Medical Hypotheses xxx (2015) xxxxxx

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

NOSH aspirin may have a protective role in Alzheimers disease

Gabi Drochioiu a, Lucia Tudorachi a, Manuela Murariu b,
a
b

Faculty of Chemistry, Al. I. Cuza University of Iasi, 11 Carol I, Iasi 700506, Romania
Petru Poni Institute of Macromolecular Chemistry, Romanian Academy, 41A Grigore Ghica Voda Alee, Iasi 700487, Romania

a r t i c l e

i n f o

Article history:
Received 16 August 2014
Accepted 6 January 2015
Available online xxxx

a b s t r a c t
Evidence indicates that inammation, oxidative stress, and the disruption of normal conformation of proteins might be directly linked to Alzheimers disease (AD). The present study was undertaken using literature data to nd a possible drug to address the multiple disorders involved in AD-associated Ab
accumulation and plaque formation. We consider NOSH-aspirin a drug of choice for reducing the inammatory areas in the brain (aspirin moiety), removing the noxious heavy metals from plaques (hydrogen
sulde), and increasing the oxygen supply to neurons since nitrogen oxide is a potent vasodilator and an
anti-inammatory agent. Several conrmatory data in literature and possible mechanisms for cellular
defence as well as novel therapeutical pathways are discussed.
2015 Published by Elsevier Ltd.

Introduction
Alzheimers disease (AD) is a major cause of disability and mortality, being characterized by insidious decline in memory and by
its unique pathology, which affect language, visuospatial perception, calculations, and executive functioning. Behavioral changes
are common in AD and include psychosis, agitation, depression,
anxiety, personality alterations, and neurovegetative changes [1].
The cardinal feature of AD is the extracellular deposition of proteinaceous amyloid-b brils as senile plaques [2,3]. In fact, protein
aggregation into amyloid brils is involved both in AD and other
neurodegenerative diseases such as Parkinsons, various dementias
and prion diseases. Nevertheless, the accumulation and deposition
of Ab proteins in the brain to form neuritic plaques are the key
pathological features of AD, even though its mechanism has not
been yet completely understood [4]. Gradual accumulation of
aggregated Ab initiates a complex, multistep cascade that includes
gliosis, inammatory changes, neuritic/synaptic change, tangles
and transmitter loss [2]. Oxidative stress and amyloid bril formation are consistent major themes among processes thought to be
involved in the pathogenesis of AD [5,6]. Oxidative stress has been
proposed as a molecular mechanism linking c-secretase to b-secretase activity [7]. For example, the total amount of iron ions in AD
brain tissues is signicantly higher compared to control samples
[911], iron accumulation in Alzheimer disease being a source of
redox-generated free radicals. Consequently, antioxidant protection in the brain is largely provided by vitamin E, glutathione,

Corresponding author.
E-mail address: manuelam@icmpp.ro (M. Murariu).

ascorbate and carnosine [8]. Besides, metal ions and acid pH induce
the formation of b-amyloid protein oligomers. However, they are
distinct from those generated by slow spontaneous ageing at neutral pH [12].
Clinicopathological and neuroradiological data show that Ab
deposition in the neuroparenchyma is closely associated with a
locally-induced, non-immune-mediated chronic inammatory
response [13]. After activation by amyloid-beta deposits, glial cells
may secrete inammatory mediators and reactive oxygen species,
which, in turn, may aggravate the aggregation of amyloid-b
[14,15]. In fact, amyloid plaques are co-localized with a variety of
inammation-related proteins, like complement factors, acutephase proteins, pro-inammatory cytokines, and clusters of
activated microglia [16]. Some authors consider that AD may be
a consequence of inammation, whereas homocysteic acid was
shown to induce amyloid-b accumulation in neuronal cells [17,18].
Recently, new hybrids known as NOSH-aspirin, which are NOand H2S-releasing agents, with anti-inammatory activity, have
been reported [1921]. They proved to have both anti-inammatory and cytoprotective actions probably due to the slowly-liberated hydrogen sulde into cell environment [22,23]. Since there
is a link between inammation and cancer, NOSH compounds have
been recommended as anti-cancer agents. Experiments showed
that NOSH-aspirin inhibited HT-29 colon cancer growth [20]. The
authors claimed that NOSH-aspirin is the rst nonsteroidal antiinammatory drug (NSAID) based agent with such high degree of
potency. NOSH-aspirin inhibited cell proliferation, induced apoptosis, and caused G0/G1 cell cycle block.
Therefore, we were interested in exploring the most signicant
events in the etiology of AD and the molecular mechanisms of Ab
accumulation and aggregation in order to nd new therapeutically

http://dx.doi.org/10.1016/j.mehy.2015.01.008
0306-9877/ 2015 Published by Elsevier Ltd.

Please cite this article in press as: Drochioiu G et al. NOSH aspirin may have a protective role in Alzheimers disease. Med Hypotheses (2015), http://
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solutions. Consequently, we are searching for a possible drug to

address the multiple disorders involved in Ab accumulation and
plaque formation. Since both inammatory events and the effect
of heavy metal or ROS are associated with AD, we consider the feasibility of using new derivatives of aspirin, like NOSH compounds,
in order to address both the prevention and improvement of this
pathology.
Premises of the hypothesis
Inammatory processes and pH
Since a mildly acidic environment together with increased Zn2+
and Cu2+ are common features of inammation, it was proposed
that Ab aggregation by these factors may be a response to local
injury [24]. There is evidence that inammatory processes may
play a very important role in the mechanism of neuronal damage
in AD [25]. During normal aging, a progressive neuroinammatory
state builds in the brain, involving astrocytes and microglia, the
primary cellular components of neuroinammation [26]. Under
inammatory conditions, low pH has a dual effect by activating
b-secretase (BACE-1) and inhibiting a-secretase (ADAM10).
Cleavage of amyloid beta precursor protein (APP) is predominantly catalyzed by a-secretases, which have an optimum pH
range of 7.48.0. Some of the cleavage is catalyzed by b secretase(s), which leave 28 amino acids on the outside of the membrane. The substrate for c-secretase is the C-terminal fragment of
APP resulted from the b-secretase activity. Then, as a result of
the c-secretase cleavage, different Ab types are rendered, but
mostly Ab40 and Ab42, both species involved in AD [27,28]. The
optimum pH of b secretases is approximately 5.0 [29], the same
with that in acidic intracellular compartments, such as endosomes
and the trans-Golgi network [30]. c-Secretase is an intramembrane-cleaving aspartyl protease complex that mediates the nal
cleavage of b-amyloid precursor protein to liberate the neurotoxic
amyloid-b peptide [31]. The aspartyl proteases generally have an
optimum pH range of 4.05.0.
Although low pH values (pH 4.05.0) might be associated with
the complete degradation of Ab peptides, a slight decrease in pH
results in partial APP degradation and Ab accumulation. Once
formed, the deposits (plaques), which contain b-amyloid aggregates and heavy metal ions [32], can hardly be decomposed via
proteolytic degradation (active a-secretase are found within neuronal membrane, limited access of enzymes to each Ab backbone,
inappropriate pH) or by solubilization.
Anti-inammatory effect of aspirin
Cyclo-oxygenase-2 (COX-2) is induced in sites of inammation,
whereas cyclo-oxygenase-1 (COX-1) is believed to produce prostaglandins, vital to stomach mucosal defense [33]. Aspirin causes a
dramatic increase in COX-2 mRNA expression and a high increase
in COX-2 immunoreactivity. Besides, the involvement of nitric
oxide (NO) in antioxidant cellular protection induced by aspirin
was demonstrated [34]. It was concluded that endothelial NO synthase is a site of action for aspirin, and that the NO/cyclic GMP system takes on a crucial function in mediating the cytoprotective
action of aspirin.
From aspirin to NOSH compounds
Recently, several derivatives of aspirin [20,35], which incorporate in their molecules both nitric oxide (NO) and hydrogen sulde
(H2S)-releasing moieties have been synthesized (they are known as
NOSH compounds or NOSH-aspirin). NOSH-aspirin proved to

inhibit the cyclooxygenase enzyme activity, being thus a potent

anti-inammatory agent.
Hydrogen sulde, H2S, was demonstrated to play an important
role in many biological systems [21]. The mechanisms of action of
NOSH aspirin assumes hydrolyzing the hybrid molecules of H2Sreleasing NSAIDs, which results in the parent NSAID and an organic
molecule from which H2S is slowly released. The NSAID component inhibits COX-1 and COX-2 resulting in compromised mucosal
defense mechanisms. However, the released H2S counteracts many
of the damaging effects of NSAIDs, by activation of KATP channels.
Moreover, H2S causes vasodilatation, thus leading to cardioprotective effects. Both NSAID moiety and the released H2S have antiinammatory effects.
Heavy metal ions
Both the degenerative diseases like cancer or diabetes and the
neurodegenerative ones are associated with metal ion imbalance.
Heavy metal ions are involved in the pathogenesis of several neurodegenerative and vascular diseases [9,12,32]. Treating the
patients with calcium disodium edetate may result in removing
the intoxicating traces of heavy metals [36]. The neurotoxicity of
Ab peptides has been linked to peroxide generation [37]. Ab produces hydrogen peroxide by the reduction of metal ions, Fe(III)
or Cu(II), setting up conditions for Fenton-type chemistry. AD is
closely related to the aggregation of Ab within the neocortex due
to metal-ionprotein interactions [3840]. Ab precipitation and
toxicity in AD are provoked by abnormal interactions with neocortical metal ions, such as Zn, Cu and Fe [4144]. Since heavy metals
are implicated in the aggregation of proteins, a combination of analytical methods among them intrinsic uorescence, circular dichroism, and high-resolution fourth-derivative absorbance analysis has
been developed to prove the metal-induced conformational
changes [45].
Hypothesis on AD prevention by NOSH-aspirin
Putting together the main AD-related ndings, one can get a
picture of the etiology and course of this neurodegenerative disease, in which is highlighted the role of inammatory agents
(Fig. 1). Pro-inammatory mediators play key roles in the etiology
of neurodegenerative diseases including AD, and neuroinammation is associated with a decrease in pH, which induce an increase
in amyloid-b peptide production by enhanced proteolysis of amyloid precursor protein. Depending on age, genetic or metabolic factors and life style, and other risk factors such as the inammatory
agents, including Ab species and their association with heavy metals, a decrease in intracellular pH may occur. Decreasing pH
enhances BACE-1 activity responsible for Ab formation and inhibits
ADAM10. Aspirin and other anti-inammatory agents may counteract the inammatory reactions and also inhibit the ROS production. However, the anti-inammatory action of NOSH-aspirin may
be more elevated than that of simple aspirin due to H2O and NO
release, which have also potent anti-inammatory properties.
Moreover, heavy metal ions are known to induce b-sheet conformation of Ab peptides, binding then to the resulted Ab oligomers
to form brils and plaques. The last ones are ROS-generating
agents. H2S may protect against increasing concentrations of free
heavy metal ions, since it is able to form insoluble suldes. Besides,
H2S may react with heavy metal ions enclosed in the plaques, and
liberate Ab oligomers, which are easier proteolytically degraded.
In brief, since the NSAIDs proved to be anti-AD agents,
whereas H2S and NO may attenuate the neurodegenerative symptoms, we consider that NOSH-aspirin, chemically named 4-(3-thioxo-3H-1,2-dithiol-5-yl) phenyl 2-((4-(nitrooxy)butanoyl)oxy)

Please cite this article in press as: Drochioiu G et al. NOSH aspirin may have a protective role in Alzheimers disease. Med Hypotheses (2015), http://
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Inflammatory
agents

Heavy
Metal
ions

NOSH
aspirin

Activated
microglia

H2S

H2S

Inflammation
NO
H 2S

Metal binding H2S

NOSH
aspirin

Aging,
Genetic
& Risk
Factors

BACE-1
activation

NOSH Inflammation
aspirin

ROS

Aspirin

Neuritic
plaque
formation

A
accumulation

NOSH
aspirin

H2S

Cross-linkage &
polymerization
of A peptides

A
accumulation

NO

Inflammation
Aspirin

NOSH
aspirin

Fig. 1. Proposed mechanism for multi-leveled anti-Alzheimer action of NOSH-aspirin. NOSH-aspirin provides by hydrolysis a NSAID compound with both anti-inammatory
action and ROS scavenging one. NO and H2S may potentate the NSAID action. H2S may react with heavy metal ions and reduce the ROS production.

O2NO
CH2
OH

OCOCH3
COOH

O
COOH

S
O
O

Salicylic acid
(2-hydroxybenzoic acid)

Aspirin
(2-acetoxybenzoic acid)

NOSH-aspirin

Fig. 2. The chemical structure of NOSH-aspirin (in bold, aspirin moiety); it is the rst dual acting NO and H2S releasing hybrid containing a 3H-1,2-dithiole-3-thione structure
able to release hydrogen sulde and another one, 4-(nitrooxy)butanoic acid, releasing NO (H2S donating compounds).

benzoate (Fig. 2), could be a drug of choice for AD prevention and

treatment with multiple therapeutic indications, since it may
reduce the inammatory areas in the brain [25], remove the noxious heavy metals in the plaques [12,32], and increase the oxygen
admission to the neurons due to NO chemical groups it contains
[46].
Hydrogen sulde may play an antioxidant function and prevents free radical-induced impairment, being benecial in treating
age-associated diseases [47]. H2S reduces cystine to cysteine in the
extracellular space, increasing the intracellular concentrations of
cysteine to increase the production of intracellular GSH. Thus,
H2S enhances the redistribution of GSH into mitochondria in Neuro2a cells [48]. Consequently, H2S suppresses oxidative stress in
the mitochondria. H2S can prevent cytokine- or oxidant-induced
oxidative damage through its antioxidative effects [36]. Besides,
it can inhibit the expression of proinammatory factors by downregulating NF-jB activation or by upregulating heme oxygenase 1
expression.
These ndings suggest that NOSH-aspirin has signicant antiinammatory properties and may be a new candidate for treating
neurodegenerative disorders that have a prominent neuroinammatory component such as AD. Moreover, NO and H2S released
from the molecules of NOSH-aspirin may enhance the effect of
Aspirin, which has both an anti-inammatory action and a ROS
scavenging one. H2S may react with heavy metal ions and reduce
the ROS production.

Hypothesis-supporting literature data

Intracerebral injection of dilute, Ab-containing brain extracts
from humans with AD or APP transgenic mice induced cerebral
b-amyloidosis and associated pathology in APP transgenic mice
in a time- and concentration-dependent manner [49,50]. The seeding activity of brain extracts is reduced or abolished by Ab immunodepletion, protein unfolding, or by Ab immunization of the host.
Studies on the long-term treatment with non-steroidal antiinammatory drugs (NSAIDs) demonstrated a decrease in the risk
of AD; besides, such treatment delays its onset or slows down its
progression [51]. The administration of COX-2 inhibitors prevents
both the inammatory reaction and the cholinergic hypofunction.
The involvement of the local inammatory reaction is conrmed
mainly by studies dealing with activated microglia, cytokines, reactive astrocytes, complement system and reactive oxygen species
(ROS) [52]. The inammatory events occur in close proximity of
beta-amyloid and tau protein deposits. The most appropriate prophylactic effect seems to be achieved by specic inhibitors of COX2. COX-2 is expressed in higher concentrations in the degenerating
cells of the brain. The NSAIDs are selective inhibitors of COX-2, and
can thereby have an anti-inammatory effect. Moreover, the NSAIDs decrease the excessive activation of some transcription factors,
like PPARgama and the nuclear factor kapa-B, which are responsible for the transcription initiation of a number of pro-inammatory
genes.

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Secretase activity and pH

The active a-secretase is present in the neuronal membrane
and has a limited access to the Ab backbone. In fact, chronic
inammation is associated with low pH values which increase
the b-secretase activity in the cerebral cortex and enhance the
b-amyloid aggregation and metal-associated oxidative stress.
ADAM10 is the most widely expressed in neurons and seems to
be the most active a-secretase [50]. Some a-secretases have a
consensus HEXXH zinc-binding motif (X represents any amino
acid) which is involved in the proteolytic activity. The putative
a-secretase cleaves the amyloid precursor protein (APP) of
Alzheimers disease in the middle of the amyloid b peptide (Ab)
domain [53]. ADAM9, ADAM 10, and ADAM 17 catalyze a-secretory cleavage and therefore act as a-secretases in A172 cells [54].
ADAM8 may play a role in soluble CD23-mediated inammation
and cell migration.
AD patients show an increase of b-secretase activity in the cerebral cortex [55]. It was shown that insulin-degrading enzyme is the
main soluble beta-amyloid degrading enzyme at neutral pH in
human brain [56]. Nevertheless, the highest beta-amyloid protein
degrading activity of this aspartyl protease in the soluble fractions
occurs between pH 4 and 5. Synthetic beta-amyloid protein (140)
is rapidly degraded by a human brain soluble fraction, optimum
activity occurring at around pH = 4 [57]. Besides, BACE-1 is
expressed in activated astrocytes around senile plaques [58], suggesting that various inammatory cytokines and forms of oxidative
stress could provoke BACE-1 expression in astrocytes. The AD brain
shows chronic inammation characterized by an abundance of
reactive astrocytes and activated microglia, which are near senile
plaques and secrete a variety of cytokines [25]. A large body of evidence suggests that by transforming from a basal to a reactive
state, astrocytes neglect their neurosupportive functions, thus rendering neurons vulnerable to neurotoxins, including proinammatory cytokines and ROS [59].
The complex dynamics of Ab may also contribute to the causative role of Ab in the pathogenesis of AD [60].
NOSH-aspirin is a NO and H2S releasing hybrid, which provokes
cell growth inhibition in the low nano-molar range [20]. NOSHaspirin inhibits COX-1 more than COX-2. H2S, in turn, is an important endogenous signaling molecule, with therapeutic potential in
age-associated diseases, being involved in aging by inhibiting freeradical reactions and activating SIRT1 [17,47]. Moreover, H2S can
prevent cytokine- or oxidant-induced oxidative damage, and
inhibits the expression of proinammatory factors either by downregulating NF-jB activation or by upregulating heme oxygenase 1
expression. Endogenous levels of 50160 lM H2S are detected in
normal human brains [61]. However, lower levels of H2S as well
as accumulation of homocysteine, a strong risk factor for the development of AD, are observed in the brains of AD patients [62].
Besides, neurotoxicity of homocysteine is associated with inhibition of endogenous H2S generation and downregulation of expression and activity of CBS in PC12 cells, being mediated by
extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation.
Moreover, it is believed that H2S could reduce neurotoxicity
induced by Hcy and that H2S may be a useful therapeutic strategy
against homocysteine-induced AD [63]. H2S may have protective
effects against Ab-induced cell injury by inhibiting inammation,
promoting cell growth, and preserving mitochondrial function in
a p38- and Jun N-terminal protein kinase (JNK)-mitogen-activated
protein kinase (MAPK)-dependent manner [64]. Moreover, H2S can
protect neurons from oxidative stress, which is characteristic for
AD. Besides, H2S protects neurons against glutamate-mediated oxidative stress by enhancing the activities of c-GCS and cystine
transport, which results in incremental changes of glutathione levels [65]. These ndings suggest that H2S, alone or released from

NOSH-aspirin, is a promising therapeutic target for treating neurodegenerative diseases.

Nitric oxide (NO) is a potent vasodilator and neurotransmitter,
being also involved in inammation and immunity [66]. Although
NO produced in infected and inamed tissues could contribute to
the process of carcinogenesis by different mechanisms [67], some
authors demonstrated its potent anti-inammatory properties
[68]. Direct effects of NO occur under normal physiological conditions when the rates of NO production are low, as in NO-releasing
reactions from NOSH-aspirin. Such reactions may serve regulatory
and/or anti-inammatory functions. Indirect effects are mediated
by reactive nitrogen oxide species formed from the reaction of
NO either with oxygen or superoxide. Such species can mediate
either nitrosative or oxidative stress [69]. Activated astrocytes or
microglia produce NO, which inhibits the cellular respiration of
neurons, also decreasing ATP levels and stimulating lactate production by these neurons. NO donors cause rapid release of glutamate from neuronal and neuronalastrocytic cultures and
subsequent neuronal death [69]. High rate of oxygen may prevent
NO-induced neuronal death. Nevertheless, the activated glia kill
neurons via NO formation, which inhibits neuronal respiration
resulting in glutamate release and subsequent excitotoxicity during times of active inammation. Indeed, the treatment with
NOSH-aspirin reduces the release of the TNFa and IL-6, and also
attenuates the activation of P38 MAPK and NFjB proteins [70].
H2S releasing compounds
Substantial evidence showed that H2S attenuates cognitive dysfunction and prevents neuronal impairment in the experimental
model of AD [71]. The mechanisms of the protective role of H2S
in AD may involve its antioxidant, anti-apoptotic, and anti-inammatory effects. Recent research also reveals that H2S afforded by
NaHS treatment attenuates neuronal death in the hippocampus
of rats injected with Ab peptide [72]. H2S dramatically suppresses
the release of TNF-a, IL-1b and IL-6, as well as inhibits the upregulation of COX-2 and the activation of NF-jB in the hippocampus.
H2S releasing compounds have effective anti-inammatory and
anti-tumor effects, as well as precise ion-channel regulation, cardiovascular protection and oxidation resistance [73]. However,
the therapeutic effects of H2S are still controversial due to conicting published results regarding the use of different H2S donors.
Therefore, it is essential to select the best H2S releasing compounds, some of which being currently used in clinical trials along
with their biological effects. Moreover, the actions of H2S are inuenced by its concentration, reaction time, and cell/disease types,
and is limited because of the instant release and short lifetime of
H2S [74]. Nevertheless, the H2S releasing compounds like NOSH
aspirin suggest hope for future investigations [75].
Since NOSH-aspirin was successfully tested on colon cancer
growth [20], when concentrations between 7.7 and 45.5 nM
proved to be effective, similar doses could be tested in AD. However, further research is needed to establish therapeutic details,
and to nd out if NOSH-aspirin can be used as preventive drug,
long lasting therapy or part of an overall treatment.
Concluding remarks
A close relationship between various concentrations of metal
ions, inammatory processes, decreased pH and Ab accumulation
and aggregation is thought to be of paramount signicance for
AD. The risk and severity of AD are reduced by antioxidant and
anti-inammatory agents or use of chelating drugs. Consequently,
we discussed here the feasibility of using some new aspirin derivatives against many pathological features of AD. Taken together,

Please cite this article in press as: Drochioiu G et al. NOSH aspirin may have a protective role in Alzheimers disease. Med Hypotheses (2015), http://
dx.doi.org/10.1016/j.mehy.2015.01.008

G. Drochioiu et al. / Medical Hypotheses xxx (2015) xxxxxx

the previous results reported in literature suggest that NOSH aspirin could have strong anti-AD potential and merits further evaluation. Even at nanomolar concentrations, NOSH-aspirin could be a
potent anti-inammatory agent, due to the three moieties its molecule contains: NSAID, H2S, and NO. Each of them has demonstrated anti-inammatory potential doubled by ROS scavenging
properties, regulatory functions, or metal binding capabilities.
Finally, NOSH-aspirin may have potential for treating neurodegenerative diseases, including AD.
Conict of interest
All authors declare that there are not any nancial and personal
relationships with other people or organizations that could
inappropriately inuence (bias) their work.

[21]

[22]

[23]

[24]

[25]

[26]

Acknowledgments
Financial support by Romanian Government (UEFISCDI IDEI
313/2011) is grateful acknowledged. LT gratefully acknowledges
the strategic grant POSDRU/159/1.5/S/137750 from EU.

[27]

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Please cite this article in press as: Drochioiu G et al. NOSH aspirin may have a protective role in Alzheimers disease. Med Hypotheses (2015), http://
dx.doi.org/10.1016/j.mehy.2015.01.008