads to the search for new natural products with anti-

inflammatory activity. Extensive scientific research deals with the finding, extracting,

pharmacological effects and mechanism by which natural products exert their activity.

In summary, we propose that a combination of metabolomics technologies with

natural product discovery processes will be highly beneficial. By increasing the

number of identifications in our metabolomics data we may provide novel structures

to be tested for bioactivity for a disease under investigation.

In view of the importance of natural products in the human health system, the

main objectives of this work are as follows:

1. Ethanolic extraction of the dried plant material followed by the fractionation

with different solvents of increasing polarity.

2. Isolation of the active principles from the biologically active fraction(s) of the

plant.

3. Structure elucidation of isolated compounds and biological evaluation of the

ethanolic extract and its fractions along with the isolated natural compounds

for their anti-inflammatory and analgesic activities with gastric ulceration

studies.

Chapter V


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Chapter V


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