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Herbal Complement
Inhibitors in the
Treatment of
Neuroinflammation
Future Strategy for
Neuroprotection
ABSTRACT: The
upregulated complement
system plays a damaging
role in
disorders of the central
nervous system (CNS).
The classical and
alternate
pathways are two major
pathways activated in
neuroinflammatory
disorders
such as Alzheimer’s
disease, multiple
sclerosis, traumatic
brain injury, spinal
cord injury,
HIV-associated dementia,
Parkinson’s disease, and
mad cow disease.
Failure of currently
available
anti-inflammatory
agents, especially
cycloxygenase
inhibitors, in offering
significant
neuroprotection in large
epidemiologic clinical
trials of CNS disorders
suggests an urgent need
for the
development of new
neuroprotective agents.
The positive preclinical
outcomes
in treating CNS
disorders by complement
regulatory molecules,
such as
vaccinia virus
complement control
protein, suggest the
possibility of using
complement-inhibitory
molecules as
neuroprotective agents.
Several active
ingredients
of herbal origin are
found to have
complement-inhibitory
activity.
These herbal ingredients
along with other
anti-inflammatory roles
might be
useful in treating
neuroinflammation
associated with CNS
disorders. Active
ingredients
of herbal origin with
complement inhibitory
ingredients are
summarized
and classified according
to their chemical nature
and specificity towards
the major pathways
activating the
complement system. The
structure activity
relationship of some
specific examples is
also discussed in this
report. This information
might be helpful in
formulating a natural
panacea against
complement-
mediated
neuroinflammation.
KEYWORDS:
neuroprotection;
neurodegeneration;
complement inhibitors;
herbal ingredients;
alternate pathway;
classical pathway;
cyclooxygenases;
vaccinia virus
complement control
protein (VCP);
Alzheimer’s disease
(AD);
HIV-associated dementia
(HAD); Parkinson’s
disease (PD)
THE COMPLEMENT SYSTEM IN
NEURODEGENERATION
The complement system is
known to perform a wide
range of functions in
the
human body. It forms an
essential component of
the host immune system
and is
associated with the
clearance of molecules
of foreign origin as
well as the elimination
of invading pathogens
from the body. It plays
an important role in
adaptive
immunity.1 However, it
is nonspecific in action
and unable to
distinguish between
self and non-self. Under
normal conditions, it is
strictly regulated by
complement
regulatory molecules.
However, in
neuroinflammatory
disorders, the
complement
regulatory molecules
fail to control the
activated complement
components. These
activated complement
components then act as a
double-edged sword and
are responsible
for the degeneration of
neurons.2 The
devastating roles of the
complement
components in
neurodegenerative
disorders are well
documented. Alzheimer’s
disease
(AD),3 multiple
sclerosis (MS),4,5
myasthenia gravis,6
Parkinson’s disease
(PD),7 traumatic brain
injury (TBI),8 and
spinal cord injury
(SCI)9 are examples of
a few disorders in which
activated complement
components play an
important role.
Not only do these
disorders arise out of
dysfunction in the
normal metabolic
machinery,
but also
neuroinflammatory
disorders associated
with microbial
infections show
involvement of
complement components.
In HIV-associated
dementia (HAD),
complement
components are
responsible for
neuroinflammation. HIV-1
and its pathogenic
proteins such as GP-120,
GP-41, and Nef-1 are
also associated with the
activation of complement
components. HIV-1 along
with the aforementioned
pathogenic
proteins is also known
to modulate the C3
promoter activity in
neurons and/or
astrocytes.10 HIV has
developed an effective
evasion strategy
involving synthesis of
HIV-associated molecules
from complement-mediated
damage. It also utilizes
the
complement opsonins in
the process of cell
entry and replication.
This whole phenomenon
is outlined in a recent
review by Stoiber et
al.11 Spongiform
encepalopathies such as
scrapie, are also
associated with the
activated complement
components.12,13
The complement system is
activated by the three
major pathways, the
classical
pathway (CP),
alternative pathway
(AP), and
lectin-mediated pathway.
Activation of
one of the pathways may
lead to activation of
the other pathway. The
C3b component
generated by spontaneous
activation of the CP
leads to activation of
the AP by formation
of the alternate pathway
C3 convertase.14 These
pathways lead to the
generation
of opsonins and
anaphylatoxins. The
final common step after
activation of the
complement system is the
generation of the
membrane attack complex
(MAC). The
complement
anaphylatoxins are
responsible for the
various proinflammatory
events
in the CNS and
chemotaxis of the
immunocompetent cells.
The brain environment
is further complicated
by release of
proinflammatory
mediators such as nitric
oxide
and glutamate.15 Mast
cells are found in the
brain and in the
proximity of neurons.
Anaphylatoxins and other
mediators may activate
secretion of
proinflammatory
molecules
from the mast cell.16
The C3a is found to be
involved in the
activation of the
mast cells through FcγRI
receptors.17
Anaphylatoxins are also
known to activate
brain astrocytes through
C3a and C5a receptors
located on them,
resulting in release
of cytokines and
chemokines involved in
the pathogenesis of CNS
disorders.18,19
One of the complement
components, C5b-9, is
also known to activate
prostaglandin
production in glomerular
epithelial cell (GEC)
injury. C5b-9
upregulates the
cyclooxygenase-2 enzyme
(COX-2) in GEC.20,21
COX-2 is found to be
associated
with the complement
components in the brain.
It selectively activates
the C1q component
of complement in the
brain.22 MAC induces
concentration-dependent
neuronal cell death and
changes in membrane
permeability to Na+, K+
and Ca2+,
release of cytokines,
eicosanoids, and
reactive-free radicals.
These changes occur at
sublytic concentrations
of MAC.23 MAC is also
responsible for the
demyelination
of neurons in
demyelinated forms of
certain disorders.24
It is therefore well
established that
inflammation plays a
major role in the
etiology
of neurodegenerative
disorders and that
complement components
are one of the
major groups of
proinflammatory
molecules that are
involved.
CURRENT
ANTI-INFLAMMATORY AGENTS
Although, inflammation
plays an important role
in CNS disorders, no
currently
available
anti-inflammatory agent
offers significant
neuroprotection in such
disorders.
Anti-inflammatory agents
used in therapy can be
broadly classified as
steroidal
and nonsteroidal agents
(SAIDs and NSAIDs,
respectively). These
drugs pose
potential health hazards
in long-term treatment.
The role of steroidal
agents such as
estrogen in the
treatment of dementia is
controversial and is not
recommended for
age-associated
dementia.25 Treatment
with a combination of
estrogen and progestin
causes a cognitive
decline in
postmenopausal women.26
Prednisolone treatment
also
failed in clinical
trials of AD.27
NSAIDs are either
nonspecific inhibitors
(mixed; inhibit both
cyclooxygenases,
COX-1, and COX-2) or
specific inhibitors
(generally target
COX-2). Both are
associated
with adverse effects.
Nonspecific NSAIDs such
as indomethacin are
associated
with gastric mucosal
damage and aggravate the
problems associated with
Helicobacter pylori.28
Recently, a selective
COX-2 inhibitor vioxx
(rofecoxib) was
removed from the market
because of the
cardiotoxicity
associated with its use.
Mixed NSAIDS and
rofecoxib are associated
with congestive heart
failure (CHF)
and hypertension.29
Whether the risk of
heart disease is
associated with COX-2
inhibition or to the
unique structure of
rofecoxib still remains
controversial. Further
research is needed in
the use of these drugs,
and it is best to avoid
using these agents
in such disorders. COX
inhibitors are
associated with the risk
of myocardial
infarction,
30 edema, and
hypertension.31
Selective COX-2
inhibitors show similar
adverse
drug-related events as
demonstrated by
nonselective NSAIDs
treatment.32 Previously,
COX-2 expression was
considered inducible,
but recent evidence
suggests that it
is constitutive in the
brain. It is expressed
by neurons and plays a
critical role in
coupling
synaptic activity to
neocortical blood
flow.33 COX-2 in the
brain is the primary
isozyme involved in
memory consolidation,
and COX-1 is associated
with memory
formation.34
Controversies regarding
the role of COX-2 in CNS
disorders, its
beneficial roles
in normal cognitive
function as well as the
adverse effects of
NSAIDs in the brain
are discussed in a
recent review by
Minghetti.35 COX
inhibitors are not only
responsible
for the generation of
harmful prostaglandins,
but also involved in the
generation
of PGE2, which is known
for its involvement in
potential beneficial
effects, such
as membrane excitability
and synaptic
transmission in the
hippocampus,36 and
neuroprotection against
TNF-α.37 Thus,
inhibition of COX
attenuates the potential
beneficial roles of
PGE2. Recent large-scale
randomized controlled
clinical trials
with NSAIDs in the
treatment of CNS
disorders yielded poor
results.38–40 However,
indomethacin was found
to be beneficial in mild
cognitive impairment and
nimesulide
was also found to be
effective.41,42 Their
beneficial effects can
be attributed The reason
for the failure of these
agents in the treatment
of neuroinflammatory
disorders can be
attributed to their
inability to target the
key component involved
in
neuroinflammation. Also,
most of them target
cyclooxygenases, whose
roles in the
CNS are controversial.
Complement plays an
important role in the
etiology of almost
all CNS disorders, as
outlined previously in
this review. The role of
the complement
components in
neuroinflammation, the
interaction with other
proinflammatory
molecules,
and the need for
complement inhibition
are outlined in a recent
review by
Kulkarni et al.43
COMPLEMENT INHIBITORS IN
NEUROINFLAMMATION
Preclinical outcomes
from our laboratory
suggest that complement
regulatory
molecules might be of
great help in the
treatment of the
aforementioned chronic
neuroinflammatory
disorders. Vaccinia
virus complement control
protein (VCP) was
found to be effective in
treating SCI and
TBI.44–46 It might be
useful in the treatment
of CNS injury associated
with AD.47 sCrry is
another complement
regulatory molecule
found to be effective in
the treatment of
allergic
encephylomyelitis.48
However,
no complement inhibitory
molecule is currently
available on the market
for the treatment
of neuroinflammatory
disorders. Complement
inhibitors are
relatively new in
drug therapy. Certain
pharmaceutical companies
are targeting the
complement inhibitors
for the treatment of
disorders such as
rheumatoid arthritis and
cardiovascular
disease.49,50 The
complement inhibitory
molecules under
development are
pexelizumab
and eculizumab. These
monoclonal antibodies
specifically target C5a,
a potent
anaphylatoxin, and are
currently undergoing
clinical trial.49,50
Recently, pexelizumab
reduced the myocardial
infarction and death
rate in patients who had
undergone coronary
artery bypass graft
surgery.51,52 However,
their potential in
neurodegenerative
disorders and their
bioavailability in the
brain have yet to be
investigated.
HERBAL COMPLEMENT
INHIBITORS
During the last two
decades, several
ingredients of herbal
origin have been tested
for their complement
inhibitory potential. To
gain some perspective
with a view to
developing suitable
complement inhibitory
molecules from naturally
occurring compounds,
some of the active
constituents of
medicinal plants with
complement inhibitory
activity (in vitro in
most cases unless
mentioned) are discussed
below.
However, none of these
agents has been tested
clinically for its
ability to offer
neuroprotection.
MEDICINAL PLANTS WITH
COMPLEMENT INHIBITORY
INGREDIENTS
Juglans mandshurica.
This plant consists of
four flavonoids and two
galloyl residues.
The flavonoids with the
most potent complement
inhibitory activity
found in
this plant are afzelin
and quercitrin. However,
the galloyl residues,
tetragalloyl glucose and
trigalloyl glucose, were
more potent than the
corresponding
flavonoids.
The tetragalloyl residue
(1, 2, 3, 4 tetragalloyl
glucose) was the most
potent, suggesting
the importance of the
galloyl moieties in
complement inhibition.53
Glycyrrhiza glabra. This
is an ancient Ayurvedic
medicine known for its
antiinflammatory
potential. The
constituents,
β-glycyrrhetinic acid
and glycyrrhizin,
were found to have
complement inhibitory
potential. Both of them
induced conformational
changes in C3.54
β-glycyrrhetinic acid
was more potent among
them. It inhibits
the CP at the level of
C2 rather than C4 and
C1q.55 Glycirrhizin
inhibited the
C3 component of the
complement anaphylatoxin
C3a and C3b.54 Apart
from direct
actions, these compounds
are known to have some
indirect
anti-inflammatory
activities,
which make them suitable
for the treatment of
several inflammatory and
autoimmune
disorders.
Crataeva nurvala. The
triterpene lupeol is an
active constituent of
this medicinal
plant. Both lupeol and a
compound synthesized
from it, that is, lupeol
linoleate, were
found to have
anti-inflammatory
potential in
adjuvant-induced
arthritis in rats, the
latter being more potent
than the former. The
anti-inflammatory
activity can be
attributed
to the complement
inhibitory activity of
these compounds. The
compounds
were considered to
reduce C3 convertase
activity. The
anti-inflammatory
activity of
these compounds was more
than that of
indomethacin; however,
further elaboration
of the complement
inhibitory activity is
essential.56
Ligustrum vulgare and
Phillyrea latifolia
Leaves. These belong to
the Oleaceae
family. The ethanolic
extracts of both plants
were found to have more
complement
inhibitory activity than
the methanolic extract.
The flavonoids apigenin,
luteolin,
and their glucosides,
are the active
constituents of these
plants. The flavones
showed
dose-dependent
inhibition of the CP.
However, no such
correlation was found
with
the AP. Further SAR
studies revealed that in
case of the glucosides,
that is, apigenin-
7-O-derivatives,
complement inhibitory
activity was optimum
with disaccharide
derivative.57
Morinda morindoides.
This is the most popular
medicinal plant in the
Democratic
Republic of Congo and is
used traditionally to
alleviate rheumatic
pain. Iridoids are
active ingredients of
this plant.
Gaertneroside,
acetylgaertneroside, and
gaertneric
acid inhibited the CP
(in vitro action).
Gaertneroside was the
most potent among
these compounds.
Iridoids failed to
inhibit the AP.58 Apart
from iridoids, Morinda
also shows quercetin and
other complement
inhibitory molecules.
Quercetin and
MO15 inhibited both the
AP and the CP. Others
showed a more pronounced
and dosedependent
effect on the CP.59
Osbeckia aspera. The
mature leaves of this
Ayurvedic medicinal
plant have been
used traditionally to
treat liver disease in
Srilanka. The herb has
immunosuppressive
capabilities through
other mechanisms apart
from complement
inhibition. The
whole plant extract was
found to have a
dose-dependent effect on
both the CP and
the AP. The effect was
more pronounced on the
CP.60
Cedrela lilloi and
Trichilia elegans. These
medicinal plants,
belonging to the
Meliaceae family, grow
in Argentina. The fresh
leaf extracts of these
two plants were
found to have
anticomplement activity.
The extracts inhibited
both the CP and the
AP of complement
activation. However, the
chemical moieties
responsible for this
and the precise
mechanism of complement
inhibitory action of
these plants are yet
to be identified. These
plants are also known to
inhibit the phagocytosis
of the peritoneal
macrophages and possess
strong antiproliferative
activity against T
cells.61 Azadirachta
indica. This is commonly
known as Neem in India
and is well known
for its medicinal value.
The crude aqueous
extract of the plant
consists of complement
inhibitory polymers NB-I
and NB-II, the former
being less active than
the latter.
Activity could be
correlated with
molecular weight, as
NB-I, a high molecular
weight compound, was
less active than the low
molecular weight
compound NB-II.
Glucose was found to be
the main carbohydrate
constituent.62
Tinospora cordifolia.
This climbing shrub,
commonly called gurcha,
is well documented
in the Ayurvedic
literature and is known
for its
anti-inflammatory and
immunomodulatory
potential. These
constituents were also
found to mediate
phagocytosis
by peritoneal
macrophages. However,
the two compounds,
syringin and cordiol,
inhibited the activation
of the complement by
inhibiting the C-3
convertase of
the CP. Like the other
active constituents,
these were also found to
potentiate the
immune response.63
Isopyrum thalictroides.
This plant is used in
Chinese medicine in the
treatment of
inflammatory disorders
such as rheumatism,
neuralgia, and
silicosis. The plant
with
several photoberbezines
and bisbezylisoquinoline
(BBI) alkaloids having
complement
inhibitory activity may
provide novel complement
inhibitory molecules.
However,
isopyruthaline (It1),
fangchinoline (It2), and
isotalictrine (It3) are
the three major active
ingredients of this
plant, whose complement
inhibitory activity has
been well studied.
These constituents were
found to inhibit the CP.
It3 was the most potent
inhibitor
of the CP and It1 the
least potent. It showed
Ca2+- and Mg2+-dependent
complement
inhibition. It inhibited
the formation of the
first component of the
complement system.
The complement
inhibitory actions of
It2 were independent of
Ca2+ ions, and in the
case of It3, its
effectiveness decreased
at a very high
concentration of calcium
ions.64
The BBIs affected the
formation of convertase
and did not inhibit the
decay of the convertase.
These iridoids also
influenced the AP.65 It3
was found to suppress
both pathways,
but It1 and It2
augmented AP hemolysis
at a higher
concentration.
Apart from these
specific plants listed
with potent complement
inhibitory molecules,
the active ingredients
of several other
medicinal plants with
known antiinflammatory
activity have shown
inhibition of the
complement system, as
outlined
in TABLE 1. These herbal
ingredients are
systematically
classified on the basis
of their complement
inhibitory activity (in
vitro and/or in vivo in
a few cases) and
chemical nature. With an
aim to develop either
specific or nonspecific
inhibitors of
the complement system,
these agents are also
classified according to
their mode of
action. The compounds
with novel action on the
complement components
are listed
separately.
Classification according
to chemical nature might
be of great help in
developing
structurally related
potent complement
inhibitory agents with
neuroprotective
roles.
CLASSIFICATION AS PER
MODE OF ACTION
As discussed previously,
the AP and CP are the
two major pathways of
complement
activation involved in
neuroinflammatory
disorders. Thus, herbal
complement
inhibitors (HCIs) can be
broadly classified as
selective inhibitors
(SIs) and nonselective
inhibitors (NSIs) of the
complement system
depending on their
ability to inhibit
one or both pathways
involved in complement
activation. SIs can
further be classified
as classical pathway
inhibitors (CPIs) or
alternate pathway
inhibitors (APIs).
Nonselective inhibitors
can be classified as
strong CP–moderate AP
inhibitors (SCPMAPs),
strong AP–moderate CP
inhibitors (SAPMCPs),
and general complement
inhibitors. The
ingredients included in
the general complement
inhibitors section
may inhibit one of the
pathways to a greater
extent than the other,
but they can be
considered as potent
inhibitors of both
pathways. This type of
classification may
help to select suitable
complement inhibitory
molecules based on the
etiology of the
disease. As discussed
previously, activation
of one pathway leads to
activation of the
other. Thus, depending
on disease status, SIs
and NSIs can be used in
therapy. These
agents are outlined in
FIGURE 1. Apart from
these compounds, novel
complement
inhibitors are outlined
separately in FIGURE 2.
Understanding the mode
of action of the
individual agent might
be of great help
in developing an
effective combination
therapy using different
complement inhibitory
molecules targeting
different complement
components. This might
also prove
useful in avoiding
irrational combinations.
Hence, the actions of
herbal ingredients
on the complement
components are
represented
diagrammatically in
FIGURE 3.
CLASSIFICATION ACCORDING
TO CHEMICAL NATURE
The ingredients of
herbal origin can be
grouped into several
classes, based on
their chemical origin.
Most compounds
inhibiting the
complement components
are
either flavonoids and
their
glucosides,53,66,67,78,81
polysaccharides,74,75,80,84
or terpenes.
56,71,87 Apart from
these major chemical
classes inhibiting
complement, other
classes of complement
inhibitors include
iridoids,58
polymers,62,73
peptides,77 alkaloids,
79 and oils.72 These are
outlined in FIGURE 4.
Synthesis of new
structurally related
analogs, systematic
comparative study of
these compounds and
study of the
bioavailability to the
brain will reveal the
novel
complement inhibitory
molecules with potent
antineuroinflammatory
activity. These
neuroprotective agents
will be of great help in
the treatment of complex
brain disorders
such as AD, HAD, and PD.
STRUCTURE ACTIVITY
RELATIONSHIP OF SOME
INGREDIENTS OF
HERBAL ORIGIN
Flavonoids and
Derivatives
(a) The presence of the
galloyl group increased
the complement
inhibitory activity
of the flavonoids.
(b) Tetragalloyl glucose
showed better activity
than did trigalloyl
glucose.
(c) There was an
increase in
anticomplement activity
in inverse proportion to
the
number of free hydroxyl
groups on the B-ring and
3,5,7-trihydroxyflavone.53
(d) In L. vulgare,
triglucosides of the
flavonoids were more
active than those of
the corresponding
flavonoids.
FIGURE 1. Classification
of HCIs based on their
mode of action and
specificity. HCIs
can be classified as
selective and
nonselective inhibitors
(SIs and NSIs,
respectively) based
on their selectivity
towards the complement
pathways. The NSIs are
further subclassified
into different subgroups
according to their
ability to inhibit one
pathway to a greater
extent
than the other to
actions other than COX
inhibition.
CONCLUDING REMARKS
This review focuses on
the detrimental roles of
the complement system in neuroinflammatory
disorders and the
inability of the
currently prescribed
NSAIDs to prevent
and treat such
disorders. The
unavailability of a
suitable complement
inhibitory
molecule in the market
leaves an urgent need
for the development of
suitable complement
inhibitory molecules
with neuroprotective
values. Complement
inhibitory
molecules of herbal
origin, classification
based on their mode of
action on one or
more complement
components, and
classification based on
chemical structure and
specificity and
selectivity towards the
particular complement
component are discussed.
Also, SAR studies of
some of the complement
inhibitory molecules are
outlined.
This collective
information, that is,
the devastating roles of
the complement
system along with
information on herbal
complement inhibitors,
may shift the focus
of scientists from the
currently prescribed
NSAIDs towards the
complement inhibitory
molecules. Complement
inhibitory molecules may
emerge as a separate
class of
antineuroinflammatory
molecules. The SAR study
outlined here may be
helpful in the
development of suitable
complement inhibitors
with neuroprotective
abilities. Information
on the mode of action of
complement inhibitors
might prove of
significant help
in designing a
combination therapy with
two or more agents with
different modes of
action on the complement
system. However,
rigorous research in
this field with special
emphasis on
bioavailability to the
brain, safety studies,
separation of
impurities, and
clinical trials of the
complement inhibitory
molecules is essential
in advocating herbal
complement inhibitors as
the next generation of
neuroprotective agents.
SUMMARY
The currently existing
NSAIDs are associated
with side effects, and
epidemiologic
trials suggest their
inability to offer
significant
neuroprotection. The
positive preclinical
outcome of the
complement regulatory
molecules, such as VCP,
in treating
neuroinflammatory
disorders suggests their
usefulness in CNS
disorders, where
complement plays a major
role. In the last two
decades, active
ingredients and extracts
of traditional medicinal
plants with
anti-inflammatory
activity have been
tested for
their in vitro
complement inhibitory
activity. The
classification, based on
their mode
of action (selectivity),
chemical nature, action
on individual complement
components,
and SAR studies
discussed in the review
may provide insight into
novel complement
inhibitors in the
future. Systematic
pharamacokinetic study
of these herbal
ingredients
may also reveal
complement regulatory
compounds, which possess
the ability to cross
the blood-brain barrier.
Thus, medicinal plants
and their active
ingredients with
complement
inhibitory activity (as
discussed in this
review) might prove
beneficial in
formulating
a natural panacea
against complex brain
disorders.
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