Secondary Metabolites of Lichens as Both Anti-aggregative and Antioxidant
Agents in Tauopathies
Alberto Cornejo1* and Carlos Areche2
1Faculty of Medicine, School of Medical Technology, Andrés Bello University, Sazié 2315, Chile
2Department of Chemistry, Faculty of Sciences, University of Chile, Ñuñoa, Santiago 8320000, Chile
- *Corresponding Author:
- Alberto Cornejo
Faculty of Medicine, School of Medical Technology, Andrés Bello University
Sazié 2315, First Floor, Santiago 8370092, Chile
Received date: February 01, 2017; Accepted date: March 30, 2017; Published date: April 11, 2017
Citation: Cornejo A, Areche C (2017) Secondary Metabolites of Lichens as Both Anti-aggregative and Antioxidant Agents in Tauopathies. J Clin
Cell Immunol 8:496. doi: 10.4172/2155-9899.1000496
Copyright: © 2017 Cornejo A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Visit for more related articles at Journal of Clinical & Cellular Immunology
This commentary described our findings of parietin, an anthraquinone, isolated from Ramalina terebrata as
inhibitor of tau protein. Moreover, we considered important to link tauopathies with reactive oxygen species since
oligomers and fibril-forming elements are responsible for activating reactive oxygen species, which cause
inflammatory response and neurodegeneration. Together, we considered important to find naturally occurring
compounds that might be able to stop aggregation and reduces ROS cells damage.
Tauopathies; Secondary metabolites; Lichens; Reactive
oxygen species; Inflammatory response; Neurodegeneration
Tauopathies and Neurotoxicity
Taoupathies are neurodegenerative disorders involving tau protein,
such as progressive nuclear palsy (PSP), corticobasal degeneration
(CBD), Pick´s disease among others. Tau is an unfolded protein which
is found mainly in axons of mature and physiologically is involved in
microtubule stability and axonal transport . However, once tau
becomes hyperphosphorylated it detaches from microtubule starting
the aggregation process [2,3]. Pathological tau aggregates are able to
activate glia cells that release cytotoxic factors, which cause pro
inflammatory cytokines such as TNF-α, IL-1 and IL-6 and chemokines
. Tau phosphorylation is increased in both physiologically and
pathological state , however phosphorylation is increased during
development, suggesting that process is needed for neuronal plasticity
. Tau phosphorylation is an event highly regulated by kinases and
phosphatases. Its balance is deregulated due to several stimuli such as oxidative stress . Tau is able to form paired helical filaments closely
related to neurofibrillary tangles [8,9]. Hyperphosphorylated tau
protein is found in patients suffering with tauopathies in cerebrospinal
fluid (CNS), which correlates well with hypocampal atrophy . In
addition, tauopathies have tau hyperphosphorylated as a hallmark;
however, the degree of phosphorylation differs among them. In
addition, it is important to notice that there is no single
phosphorylation site associated to a particular tauopathy .
Moreover, tau has the propensity to form aggregates, since inside the
full length protein (441 aminoacids) resides a region known as 4R
(four microtubule binding domain) containing two hexapeptides 275VQIINK280 and 306VQIVYK311 both associated to β sheet formation
. Increased tau phosphorylation decreased its binding for
microtubules. These species prone to form aggregates which are toxic
in both cell and transgenic mouse model [12,13]. Despite that fact,
there are evidences showing that soluble species and pre fibrils which
are more related to toxicity . An interesting UV raman spectroscopy study showed that at early stages, within the first hour, fibrillar aggregates possess a mixture of β-sheet and disordered
content. Afterward, the UVRR spectra shows a consolidation in fibril
structure, augmenting the content of β sheet , interesting is to
remark that toxicity apparently relies on β sheet content .
Tauopathies and Reactive Oxygen Species
Reactive oxygen species (ROS) are reactive molecules such as
hydroxyl (OH·), superoxide (O2·) and nitric monoxide (NO·). Besides,
other molecules like hydrogen peroxide (H2O2) and peroxynitrite
(ONOO–) are not free radicals; however they are reported to generate
free radicals [17,18].
In general, cells exposed to reactive oxygen species can overproduce
free radicals that promotes oxidative damage on macromolecules,
which can lead to pathological disorders such as stroke, chronic
inflammation, also this species contribute to develop
neurodegenerative disorders such as tauopathies. [18,19]. Once cells
are in contact with toxic species, they are able to synthetize several
enzymes in order to clear them, however residual superoxides and
peroxides remain . Moreover, there are evidences showing that
ROS were first described in Pick´s disease and CBD . It was also
described that ROS associated to tauopathies, such as
malondialdehyde (MDA) or 4-hydroxynonenal (HNE), a specie linked
to polyunsaturated fatty acids. [21,22].
In contrast, antioxidants can prevent ROS that are able to induce
injury. However, there are synthetic antioxidants that have shown
either to induced cell toxicity or mutagenesis . Thus it is timely to
search for naturally occurring antioxidants. Hence, several antioxidant
properties have been described associated to flavonoids,
hydroxycinnamic derivatives, catechins, curcumin among others
Importantly, the phenolic ring is the main moiety involved in
scavenging ROS, metal chelator and modulates both the endogenous
enzymatic-non enzymatic antioxidant system involved in neurodegenerative disorders including tauopathies .
Lichens as antioxidants and tau inhibitors source
Lichens are symbiotic association between a mycobiont (fungus)
and either algae or cyanobacterium [27-29]. Besides lichens species are
able to produce important secondary metabolites . A remarkable
feature of lichen species is their antioxidant capacity that resides in
their phenolic moieties . Interestingly, some depsides and
depsidones isolated from lichens have shown antioxidant capacity
[32-34]. Besides this, neuroprotective effect and cytotoxic potential
have been described in Cetraria islandica and Vulpicida canadensis . Two Xanthones isolated from Pyrenula japonica have a potent
antioxidant capacity as compared with α-tocopherol and 2,6-di(tertbutyl)-
4-methylphenol (BHT) . Moreover, ramalina isolated from
Antartic Ramalina terebrata presented scavenging activity and it
inhibits tyrosine enzyme activity. In addition, ramalina possess a very
little toxicity in keratinocyte and fibroblast [37,38].
A β-orcinol depsidone, stictic acid and salazinic acid showed
neuroprotective effect on U373MG cell line by diminishing ROS
production. These compounds would be useful as antioxidant agents in Alzheimer´s disease , but it is important to notice that none of
them have been tested as anti-tau inhibitor agent. Alternatively, a
derivative plant polyphenol, curcumin, has been useful, since
curcumin exerts a pleiotropic effect by combining both anti-aggregate
and antioxidant activities.
Recently, we have characterized that parietin, an anthraquinone,
isolated from Ramalina terebrata, lichen collected in the Antarctic
region of “Península Fildes”, has effect on tau aggregation . Docking studies of parietin and 306VQIVYK311 hexapeptide suggest
that parietin bind steric zippers preventing β-sheet assembly .
According to the docking model, there are both types of interaction:
hydrogen bond (HB) among phenolic groups, methoxy motif and
lysine side chains. Besides this, hydrophobic interaction also occurs
between methyl group of methoxy substituent and valine .
Interestingly, another anthraquinone, emodin, which inhibits tau
aggregation has lower IC50 instead of parietin, we hypothesize that
could be due to methoxy group at C-3 position in parietin (Figure 1).
Moreover, another anthraquinone derived from plant, rhein, can
reverse DNA methylation and de-suppression of Klotho, which has an
essential role in anti-renal fibrosis in a mouse model [41,42].
Furthermore, in a senescence-accelerated mouse model, rhein reduces
levels of Aβ , however both rhein and emodin are poorly active
against Aβ in vitro aggregation assays . Although, another
anthraquinone, emodin, exerts profound effect over tau aggregation
, and its scavenging capacity is lower as compared with alaternin
, but there is no evidence that alaternin inhibits tau aggregation.
Considering that oligomers or fibril-forming motif, exert their
influence over inflammatory system, it would be interesting to find
molecules isolated from natural sources that combine both anti-aggregative
and scavenging properties, thus it would be a proper way
to address drug design. In addition, it is interesting to mention that not
only tauopathies exerts their damage on aggregation, since in
neurodegenerative disorders such as Parkinson´s disease, α-synuclein
is also prone to form aggregates and fibrils, and their toxicity is also
linked to β sheet formation.
Figure 1: Anthraquinones compound tau inhibitors. A) Parietin IC50 72 μM over tau four microtubule binding domain (4R). B) Emodin IC50 0.3 μM over tau K-18 construct.
This work was supported by grants from the INACH RT 13-13 to
Alberto Cornejo and Carlos Areche.
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