Mol Neurobiol DOI 10.1007/s12035-015-9284-1

The Chemistry of Neurodegeneration: Kinetic Data and Their Implications Matic Pavlin 1,2 & Matej Repič 3 & Robert Vianello 4 & Janez Mavri 5

Received: 10 February 2015 / Accepted: 3 June 2015 # Springer Science+Business Media New York 2015

Abstract We collected experimental kinetic rate constants for chemical processes responsible for the development and progress of neurodegeneration, focused on the enzymatic and nonenzymatic degradation of amine neurotransmitters and their reactive and neurotoxic metabolites. A gross scheme of neurodegeneration on the molecular level is based on two pathways. Firstly, reactive species oxidise heavy atom ions, which enhances the interaction with alpha-synuclein, thus promoting its folding to the beta form and giving rise to insoluble amyloid plaques. The latter prevents the function of vesicular transport leading to gradual neuronal death. In the second pathway, radical species, OH· in particular, react with the methylene groups of the apolar part of the lipid bilayer of either the cell or mitochondrial wall, resulting in membrane leakage followed by dyshomeostasis, loss of resting potential and neuron death. Unlike all other central neural system

* Robert Vianello [email protected] * Janez Mavri [email protected] 1

2

Computational Biophysics, German Research School for Simulation Sciences, Joint Venture of RWTH Aachen University and Forschungszentrum Jülich GmbH, 52425 Jülich, Germany Computational Biomedicine, Institute for Advanced Simulations (IAS-5/INM-9), 52425 Jülich, Germany

3

Laboratory of Computational Chemistry and Biochemistry, Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland

4

Quantum Organic Chemistry Group, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000 Zagreb, Croatia

5

National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia

(CNS)-relevant biogenic amines, dopamine and noradrenaline are capable of a non-enzymatic auto-oxidative reaction, which produces hydrogen peroxide. This reaction is not limited to the mitochondrial membrane where scavenging enzymes, such as catalase, are located. On the other hand, dopamine and its metabolites, such as dopamine-o-quinone, dopaminechrome, 5,6-dihydroxyindole and indo-5,6-quinone, also interact directly with alpha-synuclein and reversibly inhibit plaque formation. We consider the role of the heavy metal ions, selected scavengers and scavenging enzymes, and discuss the relevance of certain foods and food supplements, including curcumin, garlic, N-acetyl cysteine, caffeine and red wine, as well as the long-term administration of non-steroid anti-inflammatory drugs and occasional tobacco smoking, that could all act toward preventing neurodegeneration. The current analysis can be employed in developing strategies for the prevention and treatment of neurodegeneration, and, hopefully, aid in the building of an overall kinetic molecular model of neurodegeneration itself. Keywords Neurodegeneration . Parkinson’s disease . Alzheimer’s disease . Reactive oxygen species . Oxidative stress . Heavy metal ions

Introduction Neurodegenerative diseases are mostly incurable, progressive and, ultimately, fatal disorders of the central neural system (CNS) of predominantly idiopathic origin. The most common neurodegenerative diseases are Alzheimer’s, Parkinson’s and Huntington’s diseases. In all cases, the formation of amyloid plaque in the brain is associated with neuronal death [1–5]. These excess protein aggregates clump together at axons and dendrites in neurons, thus sterically hindering the transmission

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of neurotransmitters, because vesicles (filled with neurotransmitters) can no longer move through the cytoskeleton, which is particularly problematic in the synaptic region. The same is true, although to a lesser extent, for other transporters as well [6]. Thus, fewer and fewer neurotransmitters are being released, which is reflected in the gradual loss of function [7]. An alternative mechanism of neurodegeneration is via the chemical damage to the apolar moieties of the species constituting the cellular and mitochondrial membranes by reactive radical species, which leads to the pathological process of membrane leakage. Both pathways contribute to loss of cell function and neuronal death and are reactive-species dependent and tightly connected. In this study, we mainly address the oxidative stressdependent processes of neurodegeneration [8–12] and offer prospective strategies for its prevention. We collected mechanistic details and experimental rate constants of chemical reactions associated with: the oxidative metabolism of some biogenic amines, glutamate-induced neurotoxicity, the reaction of scavengers of the reactive species, chemical reactions of superoxide dismutase (SOD), flavoenzymes like monoamine oxidases (MAO), catalase (CAT) and glutathione peroxidase (GPx) and the role of oxidised/reduced copper and iron ions that bind alpha-synuclein (αSyn). It should be mentioned that there are several other enzymes that mitigate the effect of reactive oxygen species (ROS) by repairing oxidative damage, especially with regard to the DNA molecule, but this topic is beyond the scope of this article. ROS dyshomeostasis can be understood as the point of central importance for neurodegeneration [13]. Understanding neurodegenerative routes on a molecular level is a complex and rapidly developing field. The aim of this study is not to review all the processes related to neurodegeneration but to collect available kinetic data for the reactions relevant for its development and progress, which may be employed in formulating prevention and treatment strategies, and, hopefully, aid in the building of an overall kinetic molecular model of neurodegeneration.

Role of Heavy Metal Ions In Parkinson’s and Alzheimer’s diseases, amyloid plaque is formed from αSyn [3], while, in the case of Huntington’s disease, a protein huntingtin is involved in misfolding [14, 15]. One very important question is what is the stimulus for the formation of amyloid plaque? There is growing evidence that many factors are responsible [16]. One explanation is that the beta form is intrinsically more stable per se and that, after a long enough time, proteins will spontaneously form the beta form of the amyloid peptide. There is also a growing support for the idea that chaperone proteins might be involved [17, 18]. However, it looks like the most important stimulus for plaque formation is the presence of heavy atom ions in their

oxidised state. It is well established that amyloid plaques contain increased concentrations of copper, iron and zinc [19]. Copper [20] and iron [21] appear to be primarily responsible for toxicity via oxidative-stress-type mechanisms, since they can be reversibly oxidised and reduced [22]. Oxidised forms of iron and copper bind to αSyn and trigger conformational changes associated with the formation of the amyloid plaque [23]. Reduced forms of iron and copper ions (i.e. Fe2+ and Cu+) also bind to αSyn, but the binding does not result in the insoluble beta form [24]. It is believed that, during homeostasis, both iron and copper mainly exist in the reduced form due to sufficient amounts of the reducing agents such as glutathione (GSH), uric acid and ascorbic acid [25–27]. One of the fundamental assumptions in cellular biology is that, in homeostasis, the cytoplasm has such a reducing potential that it does not allow for the formation of disulphide bridges. In other words, reduction is considered to be faster than oxidation mediated by superoxide and hydrogen peroxide. The oxidation state of iron controls its transport properties and the ratio of its oxidised and reduced forms is essential for both homeostasis and pathological changes in the brain [28]. It is also widely accepted that the oxidation and reduction of iron and copper take place either in aqueous solution or when they are already bound to αSyn. As a typical example, hemoglobin is an ironcontaining protein and, as such, upon chemical degradation it is potentially neurotoxic [29]. Despite its abundance, it is safely transported in erythrocytes that are well equipped with antioxidant species. In the case of enhanced oxidative stress, hemoglobin is suddenly exposed to hydrogen peroxide that causes dissociation of both the iron ion and the heme ring from the rest of the protein. Heme is a powerful promoter of lipid peroxidation, while iron cations themselves enter the Fenton reaction or directly induce the formation of amyloid plaque by binding to αSyn [30]. Zinc seems to be a very important factor in the pathogenesis of Alzheimer’s disease [31, 32]. It is found in up to hundred times increased concentrations in the post-mortem brains of Alzheimer’s disease patients, especially in the hippocampus [33, 34]. In contrast to iron and copper, zinc interactions with αSyn are not oxidative stress mediated, since Zn2+ is not easily oxidised or reduced under physiological conditions. However, it is known that zinc is involved in the enzymatic cleavage of amyloid precursor protein (APP), a precursor of αSyn. The enzyme that converts APP is α-secretase and its activity is attributed to the disintegrin and the metalloprotease (ADAM) family of zinc metalloproteases [35]. Zinc transport in the CNS is via zinc-permeable ion channels that are N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptors dependent [7, 36]. Since metals such as copper, iron and manganese are essential for homeostasis, specific transporters at the blood– brain barrier have developed during evolution. An agerelated increase in aluminium, copper, iron and zinc in the

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brains of patients both with and without neurodegenerative diseases has also been observed [37–39]. For a critical review of metal ion transport via the blood–brain barrier, see Yokel’s article [40]. The presence of transporters gives evidence that the permeation rate of metal ions linearly depends on their concentration in blood, assuming there is no active transport in the opposite direction. A recent report on the increased incidence of Alzheimer’s disease among residents in an area contaminated with manganese speaks in favour of this hypothesis [41]. Metal ion-dependent neurodegeneration also sheds a bad light on the application of copper and iron sulphate in viticulture and on the application of aluminium to human skin via antiperspirant deodorant products. Acid rain increases the aluminium content in surface water and, thus, might also contribute to aluminium-related neurotoxicity. On the other hand, some metals, such as lithium, have long been known to have neuroprotective effects [42].

Superoxide Radical-Related Enzymes As stated previously, neurodegeneration can be linked to an excess of ROS. In small quantities of course, ROS are essential for homeostasis and are involved in the signalling pathways associated with cell differentiation, apoptosis, cell proliferation and the regulation of redox-sensitive signal transduction pathways [43–47]. ROS are present in mitochondria and are generated from the electron transport chain [48, 49]. Estimates show that the electron transfer chain has a leakage rate of about 5 % of the total electron flow, depending on the amount of available molecular oxygen. In his review, Friedman came up with a plausible explanation as to why the brain is prone to oxidative stress: the brain accounts for about 2 % of total body weight yet consumes roughly 20 % of the total oxygen [50]. One can roughly estimate that 5 % of the total oxygen entering metabolic processes ends up as ROS. The large membrane surface area to cytoplasmic volume ratio of neurons and the membrane itself, which is mainly composed of polyunsaturated and, hence, reactive fatty acids, are additional factors that substantially contribute to the brain’s tendency to neurodegeneration [50]. Molecular oxygen is a potential acceptor of the excess electrons giving rise to superoxide radical O2·– (HO2·/O2·−; pKa =4.8), with a reduction potential O2/O2·− of −0.160 V (Table 1) [51]. Thus, a low-potential, single or double electron carriers, such as flavin goups, heme in complex III, NADH and cytochromes, are the ideal source of electrons in superoxide formation [49]. Increased concentration of low-potential electrons in the mitochondrial region gives rise to elevated levels of ROS. An additional source of electrons, and thus superoxide, is the auto-oxidation of catecholamines, such as dopamine, adrenaline and noradrenaline, to their quinone

forms [52, 53]. Moreover, phagocytes produce nonnegligible amounts of superoxide for the degradation of engulfed bacteria [54, 55]. The latter source is also associated with chronic inflammation arising from activation of the immune system. Small amounts of superoxide are released by fibroblasts, lymphocytes and vascular endothelial cells as well [56]. Abundance of molecular oxygen in the region of the mitochondrial membrane gives rise to the elevated levels of ROS including superoxide radical. SOD is an important enzyme that maintains the concentration of the superoxide radical at physiological levels by catalysing its reduction to hydrogen peroxide and molecular oxygen under acidic conditions (lower reaction pathway in Fig. 1). Interestingly, the hydrogen peroxide produced then inactivates SOD [57–59], which can be rationalised by its favourable effect on promoting the reverse reaction, suggesting that a detailed balance law controls the peroxide/ superoxide ratio. It is well established that superoxide is extremely toxic (much more so than H2O2) and that intracellular concentrations in the picomolar range are already lethal [60, 61]. Hydrogen peroxide, although more oxidising than superoxide, is biologically less toxic and even micromolar levels of H2O2 can be tolerated. H2O2 is a powerful two-electron oxidant (E0 =1.77 V, Table 1), but its reactivity toward most biological molecules is low because of the high activation energy of these oxidations. Therefore, it is effectively more diffusible than superoxide, because it is less reactive and does not, for example, enter into reactions with unsaturated fatty acids when permeating the membrane. There are three known types of SOD enzymes, which differ by the location in which they are found, as well as by the type of heavy metal atom present in their active site [65, 66]. The copper- and zinc-containing SODs (CuZnSOD) comprise most of the activity in eukaryotic cells and are mostly present in cytosol, as well as, to a small extent, in the intermembrane space of mitochondria [67–69]. It is believed that knowing where CuZnSOD are localised in mitochondria could be an important point in providing strategies for further protection from ROS and in preventing superoxide from leaking out of the mitochondria [43, 70, 71]. The manganese-containing SOD (MnSOD) are located in the mitochondrial matrix and are important in providing protection against oxidative stress caused by cellular energy production [43, 72]. Lastly, there is an extracellular SOD (ECSOD), which can be found in the extracellular matrix of both specific cell types and tissues like lung, heart and kidney, as well as in plasma, lymph, astrocytes and cerebrospinal fluid [43, 73, 74]. Regardless of the different types of SOD, they all have similar rate constants, ranging between 1.6×109 and 2.4× 109 M−1 s−1 [75, 76], and superoxide radical decomposition is first order with respect to SOD, i.e. proportional to its concentration [77]. Since SOD active sites contain heavy metal atoms that could, when liberated, induce the formation of

Mol Neurobiol Table 1 Relative reactivity, reduction potentials and pKa values of selected radical and non-radical oxidants

Oxidant Radicals (1 electron)a NO·/3NO− 1 O2/O2·− Cys–S·/Cys–S− O2·–, 2H+/H2O2 ROO·, H+/ROOH NO2·/NO2− HO2·–, H+/H2O2 RO·, H+/ROH CO3·–, H+/HCO3− O3·–, ·

+

2H /H2O, O2 OH , H+/H2O Non-radicals (2 electron)b FAD, 2H+/FADH2 HOCl, H+/Cl−, H2O ONO2H, H+/NO2−, H2O H2O2, 2H+/2H2O

Reduction potential (E0/V; pH=7.0)

Rate constant with glutathione (kGSH/M−1 s−1)b

pKa

−0.80 −0.16 0.92 0.94 ~1.00 1.04 1.06 ~1.60 1.78

Non-detectable 9.4×107 8.0×108 1.1×103 Not determined 3.0×107 Not determined 2.8×105 4.6×107

4.7 (HNO→NO−)

1.80 2.31 −0.18 1.28 1.40 1.77

8.2 (Cys–SH→Cys–S−) 4.8 (HO2· →O2·–) 3.4 (HNO2 →NO2−)

6.4 (H2CO3 →HCO3−)

7

7.0×10 1.6×1010

11.9 (OH· →O·–)

Not determined 3.0×107 6.6×102 0.9

7.4 (HOCl→OCl−) 6.8 (ONO2H→ONO2−) 11.6 (H2O2 →HO2−)

a

Data for one-electron reduction potentials collected from ref. [62]

b

Data for one-electron reduction potentials and second-order rate constants for GSH collected from ref. [63, 64]

amyloid plaques, this might be a reason why evolution was reluctant to allow the expression of excessive amounts of SOD. Moreover, the SOD reaction rate constant is pHindependent over a wide range of pH values, namely between 4.5 and 9.5, but begins to decline at higher or lower pH values [78–81]. The value of the first-order rate constant yields activation energy of around 5.1 kcal mol−1, suggesting that the reaction is controlled by diffusion. A very high turnover rate of SOD gives strong evidence that its activity is essential for homeostasis. It has to be mentioned that the superoxide radical can undergo spontaneous dismutation to H2O2, with a pH-dependent second order rate of ~5×105 M−1 s−1 at pH=7.0 (Fig. 1). However, the SOD enzyme is essential, because superoxide reacts with sensitive and critical cellular targets. For example,

it reacts with the NO· radical and makes toxic peroxynitrite ONOO− with a very high rate constant of k = 6.7 ± 0.9 × 109 M−1 s−1 [82]. In addition, SOD accelerates the destruction of superoxide by increasing the overall rate constant by around 10,000-fold, and also by making the rate of superoxide decay a first order rather than second order process with respect to the superoxide radical concentration. This means that, compared with spontaneous dismutation, SOD is more efficient at accelerating the decomposition at low superoxide concentrations. However, because an enzyme cannot change the position of equilibrium, but only the rate at which it is achieved, there is a lower limit of superoxide concentration below which the enzyme cannot reduce it. It is very difficult to determine superoxide radical steady-state concentration due to its efficient SOD catalysed metabolism together with a rapid disappearance in anoxic tissue. However, various experiments have estimated that superoxide concentration is maintained between 10−12 and 10−11 M [78, 83].

Hydrogen Peroxide-Related Enzymes

Fig. 1 Chemical reactions of the superoxide radical. The upper pathway is also known as the Haber-Weiss reaction. The lower pathway is catalysed by superoxide dismutase (SOD)

Hydrogen peroxide is not only a product of the catalysed decomposition of superoxide by SOD but also a product of the MAO-catalysed oxidative deamination of biogenic and dietary amines [84–86]. MAOs are flavoenzymes abundant in the liver and in the brain. One can speculate that MAO evolutionarily developed its role in the gastrointestinal tract to protect against the undesirable vasoactive and cardioactive

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amines occurring in food, such as tyramine. In the brain, MAO B mainly metabolises dopamine, while MAO A predominantly metabolizes serotonin, which is why these two isoforms are key pharmaceutical targets in alleviating the symptoms of Parkinson’s disease and depression, respectively [87, 88]. However, MAO selectivity is quite poor since, for example, MAO B also decomposes serotonin only five times slower than dopamine [89]. On the other hand, experiments have demonstrated that striatal dopamine tissue levels or extracellular levels are increased by the inhibition of MAO A with clorgyline [90–92]. In the human brain, MAO A exists in catecholaminergic neurons, but MAO B is found in serotonergic neurons and glial cells [93]. Interestingly, dopaminergic neurons contain more MAO A than MAO B while for serotonergic neurons the opposite is true [94, 95]. Recently, we suggested and quantified a novel two-step hydride mechanism of the MAO catalytic reaction [96, 97], which should aid in developing more specific and effective inhibitors as transitionstate analogues, acting as anti-depressants and antiparkinsonian drugs. The rate constant for MAO B catalysed dopamine decomposition is around 1 s−1, which is faster than the metal-free dopamine auto-oxidation (0.43 s−1), yet slower than when auto-oxidation is assisted with heavy metal ions (6.75 s−1) [53, 98, 99]. This gives strong evidence that the latter process, dependent on the Fenton reaction, is an important part of the hydrogen peroxide production process. For a general overview of the reactions relevant for neurodegeneration involving dopamine and its metabolites see Fig. 2.

Fig. 2 Scheme of dopamine metabolism together with the experimental reaction rate constants. MAO B stands for monoamine oxidase B

It is worth emphasising that non-enzymatic oxidation proceeds wherever dopamine and oxygen are present and is not only limited to the mitochondrial membrane and its close vicinity, where SOD and CAT enzymes are present, both of which are responsible for rapid hydrogen peroxide removal. Still, one has to bear in mind that both of these enzymes contain heavy metal ions in their active sites that could be released upon their decomposition, just as, for example, with hemoglobin, which, when removed from erythrocytes and exposed to hydrogen peroxide, releases iron ions. We note in passing that H2O2 can also be consumed by various hemoproteins, such as heme-peroxidases, hemoglobin, myoglobin and cytochrome c, in processes that oxidise these proteins. CAT is a peroxisomal enzyme and is found in nearly all living organisms exposed to oxygen. Ablation of functional peroxisomes from all neural cells in mice causes remarkable neurological abnormalities including demyelination and axonal degeneration [100]. Its high turnover number (kcat ≈107 s−1) is an indirect indication that it plays a central role in the homeostasis of ROS. The onset of Parkinson’s disease, which is associated with the loss of dopaminergic neurons, might be explained by the non-enzymatic oxidation of dopamine in the CAT lacking regions of the neuron. On the other hand, some hypotheses suggest that in some forms of the disease, lesions occur caudally in the CNS and progressively reach the mesencephalon where dopaminergic neurons are located [101]. The consequences are a massive loss of noradrenergic cells and a modest loss of serotonin cells.

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As with dopamine, noradrenaline is also able to undergo non-enzymatic auto-oxidation, but this reaction has been much less studied and, therefore, kinetic data are not available [102, 103]. However, it has been suggested that one of its metabolites may act neuroprotectively [103]. It should be noted that in the biosynthesis of noradrenaline from dopamine, an additional molecule of hydrogen peroxide is formed [41]. On the other hand, the auto-oxidation of serotonin does not proceed because it is chemically impossible to form the quinone form. Serotonin, however, reacts non-enzymatically with the superoxide radical and the reaction proceeds on the minute time scale [104] with the main product being tryptamine-4, 5-dione, which is a neurotoxin [105]. According to various sources, the total homeostatic concentration of H2O2 is between 10−9 and 10−7 M [78, 106]. Therefore, the activity of the two enzymes, CAT and GPx, that decompose hydrogen peroxide are of vital importance. Their abundance varies within different tissues [107], as CAT is mainly found in peroxisomes, while GPx is predominantly located in the cytosol and mitochondrial matrix [78]. Although both enzymes use the same substrate and operate on the same time scale (Fig. 3), they utilise different reaction mechanisms, thus yielding different products. Like SODs, CATs contain iron or manganese ions in their active sites, with both metal ions are responsible for the formation of amyloid plaque in their oxidised form, on top of the fact that such heavy metal ions form stable complexes with GSH, thus depriving it of its scavenging potential. For a schematic overview of the enzymatic decomposition of superoxide and hydrogen peroxide in eukaryotic cells, together with kinetic data, see Fig. 4.

Glutamate as a Source of ROS The main excitatory neurotransmitter glutamate plays an important role in neurodegeneration [108–112]. It is quite abundant in the human brain, with estimates showing that about 40 % of all synapses involve glutamate signalling [8]. Its toxicity mechanism is complex and, to a large extent, obscure

Fig. 3 Chemical reactions of hydrogen peroxide. The upper pathway is also known as the Fenton reaction. GSH and GSSG represent glutathione and glutathione disulphide, respectively and CAT stands for catalase. The experimental rate constants are taken from [78]

[113]. A consensus has been achieved on the conclusion that glutamate neurotoxicity takes place as a result of glutamate binding to the NMDA receptor, which is an important mechanism of excitatory synaptic transmission, and to other receptor subtypes, to a minor extent [114, 115]. Dysregulation of glutamate signalling leads to neurodegeneration prompting the development and utilisation of novel strategies to balance the beneficial and deleterious potential of this important neurotransmitter. NMDA receptor activation results in calcium and chloride ion transport to cytoplasm of the neuron. Depolarization increases calcium channel permeability and the release of calcium from the intracellular stores. Increased calcium concentration in the cytosol initiates a highly complex cascade of signalling processes leading to the increased production of ROS and neuronal death [116]. Xanthine oxidase is supposed to be the main source of ROS formation in this cascade, and its inhibition represents an interesting strategy for the prevention of neurodegeneration [117]. The enzyme is large with a known structure, having a molecular weight of 270 kDa and has two flavin co-factor molecules, two molybdenum atoms and eight iron atoms. It catalyses the transformation of xanthine to uric acid, via a complex mechanism with several intermediates, as revealed by a computational study [118]. Additional possible strategies for preventing ROS formation from glutamate sources is the inhibition of the NMDA receptor with a selective antagonist and the chelation of calcium ions [119], as well as inhibition of the enzyme glutamate carboxypeptidase II [120, 121]. Moreover, evidence is now increasing that excessive glutamate is released at the site of demyelination and axonal degeneration in multiple sclerosis plaques [122], thus raising the possibility that the modulation of glutamate release and transport, as well as a receptors blockade, might be relevant targets for the development of future neurodegenerative disease therapeutic interventions.

Reactive Oxygen Species React with Several Targets It seems that hydrogen peroxide and superoxide are less reactive than their products. The hydroxyl radical, OH·, is particularly reactive, and is formed via the Fenton (Fig. 3) and Haber-Weiss reactions (Fig. 1), being one of the most potent oxidising agents known to chemistry, with a redox potential of as much as +2.31 V (Table 1) [123]. The rate constants for these two reactions are considered too low for biological significance [124]. OH· radicals are cytotoxic and react, at diffusion-limited rates, with almost every organic species found in the cell, particularly with proteins and DNA. As such, their toxicity is non-selective and their diffusion distance is very short. Because OH· reacts rapidly and indiscriminately, anti-oxidants are not very effective, unless present in prohibitively high

Mol Neurobiol Fig. 4 Schematic representation of the ROS transformations in eukaryotic cells. Available concentrations and reaction rate constants for ROS and their reactions are shown here. Inspiration for this figure came from [78]. Abbreviations used: CAT catalase, GPx glutathione peroxidase, GSH glutathione, GSSG glutathione disulphide, SOD superoxide dismutase, UQH· ubiquinone radical

amounts. Thus, unlike with H2O2 and O2·−, there is no enzyme that specifically detoxifies OH·, and it seems that biological systems tightly regulate the availability of Fenton chemistrycapable metal ions to minimise OH· formation. As in all radical reactions, attack to one target triggers a chain of subsequent radical reactions. The reaction can also propagate to any neighbouring fatty acid side chains. Lipid peroxidation at polyunsaturated fatty acid side chain moieties is a typical and relevant example. Modified lipids can react with molecular oxygen, giving rise to a peroxy radical (lipid-OO·) that, in turn, rapidly reacts and damages membrane proteins such as enzymes and receptors [125]. Neurons with damaged membrane proteins have impaired function. Chemically modified membrane lipids have altered, typically increased, permeability, which applies to both cell and mitochondrial membranes. Increased concentration of calcium in the cytoplasm triggers a cascade of signalling events, such as nitric oxide synthase (NOS) and NMDA receptor activation, giving rise to cellular death either by apoptosis or necrosis [16], and the process is, from this point, basically the same as the increased calcium level originating from the glutamate neurotoxicity mechanism discussed above.

Protective Roles of L-carnosine Heavy metal ions catalyse the auto-oxidation of dopamine and associated production of hydrogen peroxide. It is believed that the naturally occurring dipeptide L-carnosine (β-alanyl-L-histidine) acts as an ion-chelating agent (mainly for Cu2+ and Zn2+), free-radical and reactive aldehyde scavenger [126] and anti-oxidant [127, 128], as well as both an amyloid beta toxicity and protein glycation suppressor [129]. Moreover, it has the potential to maintain the level of GPx and SOD activity [130]. L-carnosine is known to be abundant in muscle and brain tissues of humans, as well as other vertebrates, at relatively high concentrations (1–20 mM) [131, 132]. The olfactory lobe is normally enriched in L-carnosine and zinc. Loss of olfactory function and oxidative damage to olfactory tissue are early symptoms of Alzheimer’s and Parkinson’s disease. It has also been shown, through in vivo and in vitro studies, that L-carnosine can exert neuroprotective effects through various other mechanisms [127, 128, 133, 134]. In addition, there is evidence that several ageing-related molecular processes, occurring in cerebral tissue during neurodegenerative diseases, are positively influenced by members of the histidine-

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containing dipeptide family, with carnosine often showing the highest effectiveness [135, 133, 136]. Moreover, the most recent study by Attanasio et al. suggested that L-carnosine inhibits amyloid plaque formation [137] and rescues cells from beta amyloid plaque-induced neurotoxicity [136, 138–141]. It is also worth mentioning that lower L-carnosine plasma levels have been found in Alzheimer’s disease patients compared with the levels of age-matched control groups [142]. The intracellular concentration of L-carnosine is regulated by the activity of the metalloprotease carnosinases. In mammals, two isoforms of these dipeptidases have been characterised. The serum-circulating form, serum carnosinase, secreted by brain cells, is rather selective for carnosine [143]. The cytosolic isoform, tissue carnosinase, is a non-specific dipeptidase distributed in several human tissues and in rodent brain [144]. For this reason, the enzymatic hydrolysis of Lcarnosine is the main limitation for their possible effective pharmacological applications. Still, some authors put forward interesting hypotheses that lubricant drug delivery and perfume toilet water formulations [129], or lubricant eye drops and oral formulation [145], all based on non-hydrolyzed Lcarnosine, should be explored for their therapeutic potential in olfactory dysfunction, Alzheimer’s disease and other neurodegenerative disorders.

Inflammation and Neurodegeneration Inflammatory processes are always associated with the increased levels of ROS [146–151] and with neurodegeneration when they occur in the CNS [152]. Activated leucocytes are the primary sources of ROS at the site of inflammation. Viral infections associated with increased leucocyte numbers are fortunately rare in the CNS. Some authors associate neurodegenerative diseases with chronic immune activation [152, 153]. However, the CNS is to a certain extent isolated from the rest of the body in terms of immune activation, which is usually termed as Bimmune privilege^. Relatively independent immune responses have developed in the CNS versus the rest of the body, and it is evident that these immune responses are tightly regulated in the brain. Glial cells play a major role in this regulation, while neurons are assumed to play a largely passive role, being mainly the victims of immune responses. Glial cells incite pro-inflammatory responses, while astrocytes suppress helper T cells, in particular. It is interesting that neuronal expression of the cannabinoid receptor is also implicated in suppressing inflammation [154]. Evolutionary pressure has developed the immune system to protect the organism from external danger by using a complex network of immune sensors. These sensors have been optimised to detect and fight pathogens. A side effect is that these immune sensors also recognise molecules from the distressed cells [155]. Therefore, an immune response is, by

definition, also possible without pathogens. The traditional picture of the inflammatory reaction is that activated neutrophils, such as leucocytes, induce the production of a large amount of ROS and substances with killing and degrading activities, such as myeloperoxidase, defensins, elastase, collagenase, cathepsins and lysozyme. A more recent view of the immune response of the CNS is that the immune sensors are inherent to the interior of the most of the CNS cells including neurons. The activated immune system tries to remove the cause of injury and/or to proceed with the repair process through inflammation. In the case of repair failure, this immune response turns into chronic inflammation with a steady production of ROS [152]. A possible strategy for the prevention of neurodegeneration is the treatment of inflammation at the level of the arachidonic acid cascade by inhibition of cyclooxygenase-2 (COX-2). Clinical studies on the effects of the administration of non-steroid anti-inflammatory drugs, such as ibuprofen, for the prevention of Alzheimer’s [156] and Parkinson’sdisease [157] are promising. For a recent review of neurodegeneration induced by the immune response, see [158]. One can relatively safely assume that long-standing inflammatory processes in the CNS are deleterious for neurons because they produce ROS in significant quantities. There is no doubt that there is an important link between ROS, inflammation processes and neurodegeneration, and there is still a plenty of space to understand this link on the molecular level and to develop drugs that intervene in the pathways connecting these events [159, 160]. However, it remains a challenge to obtain an estimate of ROS production by inflammatory processes relative to the other sources. The quantitative data are not widely available. ROS are small species and they can be relatively easily transported across membranes, which makes kinetic studies even more demanding. A recent simulation study revealed that the hydroxyl radical can penetrate deep into the head-groups region of the membrane with no significant free energy barrier [161]. ROS levels also depend on physical exercise as reviewed in [162]. Low levels of ROS might cause insufficient gene expression for redox homeostasis and, therefore, impaired response to the oxidative challenge, eventually leading to the increased vulnerability. High levels of ROS exceed the adaptive tolerance of cells, resulting in significant oxidative damage, apoptosis, and necrosis. In this respect, moderate aerobic physical exercise appears beneficial for brain function and integrity. In concluding this section, we note in passing that the levels of nitric oxide (NO), an important cellular signalling molecule, are also increased as a result of processes involving inflammation [163]. Nitric oxide is a highly reactive system, which rapidly reacts with several ROS. Its reaction with superoxide radical ion is particularly dangerous, since it results in an extremely toxic peroxynitrite anion, ONOO− [163, 164]. Therefore, the inhibition of NOS, which catalyses the

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production of NO from L-arginine, is a promising strategy for neuroprotection [165]. However, despite significant efforts in this direction, no NOS inhibitors are yet in therapeutic use [166].

Polyamines—Therapeutic Targets and Biomarkers for Neurodegenerative Diseases Polyamines, such as spermine (SPM), spermidine (SPD) and their metabolic precursor putrescine (PUTR), all of which are required for eukaryotic cell growth [167], can also promote the formation of amyloid plaques [168]. These natural polyamines are small, flexible multivalent cationic molecules that are believed to be fully protonated at physiological pH [169]. The primary function of polyamines is to regulate gene expression [170] and promotion of cell migration [171]. Moreover, they affect an organism’s resistance to stress and infectious diseases [172, 173]. They can be found inside and outside of the cell as well as in the plasma membrane [174, 175], which indicates that polyamines and beta amyloid plaques have several potential interaction sites ranging from cellular organelles to the cytoplasm to the interior of neural cells. The polyamines’ homeostatic cellular concentrations are around 1 mM but can be increased or decreased by as much as 70 % in pathological states or in the presence of amyloid beta peptides [176–181]. For example, Gomes-Trolin and coworkers demonstrated that the average levels of SPM and SPD in the red blood cells of patients with Parkinson’s disease increase by 114 and 135 %, respectively [182]. Recent studies have shown that SPM, SPD and PUTR accelerate the aggregation and fibrillation of αSyn [176] through binding to the N-terminal region of amyloid beta peptide, which is also known to be the binding site for metal ions like Cu2+ and Zn2+. This gives evidence that, in vivo, polyamines might compete with the metal ions for binding to amyloid beta peptides, hence polyamines are believed to be able to modulate neurodegenerative processes [168]. NMR studies have provided further evidence that polyamines enhance αSyn fibrillation by increasing the extent of nucleation by ~104 and the rate of monomer addition ~40-fold [183]. However, the precise mechanism by which polyamines promote the aggregation of αSyn is not well defined, and, to date, three possible mechanisms have been suggested. The first model indicates that SPM binding reduces the net charge of αSyn from −10 to −6, which causes αSyn to rearrange to a much more compact form (the size of the protein changes by almost a factor of 2), whose accumulation increases the speed of aggregation [184]. The significantly changed size of the αSyn can be explained by the changes in the long-range electrostatics. On the other hand, combined NMR and molecular dynamics simulations studies have indicated that polyamines’ interaction with the αSyn’s polyamine binding site leads to the

formation of a more extended αSyn conformation and to the release of long-range contacts between its C-terminal and Nterminal parts [185]. According to a third model, the presence of SPD, at concentrations comparable with physiological ones, induces conformational changes in αSyn producing a misfolded state of its monomer with a higher propensity for self-assembly [186]. In any case, reducing polyamine levels can be considered as a potential therapeutic target for Parkinson’s disease and could be achieved by certain compounds that operate by either elevating polyamine catabolism or inhibiting polyamine biosynthesis, so that αSyn aggregation is effectively reduced. On cellular level, it has to be ensured that reduced polyamine levels are maintained inside the cell, as cells uptake polyamines from the external medium very rapidly. Moreover, Khalili and co-workers suggest that polyamines could serve as predictive biomarkers for HIVassociated neurocognitive disorders [187]. Along that line, in a very recent review [188], Singh and co-workers termed interactions between polyamines and αSyn Bignored avenues in αSyn associated proteopathies^ and advise that therapeutics directed at these ignored targets could turn out to be a successful combinational therapy for Parkinson’s disease.

How to Prevent Neurodegeneration?—Conclusions and Perspectives The CNS is vulnerable to oxidative stress and neurodegeneration is its direct consequence. The main reason for the oxidative stress is that human brain consumes about ten times more oxygen than is the average over all other tissues, which is directly linked to the high-energy consumption of neural signal transduction. In contrast to other cells, neurons are non-replicating and the brain is, despite massive redundancy, sensitive to the loss of function if too many neurons cease to exist. Neurodegeneration is a very complex process. We are still very far from understanding all the details, particularly on a molecular level. Nevertheless, ROS, arising from several sources, including the non-enzymatic oxidation of dopamine, electron transfer chain, molecular oxygen, MAO catalysed metabolism of biogenic and dietary amines, and inflammatory processes, are largely responsible for the damage to neurons. ROS can harm the membranes of either neurons or mitochondria, thus inducing spillage of the contents, depolarization and loss of function, followed by rapid neuronal death. Possibly more important than the toxic mechanism of ROS, is the heavy metal ion mediated one, in which the metal ions are oxidised, enhancing their binding to αSyn that then folds to a significantly less soluble beta form, which further aggregates into amyloid plaques. On the other hand, an additional factor affecting amyloid plaque formation is the direct interaction of dopamine and its quinone metabolites with αSyn, which, in

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this case, act as reversible inhibitors of the αSyn fibrillation [189–192]. GSH, present at milimolar concentrations in most cell types, is a major intracellular reductant owing to its cysteine thiol group (Table 1). However, in increased amounts, heavy metal ions form stable complexes with GSH, thus significantly decreasing its scavenging potential, and are involved in the Fenton and Haber-Weiss reactions producing OH·. On the other hand, H2O2 production from the non-enzymatic metalions mediated oxidative deamination of dopamine and noradrenaline seems to be particularly problematic, since it is not restricted to the mitochondrial membrane, where H2O2 decomposing enzymes, such as CAT and GPx are located in significant quantities. These are possible explanations for the involvement of dopaminergic neurons in the initial stages of Parkinson’s disease, while, at the same time, the loss of olfactory neurons, which are mainly glutaminergic, gives strong evidence for the important role of either the electron transfer chain or inflammatory processes in neurodegeneration. There are many dietary components that can not only scavenge ROS but also influence some of the biochemical events (signal transduction, stress protein synthesis, glycation and toxin generation) associated with neurodegenerative pathologies, thereby either ameliorating the risks or slowing down the progression of the disease [193, 194]. Although many such components are still to be explored for their therapeutic potential, their consideration is, in general, advisable. However, excessive levels of food rich in GSH and, for example, ascorbic acid typically do not give satisfactory results, due to their poor absorption, resulting in the absence of any clinically beneficial effects [195]. N-acetyl cysteine has better absorption properties and its scavenging potential is comparable with GSH, while physiological concentrations of uric acid are already close to the level of plasma solubility. Polyphenols found in red wine and grape juice and several other fruits seem to be more promising [196]. In general, food containing sulphur rich compounds, such as garlic, onion, and avocados, are also good options. Bilirubin is a very efficient ROS scavenger [197], which provides a possible explanation for a low incidence of cardiovascular diseases and, to a certain extent, neurodegeneration in patients with Gilbert-Meulengracht syndrome [16]. A promising strategy for the prevention and, to a certain extent, treatment of neurodegeneration is the administration of curcumin, an essential ingredient of curry, which has recently been demonstrated to have significant neuroprotective potential [198]. Interestingly, the prevalence of Alzheimer’s disease in India among adults aged between 70 and 79 years is 4.4 times lower than in the USA [199]. Curcumin acts as scavenger of ROS, and it chelates iron and copper ions [200]. In a mixture with beta-cyclodextrin, it not only prevents the formation of the amyloid plaque but also disaggregates it [201].

Green tea and coffee drinking seems to have neuroprotective potential. Catechins found in green tea can penetrate the hematoencephalic barrier and they act as metal chelating agents and ROS scavengers [202]. On the other hand, caffeine, as the most consumed psychostimulant in the world, is also neuroprotective. Recent experimental evidence suggests that the primary target for the neuroprotective effects of caffeine [203] is mostly through either activating or inhibiting A1 and A2 adenosine receptor subtypes [204, 205]. One can lower ROS production through the MAO pathway by inhibiting MAO [206] with one of the irreversible MAO B inhibitors, such as selegiline and rasagiline [207]. MAO A inhibitors seem to be less appropriate because of their psychoactive properties [208]. An unknown substance(s) in tobacco smoke also irreversibly inhibit MAO by up to 60 %, suggesting that sporadic smoking in low quantities could be beneficial for the prevention of neurodegeneration [206, 209, 210], while balancing its potential in the development of neoplasia and cardiovascular diseases. Interestingly, nicotine per se is a reversible inhibitor of MAO [209], while its metabolite nornicotine binds to the arginine side chain in αSyn, thus preventing conformational change to its beta form [211]. The opposite effect is observed for the butter flavorant diacetyl (Me-C(O)-C(O)-Me), which promotes the formation of beta amyloid plaque [212, 213], which is attributed to its chemical reaction with the Lys and Arg side chains. Youdim and co-workers are working toward pleiotropic MAO inhibitors that simultaneously show potential for iron ion chelation for use in treating Alzheimer’s disease [214]. The ROS production originating from inflammatory processes in the central neural system can be blocked at the level of the arachidonic acid cascade with one of the COX-2 selective non-steroidal anti-inflammatory drugs (NSAID). Ibuprofen seems to be a first-choice, because of its low ulceration potential [156, 157]. However, it remains a challenge to balance the benefit of NSAID administration with its unwanted side effects and to give recommendations for administering NSAID in the context of neuroprotection. It is probably not recommendable to administer NSAID to patients with no signs of neurodegenerative diseases, particularly as longterm therapies. Analogously, inhibition of some other biological systems or pathways, including xanthine oxidase, NMDA receptors, NOS and polyamine biosynthesis, all discussed here, could turn out to be beneficial for the neuroprotection but to what degree and when remains a question. In this work, we have presented a few known chemical mechanisms of neurodegeneration on the molecular level together with the accompanying kinetic data where available. One can view neurodegeneration as the interplay of several chemical reactions with complex kinetics. We hope that our results will offer new insight into the features of molecular events linked to neurodegeneration, paving the way toward new strategies for the prevention of and protection from these

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debilitating diseases. In conjunction with additional clinical, experimental and theoretical work [215], the data presented here should help toward better understanding of the mechanisms for neurodegeneration and, hopefully, aid in the building of its kinetic molecular model. Acknowledgements We would like to thank Prof. Paolo Carloni (German Research School for Simulation Sciences, Jülich, Germany) and Prof. Simon Podnar (Institute for Clinical Neurophysiology, University Medical Centre Ljubljana, Slovenia) for many stimulating discussions. M.R. and J.M. would like to thank the Slovenian Research Agency for the financial support in the framework of the programme group P1–0012 and within the corresponding research project contract No. J1-2014. R.V. gratefully acknowledges the European Commission for an individual FP7 Marie Curie Career Integration Grant (contract number PCIG12GA-2012-334493). M.P. would like to acknowledge the German Research School for Simulation Sciences (GRS) for the administrative and financial support. M.R. would like to acknowledge Sciex grant 14.141 for financial support. Part of this work was supported by COST Action CM1103. The authors thank Ms. Charlotte Taft for a careful proofreading of the manuscript. Compliance with Ethical Standards The authors declare that this entire submission complies with the ethical standards of the journal as there are no conflicts of interest and the research presented here did not involve human participants and/or animals. Conflict of Interest The authors declare that they have no conflict of interest.

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