Chapter

MARINE SPONGE COMPOUNDS WITH ANTI-

INFLAMMATORY ACTIVITY IN 2012–2016;
AND THEIR MECHANISM OF ACTION

Maushmi Kumar *

SVKM’S NMIMS, Shobhaben Pratapbhai Patel School of Pharmacy

and Technology Management, Mumbai, India

ABSTRACT
This chapter presents an overview of the development and study of marine sponge’s
bioactive compounds for anti-inflammatory activity for last four years i.e., 2012-2016.
Marine pharmacology during 2009–2011 remained a global enterprise contributing to the
preclinical pharmacology of 262 marine compounds which are in pharmaceutical
pipeline. There is no updated review for the studies done on marine sponge’s compounds
showing anti-inflammatory activity after 2011. This chapter is a sincere effort to present a
systematic review of the preclinical pharmacology of marine sponge and its associated
microbes/symbionts compounds for potential activity in inflammation.

Keywords: porifera, inflammation, inflammatory mediators, IL-1, IL-6, TNF-α, PGE2

1. INTRODUCTION
An inflammatory response is a natural defensive mechanism triggered by body tissues on
being damaged by invading pathogens, physical stress, injury, persistent foreign bodies and
by autoimmune reactions. Depending on the stimuli and the causative agents, it can be short
or long lasting. Chronic inflammation involves the release of a number of mediators such as
monocytes, macrophages, lymphocytes, plasma cells and fibroblasts that are not prominent in
the acute response (Beg et al., 2011). The defence elements of body is found majorly in blood
and during inflammation these cells and chemicals leave the blood and enter the tissue around
* *
Email: maushmiskumar@gmail.com.
2 Maushmi Kumar

the injured or infected site to protect and fight damage. Any type of infection caused by a
bacterium, virus or fungus, commonly causes inflammation; while inflammation is the body's
own response to it. It is part of many other common acute and chronic diseases. The
therapeutic strategy for the treatment of patients with inflammation has been first, the relief of
symptoms and the maintenance of function; and second the slowing or arrest of the tissue-
damaging process. Nonsteroidal anti-inflammatory drugs (NSAIDs) relieves pain for
significant periods, nonopioid analgesics are appropriate for the treatment of both acute and
chronic inflammatory conditions. The glucocorticoids also have powerful anti-inflammatory
effect but their toxicity limits their use mostly in cases of rheumatoid arthritis. The identified
targets for inflammation are the pro-inflammatory mediators cyclo-oxygenase 1 and 2 (COX-
1/-2), mitogen-activated protein kinases (MAPKs), janus protein tyrosine kinases (JAKs),
nuclear transcription factor (NF-κB) and signal transducers and activators of transcription
(STAT) which all directly or indirectly lead to the production of a vast number of pro-
inflammatory cytokines and regulatory proteins such as IL-1/6, TNF-α, MIF, IFN-γ, MMPs
(Kulkarni et al., 2006).
The role of natural products as therapy in inflammation has been recognized since ancient
ages, and major progress has been done using combinatorial chemistry. Natural products with
anti-inflammatory activity have been traditionally used for inflammatory conditions such as
fevers, pain, migraine and arthritis (Yuan et al., 2006). Many such natural products and their
derivatives with anti-inflammatory activity have been studied in detail like curcumin,
parthenolide, resveratrol, cucurbitacins, 1, 8-cineole, salicylate, epigallocatechin-3-gallate,
pseudopterosins, quercetin, lyprinol, bromelain, flavonoids, saponins and Boswellia serrata
gum resin. Recently there is also lot of interest in multi-target drug concept to use the huge
array of natural products with privileged scaffolds for developing safe anti-inflammatory
multi-target drugs (Koeberle et al., 2014). In investigation of extracts from a marine
organisms- sea urchin, Echinus esculentus for anti-inflammatory activity, UPLC-ToF-MS and
NMR analysis concluded the purified compound with a phosphocholine group with an
unknown side chain. A bryozoan, Eucratea loricata’s organic extract revealed anti-
inflammatory activity in NFκB, TNF-α and IL-1β screening (Do Thuy, 2012). There are
many anti-inflammatory natural compounds reported from marine sponge, varying widely in
both chemical structure and biological activity. The anti-inflammatory compounds from
marine sponge are dominated by terpenoid compounds, especially sesterterpenes (Keyzers
and Davis-Coleman, 2005).
In this chapter we review the development of marine sponge’s anti-inflammatory
compounds for last four years i.e., 2012-2016. A systematic review of the preclinical
pharmacology of marine sponge and its associated microbes/ symbionts compounds for
potential activity in inflammation is discussed.

2. MARINE SPONGE’S ANTI-INFLAMMATORY ACTIVITY

Twenty four anti-inflammatory compounds were reported during the year 2008-11, which
may be classified into diverse structural types: terpenes, non-terpenes, alkaloids and peptides.
Marine sponges are the richest source of anti-inflammatory compounds among other marine
invertebrates such as ascidian, soft coral, cnidarians and gorgonian. The anti-inflammatory
3 Marine Sponge Compounds with Anti-Inflammatory Activity …

sponge natural product is dominated by isoprenoid derived metabolites, especially

sesterterpenes followed by nitrogenous compounds- alkaloids, peptides etc. (Keyzers and
Davis-Coleman, 2005). New treatment approaches for acute and chronic inflammation is
investigating novel anti-inflammatory molecules which can target Toll-like receptor (TLR)
signaling pathways. Fung et al. (2014) worked on crude marine sponge extracts and identified
compound Girolline which targeted TLR5 signalling. It inhibited signaling through both
MyD88-dependent and independent TLRs (i.e., TLR2, 3, 4, 5, and 7) and reduced cytokine
(IL-6 and IL-8) production in human peripheral blood mononuclear cells and macrophages. In
other study, Geodia cydonium extract induced a reduction in VEGF (vascular endothelial
growth factor) and proinflammatory cytokines (CCL2, CXCL8, CXCL10, IFN-γ, and TNF-α)
levels in human breast cancer cell line MCF-7 cells, indicating an anti-inflammatory effect
(Costantini et al., 2015). Spongia officinalis was investigated for in vivo anti-inflammatory
activity using the carrageenan-induced paw edema model in rats. The methanol extract (25,
50 and 100 mg/kg) produced a significant reduction of the edema and the semi-purified
fraction F3 from methanol extract exhibited significant activity at the dose of 50 mg/kg, at the
third hour after carrageenan injection, with 72.85% reduction in paw volume (Dellai et al.,
2012). The methanolic extract of the Red sea marine sponge Xestospongia testudinaria
prevented carrageenan-induced acute local inflammation in rats. Methanolic extract (100
mg/kg) of red sea sponge Xestospongia testudinaria decreased % increase in paw weight
measured at 1, 2, 3 and 4 h after carrageenan injection. The extract decreased paw
malondialdehyde (MDA) and nitric oxide (NO) and decreased the inflammatory cytokines,
tumor necrosis factor-α (TNF-α), interleukin-1 β (IL-1β) and IL-6 (El-Shitany et al., 2015).
Phorbaketal A, a tricyclic sesterterpenoid was isolated from the marine sponge Phorbas sp. It
significantly inhibited the production of nitric oxide (NO), by showing suppression in the
expression of inducible NO synthase at both the mRNA and protein levels in LPS- induced
RAW 264.7 cells. Further, it also reduced production of inflammatory cytokines such as
tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and monocyte chemotactic protein-1
(Seo et al., 2015). The ethanol extract of the demosponge Homaxinella cf. balfourensis
showed activity by reducing the release of IL-1β and PGE2 only at the highest, but not
cytotoxic concentration of 250μg/mL significantly. The extract of Isodictya erinacea
inhibited the release of IL-1β and PGE2, although not affecting LTB4in a dose dependent
manner. The extracts of the sponge Isodictya toxophila and Mycale (Oxymycale) acerata’s
decreased the release of IL-1β, LTB4 and PGE2 release at the lower concentration of
50μg/mL, which was not cytotoxic (Moles et al., 2014). Solomonsterol A, a selective
pregnane X receptor (PXR) agonist was isolated from the marine sponge Theonella swinhoei.
It exerted anti-inflammatory activity along with attenuation of systemic inflammation and
immune dysfunction in a mouse model of rheumatoid arthritis. It reduced the degree of joint
damage by inhibiting the expression of pro-inflammatory mediators. (Mencarelli et al., 2014).
In another study on the anti-inflammatory effect of compound 11-oxoaerothionin isolated
from the Verongida sponge Aplysina fistularis, a concentration-dependent inhibition of iNOS
(inducible nitric oxide synthase) protein, NO -2 (nitrite), proinflammatory cytokines and PGE2
(prostaglandin E2) production was observed, when RAW264.7 cells and primary
macrophages were preincubated with the compound after stimulation with lipopolysaccharide
(Medeiros et al., 2012).
Aeroplysinin-1 is a secondary metabolite isolated from marine sponge Aplysina genus
with a wide spectrum of bio-activities. It is a chiral, optically active molecule. The
4 Maushmi Kumar

enantiomer (-)-aeroplysinin-1 was isolated from Ianthella ardis and (+)-aeroplysinin-1 was
the first brominated derivative from Aplysina aerophoba isolated by Fattorusso & Minale
(1972). The dextrorotatory enantiomer has been investigated extensively. It has potent
antibiotic effects on gram-positive bacteria and several dinoflagellate microalgae. In
preclinical studies, (+)-aeroplysinin-1 have shown promising anti-inflammatory, anti-
angiogenic and anti-tumor effects. Due to its versatility, it is of pharmaceutical interest for
treatment of different pathologies (Garcia-Vilas et al., 2015). Another marine sponge
Neopetrosia (order Haploscleridae, family Petrosiidae) whole crude extract and its isolated
compounds revealed antimicrobial, anti-fouling, anti-HIV, cytotoxic, anti-tumor, anti-oxidant,
anti-protozoal, anti-inflammatory activities. Total extracts of N. proxima (100 mg/Kg) and N.
rosariensis (100 mg/kg) significantly inhibited the paw edema of rats 60% and 72% resp.
Dichloromethane and methanol fractions of N. proxima reduced myeloperoxidase activity and
dichloromethane fraction of N. rosariensis significantly inhibited nitric oxide (66%),
prostaglandin E2 (30.5%) and tumor necrosis factor alpha production (72%) (Franco et al.,
2012; Qaralleh 2016). The crude extract of sponge Reniera sarai, also displayed anti-
inflammatory activities (Dhinakaran et al., 2014). Red sea sponges Scalarispongia
aqabaensis and Callyspongia siphonella are poorly investigated genera for their compounds
and biomedicinal value. Sterols scalaristerol (5α, 8α- dihydroxycholest-6-en-3β-ol) from
Scalarispongia aqabaensis, and callysterol (ergosta-5, 11-dien-3β-ol) from Callyspongia
siphonella were isolated for its anti-inflammatory activity in rat-hind paw edema. The results
indicated that callysterol has a strong anti-inflammatory activity, which was comparable to
cortisone, while compound scalaristerol showed moderate anti-inflammatory activity.
Callysterol affected the release of superoxide anion and thromboxane B2 in a concentration-
dependent manner. It showed close to 50% inhibition at approximately 10 μM (Youssef et al.,
2010).

3. CHEMICAL STRUCTURES OF COMPOUNDS ISOLATED AND THEIR

MECHANISM OF ACTION
A wide range of chemical compounds from various marine invertebrates have been
investigated for their anti-inflammatory properties (Table 1). Most of them exhibit
phospholipase A2 inhibitory activity. They also control nuclear factor-B activation and
inflammatory gene expression (Alcaraz & Paya, 2006). Some sesquiterpenes were found to
inhibit human neutrophil degranulation, superoxide generation, leukotriene B4 production
(variabilin), TPA (12-o-tetradecanoylphorbol-13-acetate)-induced ear oedema (variabilin,
bolinaquinone, topically) as well as carrageenan induced paw oedema (variabilin,
petrosaspongiolide M and bolinaquinone, p.o.) in mice (Giannini et al., 2001; Haefner 2003).
 Table 1. Compounds isolated from marine sponge and fungus and their mechanism of action

Sr. no. Compound Sponge Molecular mechanism Reference

1. Phorbaketal A Phorbas sp. Suppressed the expression of Seo et al., 2015
inducible NO synthase,
reduced the LPS-induced
production of inflammatory
cytokines - tumor necrosis
factor-alpha, interleukin (IL)-
1beta, IL-6, and monocyte
chemotactic protein-1.

2. (+) Aeroplysinin- 1 Aplysina Decreased the expression Garcia-Vilas et

aerophoba levels of mRNA and protein al., 2015
levels of MMP-2, MCP-1,
TSP-1, COX-2, Il-1α and
MMP-1.

3. Scalaristerol Scalarispongia No effect on release of Youssef at al.,

aqabaensis superoxide anion and 2010
thromboxane B2
 Table 1. (Continued)

Sr. no. Compound Sponge Molecular mechanism Reference

4. Callysterol Callyspongia Inhibition of release of Youssef at al.,
siphonella superoxide anion and 2010
thromboxane B2

5. Solomonsterol A Theonella Reduces the expression of Mencarelli et al.,

swinhoei TNFα, IFNγ and IL-17 and 2014
chemokines-MIP1α and
RANTES.

6. Dactyloquinone B Dactylospongia Mixture of both compounds

elegans decreased production of TNF-
α, IL-1β, and IL-6 production.
decreased the production of Lee et al., 2015
NO production, and iNOS and
COX-2
expression
Sr. no. Compound Sponge Molecular mechanism Reference
7. Cyclospongiaquinone-1 Stelospongia
conulata
Kazlauskas et al.,
1978

8. Mycoepoxydiene Marine fungus inhibition of NF-κB and Chen et al., 2012

Diaporthe sp. MAPK pathway activation
8 Maushmi Kumar

4. ANTI-INFLAMMATORY ACTIVITIES OF BACTERIA ASSOCIATED

WITH MARINE SPONGES

Anti-inflammatory activity of secondary metabolites produced by Theonella sp. was

studied using RAW 264.7 macrophages. Inhibition of nitric oxide (NO) production in
lipopolysaccharide stimulated RAW 264.7 cells is a well-established assay to screen anti-
inflammatory activity. The inhibition level of NO released by RAW 264.7 was estimated
from nitrate standard curve. Two isolates TM 1.8 and TM 1.9 possessed anti-inflammatory
activities of 112.06% and 109.7% respectively for every 1ug/L sample. The result was
compared in inhibiting NO production compared to positive control N-Monomethyl-L-
arginine Monoacetate (L-NMMA) which showed an inhibitory activity at 87.41% for every
1ug/L sample (Radzi et al., 2015). New tanzawaic acid derivative tanzawaic acid Q, and four
known analogues, tanzawaic acids A, C, D, and K were investigated from a marine-derived
fungus Penicillium steckii 108YD142. These compounds significantly inhibited nitric oxide
production and the new tanzawaic acid Q inhibited the lipopolysaccharide (LPS)-induced
inducible nitric oxide synthase and cyclooxygenase-2 proteins and mRNA expressions in
RAW 264.7 macrophages. The result of this study demonstrated that the new tanzawaic acid
derivative inhibits LPS-induced inflammation (Shin et al., 2016).

5. SYNTHETIC COMPOUNDS FROM THE MARINE SPONGE

COMPOUNDS LEAD
Several inflammatory diseases most notably rheumatoid arthritis, is related to P2X7R
activation, which has earned great attention and interests in the application of new treatments
through the inhibition of this receptor (Toulme et al., 2010). The functional role of the P2X7R
in the inflammatory event is well known as an important mediator in the expression and
release of important cytokines and inflammatory mediators. Because of its significant role, it
is recently considered as an important anti-inflammatory and pain target, and it has received
lot of attention from pharmaceutical companies for evaluating clinical trials based on it
(Soares-Bezerra et al., 2013).

Table 2. Synthetic compounds from the marine sponge

compounds as a lead

Target effects Compounds Reference

1. P2X3R and P2X2/3R AF-353 Gever et al.,
and. (Roche Pharmaceuticals) 2006
A-317491
(Abbott Laboratories)
2. P2X7 receptors Cyanoguanidines A-438079, A- Nelson et al.,
740003 and A804598 2006
3. Anti-inflammatory action in Carteramine A Kobayashi et
human neutrophils al., 2007
9 Marine Sponge Compounds with Anti-Inflammatory Activity …

Several new synthetic compounds have been developed for both the P2X3R and
P2X2/3R and P2X7 receptors. AF-353 is the most notable synthetic compound developed by
Roche Pharmaceuticals (Gever et al., 2006) and A-317491 developed by Abbott Laboratories
for P2X3R (Gunosewoyo & Kassiou, 2010). Disubstituted tetrazoles, the cyanoguanidines A-
438079, A-740003 and A804598 with action on hP2X7R (human)/mP2X7R (mouse) and
rP2X7R (rat) are the candidates for a potential antagonist for P2X7R (Nelson et al., 2006).
The compounds are listed in Table 2. TerraMarine Pharmaceuticals, New Zealand has already
identified two promising anti-inflammatory compounds from marine organisms. The first one
was patented in September 2005, and is now being improved for its effectiveness and
usability. Further, they also plan to study the compound’s action in the body and its
pharmacokinetic properties. The study will help to determine the correct dosage of the
compound and also its development into a usable drug. TerraMarine is also in process to file
the provisional patent for the second compound. Owning a patent will achieve TerraMarine
the rights to use the chemical structure of the compound as an anti-inflammatory drug or any
other for 16 years (Proffitt 2006).

CONCLUSION
Research work summarized in this chapter highlights the ongoing search and
development in the field of marine sponge’s bioactive compounds and their extraordinary
potential as a source of novel bioactive compounds and drugs. In the meantime, much work is
in progress with reference to the clinical trials and bringing the drug in the market. However,
this ultimate step is dependent on the extent to which the pharmaceutical industry shows its
preparedness to grasp such opportunities. The recent policy adopted by most governments
worldwide is encouraging and aims at funding basic research, clinical and the manufacturing
industry. There is need of continuous effort in preclinical and clinical studies of the marine
anti-inflammatory compounds to be tested so that more and more marine drugs are launched.
The continuous search for marine sponge leads, and its transformation into a drug with such
financial support will ensue good results.

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