NOSH aspirin may have a protective role in Alzheimer’s disease

Medical Hypotheses xxx (2015) xxx–xxx

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NOSH aspirin may have a protective role in Alzheimer’s 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 inflammation, oxidative stress, and the disruption of normal conformation of proteins might be directly linked to Alzheimer’s disease (AD). The present study was undertaken using literature data to find 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 inflammatory areas in the brain (aspirin moiety), removing the noxious heavy metals from plaques (hydrogen sulfide), and increasing the oxygen supply to neurons since nitrogen oxide is a potent vasodilator and an anti-inflammatory agent. Several confirmatory data in literature and possible mechanisms for cellular defence as well as novel therapeutical pathways are discussed. Ó 2015 Published by Elsevier Ltd.

Introduction Alzheimer’s 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 fibrils as senile plaques [2,3]. In fact, protein aggregation into amyloid fibrils is involved both in AD and other neurodegenerative diseases such as Parkinson’s, 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, inflammatory changes, neuritic/synaptic change, tangles and transmitter loss [2]. Oxidative stress and amyloid fibril 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 significantly higher compared to control samples [9–11], 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: [email protected] (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 inflammatory response [13]. After activation by amyloid-beta deposits, glial cells may secrete inflammatory 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 inflammation-related proteins, like complement factors, acutephase proteins, pro-inflammatory cytokines, and clusters of activated microglia [16]. Some authors consider that AD may be a consequence of inflammation, 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-inflammatory activity, have been reported [19–21]. They proved to have both anti-inflammatory and cytoprotective actions probably due to the slowly-liberated hydrogen sulfide into cell environment [22,23]. Since there is a link between inflammation 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 first nonsteroidal antiinflammatory 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 significant events in the etiology of AD and the molecular mechanisms of Ab accumulation and aggregation in order to find new therapeutically

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

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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 inflammatory 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 Inflammatory processes and pH Since a mildly acidic environment together with increased Zn2+ and Cu2+ are common features of inflammation, it was proposed that Ab aggregation by these factors may be a response to local injury [24]. There is evidence that inflammatory processes may play a very important role in the mechanism of neuronal damage in AD [25]. During normal aging, a progressive neuroinflammatory state builds in the brain, involving astrocytes and microglia, the primary cellular components of neuroinflammation [26]. Under inflammatory 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 7.4–8.0. 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 final cleavage of b-amyloid precursor protein to liberate the neurotoxic amyloid-b peptide [31]. The aspartyl proteases generally have an optimum pH range of 4.0–5.0. Although low pH values (pH 4.0–5.0) 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-inflammatory effect of aspirin Cyclo-oxygenase-2 (COX-2) is induced in sites of inflammation, 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 sulfide (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-inflammatory agent. Hydrogen sulfide, 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 antiinflammatory 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-ion–protein interactions [38–40]. Ab precipitation and toxicity in AD are provoked by abnormal interactions with neocortical metal ions, such as Zn, Cu and Fe [41–44]. Since heavy metals are implicated in the aggregation of proteins, a combination of analytical methods among them intrinsic fluorescence, 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 findings, one can get a picture of the etiology and course of this neurodegenerative disease, in which is highlighted the role of inflammatory agents (Fig. 1). Pro-inflammatory mediators play key roles in the etiology of neurodegenerative diseases including AD, and neuroinflammation 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 inflammatory 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-inflammatory agents may counteract the inflammatory reactions and also inhibit the ROS production. However, the anti-inflammatory action of NOSH-aspirin may be more elevated than that of simple aspirin due to H2O and NO release, which have also potent anti-inflammatory properties. Moreover, heavy metal ions are known to induce b-sheet conformation of Ab peptides, binding then to the resulted Ab oligomers to form fibrils 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 sulfides. 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)

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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

Aβ accumulation

NOSH aspirin

H2S

Cross-linkage & polymerization of Aβ peptides

Aβ 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-inflammatory 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

O

S O O

S

Salicylic acid (2-hydroxybenzoic acid)

S

Aspirin (2-acetoxybenzoic acid)

NOSH-aspirin

Fig. 2. The chemical structure of NOSH-aspirin (in bold, aspirin moiety); it is the first dual acting NO and H2S releasing hybrid containing a 3H-1,2-dithiole-3-thione structure able to release hydrogen sulfide 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 inflammatory 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 sulfide may play an antioxidant function and prevents free radical-induced impairment, being beneficial 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 proinflammatory factors by downregulating NF-jB activation or by upregulating heme oxygenase 1 expression. These findings suggest that NOSH-aspirin has significant antiinflammatory properties and may be a new candidate for treating neurodegenerative disorders that have a prominent neuroinflammatory 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-inflammatory 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 antiinflammatory 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 inflammatory reaction and the cholinergic hypofunction. The involvement of the local inflammatory reaction is confirmed mainly by studies dealing with activated microglia, cytokines, reactive astrocytes, complement system and reactive oxygen species (ROS) [52]. The inflammatory events occur in close proximity of beta-amyloid and tau protein deposits. The most appropriate prophylactic effect seems to be achieved by specific 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-inflammatory 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-inflammatory 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 inflammation 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 Alzheimer’s 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 inflammation 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 (1–40) 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 inflammatory cytokines and forms of oxidative stress could provoke BACE-1 expression in astrocytes. The AD brain shows chronic inflammation 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 proinflammatory 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 proinflammatory factors either by downregulating NF-jB activation or by upregulating heme oxygenase 1 expression. Endogenous levels of 50–160 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 inflammation, 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 findings 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 inflammation and immunity [66]. Although NO produced in infected and inflamed tissues could contribute to the process of carcinogenesis by different mechanisms [67], some authors demonstrated its potent anti-inflammatory 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-inflammatory 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 neuronal–astrocytic 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 inflammation. 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-inflammatory 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-inflammatory 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 conflicting 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 influenced 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 find 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, inflammatory processes, decreased pH and Ab accumulation and aggregation is thought to be of paramount significance for AD. The risk and severity of AD are reduced by antioxidant and anti-inflammatory 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,

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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-inflammatory agent, due to the three moieties its molecule contains: NSAID, H2S, and NO. Each of them has demonstrated anti-inflammatory potential doubled by ROS scavenging properties, regulatory functions, or metal binding capabilities. Finally, NOSH-aspirin may have potential for treating neurodegenerative diseases, including AD. Conflict of interest All authors declare that there are not any financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work.

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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.

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