Neurodegenerative diseases – Understanding their molecular bases and progress in the development of potential treatments

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Contents lists available at ScienceDirect

Coordination Chemistry Reviews journal homepage: www.elsevier.com/locate/ccr

Review

Neurodegenerative diseases – Understanding their molecular bases and progress in the development of potential treatments Magdalena Rowinska-Zyrek a,∗ , Milena Salerno b , Henryk Kozlowski a a b

Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw, Poland Université Paris 13, Sorbonne Paris Cité, Laboratoire CSPBAT, CNRS (UMR 7244), UFR-SMBH, 74 rue Marcel Cachin, 93017 Bobigny, France

Contents 1. 2. 3. 4. 5.

6. 7.

8.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology of alpha-synuclein in Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Amyloid beta in Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Misfolded prion proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recommended traditional therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Prion disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Blood–brain barrier: the major obstacle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Possible metal-related therapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. Prion disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

a r t i c l e

i n f o

Article history: Received 31 December 2013 Received in revised form 22 March 2014 Accepted 24 March 2014 Available online xxx Keywords: Neurodegeneration Metal ion imbalance Possible treatment

00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00

a b s t r a c t Neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and prion diseases have at least three common denominators: (i) progressive loss of neuron function, which leads to cognitive decline; (ii) the molecular basis of the disease, which involves metalloprotein misfolding and aggregation (amyloid beta, alpha synuclein, and prion protein), or metal ion (Cu2+ , Zn2+ , and Fe3+ ) imbalances that result in oxidative stress; and (iii) the current lack of a therapy to reverse or stop the progression of symptoms. These problems are discussed collectively in the present review. First, the molecular bases of these three diseases are explained in brief, with a special focus on the role of coordination chemistry in each case. Next, several commercial drugs that can be used to treat the symptoms are presented, i.e., those that do not aim to achieve metal ion homeostasis, which may be less well known in the bioinorganic community; and those that aim to achieve metal ion chelation, including the molecular scaffolds of those currently in clinical trials and the most promising targets that are still being studied in vitro. Another very important issue summarized in this review encompasses the strategies that have been developed to overcome the blood–brain barrier (BBB) and deliver drugs inside the brain. The BBB is a major obstacle in the development of drugs for treating central nervous system diseases. The BBB includes anatomical, physicochemical, and biochemical mechanisms that control the exchange of molecules between the blood and brain, thereby making the BBB virtually impermeable to drugs that might be used to treat neurodegenerative diseases. The non-optimistic nature of this review has a dual role. First, we present a true picture of the progress in the development of potential therapeutics. Second, we aim to encourage further targeted research in this area. © 2014 Published by Elsevier B.V.

∗ Corresponding author. Tel.: +48 71 3757251. E-mail address: [email protected] (M. Rowinska-Zyrek). http://dx.doi.org/10.1016/j.ccr.2014.03.026 0010-8545/© 2014 Published by Elsevier B.V.

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1. Introduction According to the World Health Organization, the three main causes of death in developed countries are cardiovascular disease, cancer, and neurodegenerative diseases. Bioinorganic chemistry has an important role in the latter two illnesses, where it facilitates the design and improved understanding of the principles of metalbased drugs (e.g., the well-known cisplatin, which is an anticancer drug) and metal chelators (in neurodegenerative diseases). In this review, we focus on the roles of metal ions in neurodegeneration by summarizing the molecular basis of the disease, the impact of metal ions during pathogenesis, the commercially available (nonmetal-related) drugs, potential metal chelation treatments, and the main obstacle to their application: the blood–brain barrier (BBB). The role of metal ions in neurodegenerative diseases is a rapidly expanding subfield of bioinorganic chemistry. Recently, several comprehensive reviews have been published on the roles of metal ions in Parkinson’s, Alzheimer’s, and prion diseases [1–3], as well as metal ion chelators that might be used as potential therapeutics [4,5]. The first sections of this review explain the molecular basis of the three diseases. Each of these sections begins with a short, descriptive outline of the disorder, which briefly summarizes the symptoms and the social scale of the problem. Next, the molecular bases of the diseases are clarified, where we describe the proteins involved in neurodegeneration and their complex relationships with metal ions. The coordination sites are highlighted and the possible metal ions involved are explained in detail. The later sections focus on possible treatment strategies by summarizing the traditional, non-metal-related drugs that are available in clinics and discussing the recent progress made in the design of possible therapeutics based on metal ion chelators. Special attention is given to the results of the clinical trials of two Prana Biotechnology products (clioquinol and PBT2) and to the possible modifications that can be made to functionalize metal-chelating molecules with additional therapeutic moieties, or with groups that may make them more permeable through the BBB. This major obstacle, the BBB, is indeed the biggest problem that needs to be overcome to facilitate the design of drugs to combat neurodegeneration. We focus on this issue in Section 6. This review provides a comprehensive summary of all of these areas in one study. In particular, the sections that describe the commercially available drugs and the problems of overcoming BBB may be fairly novel and they provide a useful synopsis of this area for coordination chemists.

2. Pathology of alpha-synuclein in Parkinson’s disease Parkinson’s disease (idiopathic, essential, or primary) is named after the British physician James Parkinson, who described the “shaking palsy” in 1817, although the disease itself has probably existed for many centuries because similar symptoms are described in texts related to Chinese medical practice that date from several centuries BC. In industrialized countries, the current prevalence of Parkinson’s disease (PD) is ca 1% in people aged >60 years [6]. The prevalence rises sharply with age after 60 years and the number of patients is expected to double by 2030 [7]. The typical symptoms of PD are bradykinesia (difficulty in movement), shuffling gait, micrographia (small, compressed handwriting), memory lapses, a ‘masked’, expressionless face, trembling in the hands and forearms, loss of spontaneous movement, difficulty swallowing, and impaired coordination. One third of patients develop dementia and depression [8]. The pathological molecular feature of PD is the loss of neurons in the substantia nigra or, more specifically, the front part of the pars compacta, which affects up to 70% of the cells by the time of death [9]. Histopathological analyses indicate the presence of

5–24 ␮m spherical inclusions with a dense eosinophilic core composed of Lewy bodies, as well as nigrostriatal dopamine cell loss and the death of astrocytes (star-shaped glial cells). Another molecular hallmark of PD is a decreased ferritin level, which results in high concentrations of free Fe3+ in the brain. Fe3+ and other metal ions undergo an oxidation cycle where reactive oxygen species (ROS) are produced, which damage the surrounding brain cells [10]. Further oxidative damage is caused by overactive monoamine oxidase (MAO) production, which generates H2 O2 that damages dopamine [11]. The etiology of the disease remains unclear, but the most convincing (and also the most general) theory explains the cumulative loss of dopamine neurons based on environmental exposure to toxins, excitotoxicity, and oxidative stress. The most widely used drug, levodopa, allows the neurons to produce new dopamine. However, there is no way to prevent or cure PD and this drug may cause side effects and lose its effectiveness over time. Alpha-synuclein (aS) is the main component of Lewy bodies, which are a hallmark of PD [12]. Its function is not yet fully understood. However, it has been suggested that it is involved in the metabolism of dopamine, synaptic vesicle transport, recycling at the presynaptic terminal, and recycling of the SNARE complex [13]. The 140-amino acid long, natively unfolded aS comprises three regions (Fig. 1A): (i) the N-terminal domain (1–60), which is involved in lipid binding with KTKXGV sequence repeats; (ii) the self-aggregating NAC domain (61–95), which initiates fibrillation [14], and (iii) the C-terminal region (96–140), which is responsible for blocking filament formation [15]. Alpha-synuclein binds Fe2+ , Ni2+ , Co2+ , and Mn2+ weakly [16,17]. It is likely that these metal ions are anchored to Asp121 and that their binding does not induce any major structural change in the peptide. In contrast to other metals, Cu2+ binds aS specifically and with high affinity, thereby increasing its rate of aggregation and oligomerization [18–20]. Up to three Cu2+ ions can be bound: two with high affinity at the N-terminus sites and one with low affinity site at the C-terminus (Fig. 1B) [21] The N-terminal high-affinity binding sites are: (i) the Met1 N-terminal amine group, i.e., an amide backbone nitrogen, the carboxylic side chain of Asp2, and a water molecule [22]; (ii) His50, i.e., the deprotonated amide nitrogens from His50 and Val49, and water [23]. Alternatively, a macrochelate may be formed between His50 and the N-terminus. The low-affinity Cu2+ binding site at the C-terminus involves: (iii) Asp121, Asp119, Asn122, and Glu123 (Fig. 1B) [21]. Much effort has been made to characterize Cu2+ binding to aS both in the presence of two independent N-terminal high-affinity copper-binding sites [24] and via the formation of a macrochelate involving the amino terminal region and the His50 imidazole, but this is still a matter of debate [24–26]. We must stress that the metal-binding affinities are not discussed in detail in this review. Please refer to recent reviews of this subject for a thorough discussion and a detailed explanation of why the stability constants reported in the literature vary so widely, as well as why it is difficult to unify the constants calculated with different techniques in various experimental conditions [27,28]. To understand the metal–protein binding properties, model peptides are often used that mimic the unstructured metal binding sites [29]. This approach has also been used to understand the binding properties of His50 based on a peptide that encompasses residues 45–55 of the native aS and aS with two mutations in that region, i.e., E46K and A53T, which are linked to familial early onset PD. All three species form a 1N complex at pH 6.5, where His50 imidazole is the Cu2+ anchoring site. The involvement of Glu46 carboxylate with the native peptide and with A53T has also been suggested. At physiological pH, the metal binding mode of this model peptide changes to [Nim , 2 N− , 1O], where Nim is the His50 imidazole,

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self-aggregating NAC domain which initiates fibrillation

3

the C-terminal region responsible for blocking filament formation(96–140)

A)

D119 KAKEGV

KTKQGV

KTKEGV

KTKEGV

KTKEQV

H50

B)

D121, N122,E123

O O

Asp2

CH3

2-

Cu O N

O

S

N O

Glu123 CH3 +

OH2

Met1

N H2

O O

2-

Cu O

Asp119 CH 3

O O

N His50 *

H3C

Asp121

H3C

* or H2O

Fig. 1. (A) Schematic outline of alpha-synuclein. The residues involved in Cu2+ binding are highlighted. Please note that His50 can be replaced by a water molecule. (B) Representation of the Cu2+ binding modes with the N-terminal (left) and C-terminal (right) regions of alpha-synuclein.

the two amide nitrogens belong to His50 and Val49, and the oxygen ligand binds to a water molecule [22]. Additional data that support the proposed Cu2+ binding mode have been provided by copper binding studies using betasynuclein, a protein that is highly homologous to alpha-synuclein but without the central hydrophobic region [19]. Interestingly, beta-synuclein was recently proposed to be an inhibitor of aS aggregation and it may be considered as a novel treatment for neurodegenerative disorders [30,31]. Numerous studies have been performed to understand the binding mode, as well as the impact of Cu2+ on the biological activity of aS and its involvement in the pathology of PD. The redox activity of copper is an important issue for understanding the molecular basis of the disease. Cu+ should also be considered because both Cu+ and Cu2+ -aS complexes may cause oxidative cell damage via ROS production [32,33]. Cu2+ -aS complexes are usually found outside the cell, in the plasma, and in cerebrospinal fluid, where aS is secreted and the normal mean copper concentration is <20 ␮g/L [34,35]. Based on the simplification that Cu2+ is present mostly outside the cell whereas Cu+ is found in the highly reductive environment of the cytosol, the interactions between aS, which is present mostly in the cytosol of the presynaptic neuron, and Cu+ are also of great biological importance. In the cell, the majority of Cu+ ions are probably bound to Cys-rich proteins and peptides (because of the very high affinity of this metal for free thiols), thus the binding of some Cu+ with aS cannot be excluded. Relatively little is known about these interactions. Recent studies have proposed the binding of one Cu+ to two N-terminal thioether sulfurs from Met1 and Met5 [36], and a second to the side chains of Met-116 and Met-127 [37]. Recent NMR studies show that the metal’s interaction with the N-terminal regions does not cause any significant structural rearrangements, whereas a ␤-turn in the backbone is induced when the second binding site (Met-116 and Met-127) is occupied [37]. Clearly there should be greater attention to the interactions between Cu2+ and aS, but it should be noted that in vivo, the Cu2+ /Cu+ redox chemistry might one of the most important events in the pathophysiology of PD by causing the formation of ROS, thereby leading to the oxidation of amino acid residue side chains, formation of protein–protein cross-linkages, oxidation of the protein backbone, and protein fragmentation (for a recent review, please refer to [38] and references therein).

3. Amyloid beta in Alzheimer’s disease Alzheimer’s disease (AD), the most common form of neurodegenerative disease, was first described by the German psychiatrist Alois Alzheimer in 1906 [39]. AD is usually diagnosed in people in their late sixties, although the rare form of early-onset AD can occur much earlier. AD is currently the sixth most common cause of death in the USA. Worldwide, the statistical prevalence of AD is difficult to estimate precisely, but >26 million is a reasonable estimate and this is expected to triple by 2050, affecting one in 85 people [40]. The first sign of AD is forgetfulness, but the disease soon develops into a serious and debilitating disorder that includes confusion, personality changes, anxiousness, irritability, memory loss, and intellectual disturbances. Eventually, AD patients can no longer function independently. Statistical analyses show that AD patient dies about 8–12 years after being diagnosed. At present, there is no treatment available to cure or stop the progression of AD. The FDA-approved drugs that will be discussed in this chapter temporarily slow the worsening of symptoms for about 6–12 months in about half of the individuals who take them [41]. Truly effective therapies do not exist. AD symptoms develop because of a progressive loss of neurons. The brain changes observed post mortem in AD patients are characterized by amyloid plaques deposited around neurons and neurofibrillary tangles, which are twisted fibers inside neurons [42]. Research has been conducted to understand the molecular basis of the disease. AD is triggered by the accumulation of the amyloid beta peptide (Ab) due to the overproduction of Ab, the deposition of its toxic oligomers, and the failure of clearance mechanisms. Ab, the molecular hallmark of AD, is a 39–43 amino acid peptide and it is the main component of amyloid plaques in the brains of AD patients. It is the result of the proteolytic cleavage of a transmembrane glycoprotein, amyloid precursor protein (APP) [43]. The most common fragments are Ab 1–40 and Ab 1–42, where the latter is more amyloidogenic, extremely prone to self-aggregation, and it forms large, insoluble extracellular deposits that are rich in beta sheet [44]. Ab 1–42 is most common in plaques, where it binds metals such as Cu2+ , Zn2+ , and Fe3+ . The impact of metal ions is still not fully understood. They may contribute to peptide aggregation or to the generation of ROS, ultimately causing neuronal damage [45]. Ab oligomers are neurotoxic because they block the proteasome

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amyloid beta (1-40)

A) D1 A2

H5

H13 H14 beta sheetregion

B)

O OH Asp1

Ala2

H3C H2N

O 2Cu N N

H3C

His13/14

N H

N

CH3

O

His6

+

Cu

N O

N H

O

2-

NH 2

Asp1

NH His

HO

CH3

Fig. 2. (A) Schematic diagram showing the minimal sequence of amyloid beta involved in copper binding. The residues involved in Cu2+ binding are highlighted. (B) Representation of the Cu2+ -amyloid coordination modes at low pH (left) and high pH (right).

function and inhibit mitochondrial activity. The loss of the normal physiological functions of Ab may contribute to neuronal dysfunction. In a healthy brain, Ab interacts with signaling pathways that regulate the phosphorylation of tau protein. The hyperphosphorylation of tau disrupts its normal function in regulating axonal transport, which leads to the accumulation of neurofibrillary tangles. Moreover, the degradation of tau is inhibited by Ab [46]. The Ab peptide comprises two regions: the N-terminal region, (Ab 1–28), which corresponds to the extracellular region of APP before cleavage, and the C-terminal region (Ab 29–40 or 29–42), which is the trans-membrane region of APP. Postmortem brain analyses of AD patients show that the Ab found in amyloid plaques binds high levels of zinc, copper, and iron [47,48]. The coordination of these metal ions modulates the pathogenic aggregation [49,50]. The minimal binding motifs for Cu2+ and Zn2+ are the first 16 amino acids (Ab 1–16, Fig. 2A) [51–53]. There are two main Cu2+ binding modes to Ab 1–16, i.e., one at pH 6.5 and another at pH 8. Both forms can be present in physiological conditions. The coordination mode at a lower pH is still under debate [54], although a consensus has been reached and its is most likely that the His6 imidazole, His13 or His14 imidazole, a terminal Asp1 amine group, and an Asp1 or Glu11 carboxyl group participate in coordination (Fig. 2B) [55–57]. The possible coordination mode changes at a higher pH, where it involves either the imidazole nitrogens from His6, His13, His14, and Ala2 carbonyl oxygen [56], or the imidazole of one of the histidines, the N-terminal Asp1 amine, an Ala2 amide backbone nitrogen, and carbonyl oxygen (Fig. 2B) [57]. Cu+ also binds to this 16-amino acid fragment, where the coordination geometry is linear and it involves His13 and His14 [58]. These two histidines, as well as His6, Asp1, and Glu11, are involved in the coordination of Zn2+ , as demonstrated by nuclear magnetic resonance (NMR) [59]. Surface plasmon resonance and mass spectrometry studies have shown that zinc binding to His14 and Glu11 induces the dimerization of Ab. Fe2+ binds to two histidines (6 and 13 or 14), a terminal amine group, a carboxylic acid from Asp1 or Glu3, and a carbonyl group from Asp1 or His6 [60]. The affinities of Ab for different metal ions have been reviewed recently [3,61]. It is particularly difficult to compare the affinity of

each metal because it depends greatly on the length of the protein or peptide, the technique used to study the metal complexes, and the experimental conditions employed. Differences in the approach can yield results that vary by several orders of magnitude. 4. Misfolded prion proteins Prion diseases are fatal neurodegenerative disorders that are characterized by progressive brain degeneration, which is caused by a protein infectious agent that induces protein conformational changes [62]. They are the most rare of the neurodegenerative diseases and they affect only one person per million [63]. Human prion diseases include Creutzfeldt-Jakob (CJD), Gerstmann-SträusslerScheinker, fatal familial insomnia, and kuru diseases [64,65]. The most common animal version of the disease is the so-called “mad cow disease” (bovine spongiform encephalopathy). The typical symptom of the most common form of CJD, sporadic CJD, is a rapidly progressing dementia. Death usually occurs in less than one year after the first symptoms are noticed [66,67]. The less common variant CJD (vCJD) affects younger patients and it progresses as rapidly as CJD after the first symptoms appear, although it is preceded by a long incubation period of ca 17 years [68]. CDJ originates sporadically, whereas vCJD can be transmitted by several mechanisms such as blood transfusion, iatrogenic transmission, or the ingestion of food contaminated with the agent of bovine spongiform encephalopathy [69,70]. The molecular mechanism of prion pathologies is not yet fully understood, but some aspects are generally accepted, such as progressive neuron loss, spongiform degeneration, and brain inflammation [71]. The molecular cause of this state is the misfolded prion protein (PrPSc , Sc for scrapie), which is the pathogenic isoform of a natively folded cellular prion protein (PrPC ) that is normally present in the brains of healthy individuals. PrPC is monomeric, water soluble, and it comprises three helical domains and two short ␤ sheets, whereas the pathogenic PrPSc has large ␤domains, is insoluble, protease resistant, and prone to aggregation [72]. More than 30 years have passed since Prusiner first described PrPSc [73], but still no drugs are available that can stop or delay the progression of the disease. The biological functions of PrPC are also

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not well established. However, it is clear that this protein is well conserved in mammals where it is located in lipid rafts of cell membranes, to which it is attached via a glycosylphosphatidylinositol anchor [74]. The proposed physiological activities of the native PrPc are neuroprotection [75], antioxidative stress [76], copper binding [77], and protection against cell death [78]. The conversion of natural PrPC into the pathogenic PrPSc form is responsible for the development of the pathology for two reasons: (i) the toxicity of the aggregated PrPSc [79], and (ii) the loss of the biological activity of PrPc after it is transformed into the PrPSc isoform [80]. The nonpathogenic PrPC has a flexible N- terminal region (residues 23–120) and a conserved globular C-terminal domain (residues 121–231) (Fig. 3A). The N-terminal region of the human PrPC comprises four PHGGGWGQ octarepeats (residues 60–91), which are flanked by two positively-charged clusters (residues 23–27 and 95–110). Histidine imidazoles in the octarepeat regions (His61, His69, His77, and His85) as well as His96 and His111 are potential metal-binding sites [81]. PrPC is a copper-binding protein [82] but it also binds other metals ions, such as Zn2+ , Fe2+ , and Mn2+ [83], although copper binding is thermodynamically preferred over other metal ions [52,84] and it has a more pronounced biological effect, where it stimulates the endocytosis of PrPC [85,86]. PrPC appears to have two basic functions: (i) the transport of Cu2+ and Zn2+ [87], and (ii) an antioxidant (superoxide dismutase-like) activity [88,89], although the latter function is still under debate [90,91]. At physiological pH, the soluble PrPC can bind 1–4 Cu2+ ions in vivo [89]. The primary binding sites for copper are the octarepeat regions, which promotes structuring of the otherwise unstructured N-terminal region [92] Each of the four octarepeats (PHGGGWGQ) can bind one copper ion, which means that up to four copper ions can bind to the overall octarepeat region. The fifth and possibly the sixth Cu2+ ions can bind to two other histidines outside the repeat region, i.e., His96 and His111 [81]. It is still under debate whether only one copper ion can bind to the two His residues in a multiHis mode [93], or if His96 and His111 are two independent binding sites [94]. Regardless of the coordination mode, the binding of Cu2+ to this region plays a role in the structural rearrangements that lead to the formation of the pathogenic isoform. In the octarepeat region, the His imidazoles are the primary copper-binding sites. There are two possible binding scenarios. First, if the pH is slightly lower than physiological pH and the Cu2+ to PrPC ratio is equimolar, the metal ion binds to four His imidazoles [95]. Second, at physiological pH and higher Cu2+ concentrations, the main chain amide nitrogens begin to participate in the coordination by forming square-planar copper complexes with a {Nim , 2 N− , CO} donor set (Fig. 3B) [96,97]. There are different thermodynamic parameters for the Cu2+ – prion or Cu2+ – prion fragment complexes with Kd values that range from micromolar to nanomolar [98–100] or even femtomolar levels [101], depending on the protein fragment used, the technique employed, and the experimental conditions (for an explanation of the specific differences, please consult recent reviews [25,102]). As mentioned earlier, PrPC can coordinate with other divalent metal ions. It binds Zn2+ [83,103] with a lower affinity than Cu2+ [104], but this event is still biologically relevant because the physiological concentration of zinc in the brain is significantly higher than that of copper. At low Cu2+ concentrations, Zn2+ can occupy the octarepeat region coordination sites and when the amount of copper increases, Cu2+ binds outside the octarepeat region to His111 and His96. At physiological pH, Zn2+ binds to the protein via three or four nitrogens from His imidazole side-chains [105] and saturation is achieved only after one Zn2+ equivalent is bound [106].

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The binding of Mn2+ to PrP increases the ␤-sheet content of PrPC , thereby leading to fibril formation [104], and the pathogenic PrPSc form was isolated from the brains of mice with scrapie or patients with CJD where manganese was coordinated with PrPSc [107,108]. The levels of Mn2+ have been found to increase approximately 10-fold in the brain tissues of sCJD patients [108]. The main Mn2+ binding site is located outside the octarepeat region, at His111 and His96 [109]. The biological effect of metal coordination with PrP is still under debate, but it is usually accepted that a neurotoxic species is generated if more than four copper ions are bound. After the fifth Cu2+ binds to PrPC , the protein undergoes a conformational transition into a highly protease-resistant, neurotoxic conformer with a high ␤-sheet content [110]. Cu2+ can also bind to previously formed prion fibrils, thereby increasing protection against proteolytic degradation [111]. However, the binding of copper to the unstructured N-terminus can also prevent the establishment of the ␤-sheet core of the amyloid, which can contribute to the nonamyloid aggregation pathway [112]. Similar to Cu2+ , Zn2+ can also inhibit the fibrillization of PrPC by bridging prion molecules and producing neurotoxic aggregates [103,111]. 5. Recommended traditional therapies To provide a comprehensive overview of these diseases, it is necessary to understand the current state of knowledge at the molecular level, the impact of metal ion binding on the pathogenesis of the diseases, and details of clinical trials and future potential therapies, while it is also important to know how these disorders are currently treated in the clinic. The next three sections (one for each disease) review the recommended traditional therapies. The next section discusses the biggest obstacle to the application of any brain-directed medication, the BBB, and the following section describes progress in metal-based treatment. Drugs that possess at least two active groups are a specific focus, i.e., one that is already used in the clinic that permits blood brain permeability and another that involves a metal-chelating agent. Before this discussion, some fundamental details of the standard clinical treatments are provided in the current section. We should note that if our discussion sounds too optimistic and gives an overall impression that neurodegenerative diseases will soon be overcome by chelating metal ions and designing multifunctional drugs, this is not the authors’ intention. The following is a substantive descriptive overview of the commercially available established strategies for treatment, including information about drugs that have been or are currently in clinical trials and detailed knowledge of the metal-chelating drugs that are currently in development. 5.1. Parkinson’s disease As stated earlier, the main pathological factors involved in PD are: (i) aS aggregates in Lewy bodies; (ii) abnormal metal ion concentrations; (iii) an increased concentration of iron in the substantia nigra and simultaneous decrease in the amount of ferritin, which results in the production of ROS; and (iv) MAO overactivity, which catalyzes the breakdown of dopamine [113]. The level of striatal dopamine declines to about 10% of the normal level. This leads to a cascade of events, such as the hyperpolarization of postsynaptic D2 receptors, inhibition of Ca2+ channels, inhibition of adenylate cyclase, and dopamine-acetylcholine imbalance. The drugs that are currently used to treat PD do not stop disease progression and they only treat the motor symptoms [114]. The man aim of the non-metal-related drugs is to increase dopamine-mediated postsynaptic inhibition by enhancing the D2 receptor activity. This can be achieved in three different ways: (i)

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Fig. 3. (A) Schematic diagram showing the prion protein sequence. Residues involved in Cu2+ binding are highlighted in red. (B) Representation of the coordination of Cu2+ with the so-called octarepeat region of the prion protein at low pH (left) and high pH (right).

by producing more dopamine from the drug levodopa (l-DOPA), a precursor of DOPA, which, unlike dopamine, can cross the BBB; (ii) by stimulating D2 receptors (subtypes of dopamine receptors) directly with synthetic selective agonists (e.g., bromocriptine, a D2 agonist); or (iii) by preventing dopamine or l-DOPA from being metabolized by catechol-O-methyltransferase (COMT) or MAO using COMT inhibitors (tolcapone or entacapone) and MAO inhibitors (rasagiline or selegiline) [115]. l-DOPA (Bendopa® , Dopar® , or Larodopa® ) is the most common drug prescribed to treat neurodegenerative diseases. It drastically increases the dopaminergic activity in substantia nigra neurons. l-DOPA is converted into dopamine by aromatic amino acid decarboxylase (AAAD), which is also known as DOPA decarboxylase. It improves the symptoms of the disease, such as bradykinesia, rigidity, and depression, but it does not cure the disease itself. l-DOPA has numerous side effects, such as nausea, tachycardia (because of the conversion of dopamine to norepinephrine in the periphery), dyskinesia, or anxiety. A drug with a chemical structure that resembles l-DOPA, carbidopa, helps to overcome the side effects of levodopa. Carbidopa (Lodosyn® when pure, or Atamet® , Parcopa® , and Sinemet® when combined with l-DOPA) inhibits the conversion of l-DOPA into dopamine by l-AAAD (DOPA decarboxylase) peripherally (outside the brain). Like dopamine, carbidopa cannot cross the BBB. Thus, more l-DOPA is able to enter the brain and less of it is converted into dopamine outside the brain, which causes the aforementioned side effects. Another strategy that aims to prevent the metabolism of l-DOPA outside the brain (i.e., to inhibit the enzymes that degrade it) is the use of COMT Inhibitors, i.e., tolcapone (Tasmar® with numerous side effects, including a risk of fatal liver damage) and entacapone (either alone in Comtan® or in combination with levodopa and

carbidopa in Stalevo® ). Both drugs increase the half-life of l-DOPA by approximately 1 h. MAO Inhibitors such as selegiline/deprenyl (Eldepryl® ) and rasagiline (Azilect® ) preserve the previously formed dopamine, and this class of drugs inhibits the metabolic inactivation of dopamine by MAO type B in the substantia nigra and striatum. Dopamine D2 receptors can be stimulated directly without the presence of dopamine using dopamine D2 receptor agonists. Commercial examples include bromocriptine (Parlodel® ), which is used as an adjunct with l-DOPA (this is particularly helpful in the socalled “ON-OFF” syndrome, where patients experience the return of symptoms after the usually sufficient doses of l-DOPA are no longer effective after several years of l-DOPA therapy) or pergolide (Permax® ), where the latter was withdrawn from several markets after being associated with cardiac issues. Anticholinergics are another group of drugs, which aim to restore the balance between the activities of dopamine and acetylcholine in the brain by reducing the overactivity of acetylcholine. Anticholinergics that are available on the market include Benzhexol® , Orphenadrine® , Procyclidine® , and Benztropine® . The antimuscarinic drug amantadine (Symmetrel® ) is an antiviral drug, which was previously used to prevent Asian influenza. Its pharmacological effect is complex and not fully understood, although it increases the release of dopamine in the brain and antagonizes some of the effects of glutamine by blocking the glutamate receptor [116]. Additional treatments that aim to decrease oxidative stress include high doses of vitamin E. 5.2. Alzheimer’s disease Several drugs are available that aim to improve cognition in AD. Acetylcholine esterase inhibitors increase the levels of

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Fig. 4. Recommended traditional therapies for: (A) Parkinson’s disease and (B) Alzheimer’s disease.

acetlycholine in the areas of the brain that are important for memory. Tacrine (Cognex® ) was one of the first acetylcholine esterase inhibitors to be prescribed but it is used rarely at present because of its numerous side effects (nausea and diarrhea) and the fact that it is not selective for the central nervous system (CNS) and has a high risk of hepatotoxicity. The more commonly prescribed drugs are donepezil (Aricept® ), rivastigmine (Excelon® ), and galantamine (Razadyne® ), all of which cross the BBB and they are more selective inhibitors of acetylcholinesterase in the brain. They also cause fewer side effects. According to the Alzheimer’s Association, cholinesterase inhibitors can delay the worsening of symptoms by 6–12 months on average in about half of the people who take them [117]. The second class of commonly used drugs comprises N-methyld-aspartate receptor or glutamate receptor blockers. The FDA approved drug memantine (Namenda® ) regulates the activity of glutamate, thereby delaying the worsening of cognitive symptoms. Its common side effects are headache, constipation, and dizziness. High doses of the antioxidant vitamin E are also helpful for treating cognitive symptoms of AD. In some cases, second generation antipsychotics (risperidone or olanzapine) have been used to calm aggression and psychosis in the later stages of the disease (Fig. 4).

The BBB includes anatomical, physicochemical, and biochemical mechanisms that control the exchange of molecules between the blood and brain [118]. These mechanisms make the BBB virtually impermeable to drugs developed for the treatment of neurodegenerative diseases. In this section, we provide insights into how potent this barrier can be. The BBB is localized at the interface between the blood and the cerebral tissue, where it is formed by the endothelial cells of cerebral blood vessels, which exhibit a unique phenotype that is characterized by the presence of intercellular tight junctions (TJs), adherens junctions (AJs), and the polarized expression of numerous transport systems [119]. The functions of the BBB mainly comprise: (i) maintenance of CNS homeostasis, (ii) protecting the brain from the extracellular environment, and (iii) ensuring a constant supply of nutrients via specific transport systems. The permeability of the BBB is controlled by the biochemical properties of brain microvascular endothelial cells, but specific interactions between endothelial cells and the basement membrane, as well as neighboring perivascular pericytes, glial cells, and neurons, also play roles in the characteristics of the BBB. Overall, they constitute the neurovascular unit (Fig. 5) [120]. This concept was proposed to highlight the functional interactions that control the integrity of the BBB [121].

5.3. Prion disease The brevity of this section makes it obvious that no drugs can cure or relieve the symptoms of prion disease. The rarity of this disease (one person per million) means that developing drugs and conducting clinical trials is even more complicated than that for other neurodegenerative diseases. However, some metal-related therapies have been investigated, which we discuss in the next section. 6. Blood–brain barrier: the major obstacle In recent decades, significant progress has been made in understanding the molecular basis of neurodegeneration, particularly the target proteins and the metals that should be chelated. However, the BBB remains the biggest obstacle to exploiting this knowledge and developing drugs to treat diseases of the CNS.

Fig. 5. Schematic representation of a neurovascular unit.

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The TJs between brain endothelial cells are composed of three major transmembrane proteins (or protein families), i.e., occludin, claudins, and junction-associated molecules, as well as several cytoplasmic proteins including zonula occludens (ZO)-1, ZO-2, and ZO-3, which interact with these transmembrane proteins in multiprotein complexes that are linked to the actin cytoskeleton. AJs are composed of cadherins and catenins, and they are localized below the TJs. In the basal region of the lateral plasma membrane, the AJs are replaced by a continuous belt called the adhesion belt [122]. AJs mediate events such as the adhesion between brain endothelial cells, contact inhibition during vascular growth and remodeling, the initiation of cell polarity, and the regulation of paracellular permeability, as well as contributing to the barrier function [123]. Cell–cell adhesion via the linking of actin filaments involves VEcadherin and catenins, which are the components of AJs [124]. The cadherin family and their intracellular-associated catenin proteins form complexes, which have central roles in the sorting and morphogenetic processes in developing animal tissues, and they maintain the integrity and identity of adult tissues [125]. The presence of TJs means that the permeability of the BBB to blood-borne solutes depends largely on their molecular weight and lipophilic/hydrophilic characteristics. Amino acids are transported actively through the brain endothelium by a large family of solute carrier transporters. In addition, proteins can cross the BBB in an efficient manner via receptor-mediated transport, (e.g., transferrin, insulin, insulin-like growth factor, leptin, and low-density lipoproteins) [118]. By contrast, ATP-binding cassette (ABC) efflux transporters, such as P-glycoprotein (P-gp, ABCB1/multidrug resistance (MDR1)) and breast cancer resistance protein (BCRP) (ABCG2), restrict the entry of many compounds into the brain, including many commercial drugs. P-gp is present in the luminal membrane of the endothelial cells (Fig. 6) [126] and BCRP has been immunolocalized to the luminal membrane of microvessel endothelial cells. However, it has been proposed that the presence of P-gp in the BBB is responsible for the inability of most, if not all, hydrophobic, membrane-permeable drugs to pass through the BBB [127]. Overexpression of P-gp has been linked to MDR in mammalian cell lines and human cancers. This protein is a promiscuous transporter that can interact with natural and structurally diverse modulators, which are generally nonpolar and weakly amphipathic compounds. However, in the blood–brain and blood–tissue barriers, the probable role of P-gp is to protect these organs from toxic compounds that might enter the circulatory system. These characteristics of the BBB demand the development of novel strategies to overcome this barrier and to deliver drugs inside the brain. Thus, neurosurgical techniques have been used to access the CNS. However, the use of these techniques is hazardous, expensive, and of limited value in the administration of therapeutics drugs that are directed at nonlocalized diseases such as AD or PD. Numerous drug delivery strategies have been proposed as alternatives to invasive neurosurgical techniques, including the use of nanoparticle-based drugs. Nanoparticles have been proposed as vectors that can interact with brain endothelial cells and deliver other molecules such as nucleic acids or proteins inside the brain, but without interfering with its normal function [128]. Different types of nanoparticles have been synthesized to achieve this goal, particularly polymeric nanoparticles with interesting characteristics in terms of their biocompatibility, biodegradability, and functionalization. It has been proposed that polymeric nanoparticles can cross the BBB (e.g., fluorescein-labeled poly(nbutylcyano-acrylate)) [121]. However, there are some concerns about the biodegradation of these materials. Poly(butyl cyanoacrylate)s are prone to hydrolysis and their degradation lead to the formation of water-soluble polycyanoacrylic acid and alcohol, which causes toxicity [129,130]. However, compared with

polymeric nanoparticles, solid lipid nanoparticles have lower cytotoxicity and higher drug-loading capacities, although their use may be limited by their low hydrophilic drug-loading, thereby limiting their use to carriers for hydrophobic drugs, proteins, or peptides. In addition, an in vivo study showed that a solid–lipid nanoparticle system was preferentially targeted at the liver followed by the brain [131]. One of the major constraints on the use of nanoparticles as delivery systems is their rapid clearance from the blood circulation, where most colloidal drug carriers are removed rapidly from the bloodstream after vascular administration and they accumulate in the liver and/or spleen [128]. This could be due to their size and low capacity for crossing plasma membranes, so they remain in the bloodstream. Other methods for delivering drugs into the brain include disruption of the BBB, where intra-arterial mannitol application is a classical method [132]. Mannitol is capable of opening the BBB by temporarily shrinking the endothelial cells and simultaneously distending the TJs. However, this method is not without complications, such as seizures after BBB disruption. Furthermore, the permeability effect of intra-arterial mannitol is largely reversed within minutes [133]. Bradykinin can also be used for BBB disruption, where the intracarotid infusion of bradykinin selectively increases the permeability of brain tumor capillaries by twofold to 12-fold, thereby allowing the transport of molecules with masses ranging from 100 to 70,000 daltons across the BBB. However, bradykinin does not increase the permeability of the normal BBB, except at extremely high doses [134]. In another approach, Choi et al. proposed the use of short ultrasonic pulses and microbubbles to facilitate localized neuronal delivery by disrupting the BBB [135]. Focused ultrasound-induced BBB disruption has been used to successfully deliver large molecular agents such as 70-kDa dextrans and herceptin in murine models [136]. This method is noninvasive (delivered to the brain through the intact skull). Nevertheless, transcranial ultrasound propagation, while maintaining a tight focus and a safety level, remains a challenge. This technique also has concerns about the dose and the distribution of the agents that are delivered. Furthermore, it can cause erythrocyte extravasation and neuronal damage. Intranasal administration has been used to deliver peptides, metals, viruses, plasmid, siRNAs, and bacterial phages into the brain directly, and this has been proposed as a technique for overcoming the BBB. Following intranasal administration, substances can access the brain via olfactory, trigeminal, vascular, or cervical node routes [137]. Intranasal drugs may prevent living neurons from undergoing further damage in ischemic stroke and AD. In addition, intranasal delivery may provide an alternative strategy for stem cell-based therapy [138]. Stem cells have been shown to have a great potential for the treatment of many neurological disorders such as AD. During AD, there is a progressive loss of neurons and it has been shown that stem cells retain their ability to differentiate into neurons [139] so they could potentially be used to restore the neuronal loss. Further studies are still required to identify the side effects of the intranasal delivery of stem cells, such as tumors, which are a potential risk in all stem cell-based therapies [138]. Intranasal administration could be a viable method for treating BBB disorders, but the route taken by drugs from the nose to the brain is not well understood. Furthermore, it should be remembered that the quantities of drugs that have been reported to access the brain are very low. Thus, greater efforts should be made to enhance the nose-brain transport process by formulating appropriate drugs. There are many routes for drug delivery to the brain, but only drug delivery via the vascular route will allow the widespread diffusion of the infused drug throughout the whole brain due to the large surface area of the human BBB [140]. Indeed, almost every neuron has its own brain capillary that supplies oxygen and nutrient [141]. Thus, passive diffusion can facilitate brain drug delivery

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Fig. 6. Expression of the ABC transporters P-gp and BCRP in the endothelial cells of the blood–brain barrier.

systems that fully respect and maintain the BBB integrity. However, the design and production of drugs with an enhanced capacity for entering the brain should be considered. It should be noted that large macromolecules (e.g., proteins, viruses, lipoprotein particles, nanoparticules, and antibodies) require more complex mechanisms to traverse membranes because they are selectively transported in and out of cells via endocytosis and exocytosis (secretion). Passive diffusion allows small and lipophilic molecules, including most drugs, to enter and exit cells easily, which could be a good and simple strategy. The majority of drugs are known to pass through the membrane by passive diffusion. Membranes are not impenetrable walls, thus membrane permeability is also a key determinant of the effectiveness of drug absorption, distribution, and elimination. The rate at which a molecule diffuses across a membrane depends on its size and its degree of hydrophobicity. In addition to the hydrophobicity, the pH of body compartments (or cellular compartments) influences the lipid diffusion of drugs. The ability of drugs to diffuse across membranes is influenced greatly by the ionizability of the drug in the surrounding medium. The fraction of the drug that is uncharged or positively charged (with delocalized charge) can diffuse across membranes. A plasma membrane potential of −50 to −70 mV (interior vs exterior) is characteristic of mammalians cells. Thus, the use of small metal-related drugs or molecules that are capable of chelating metals in the brain may be promising and interesting strategies for the treatment of CNS diseases, which should be encouraged. 7. Possible metal-related therapeutics The underlying concept of using metal chelators as therapeutics for neurodegenerative diseases is quite simple, because it assumes that metal ions are the main causes of pathogenic protein deposits and abnormal oxidative stress. Therefore, if metal homeostasis is preserved, or if there is not an excess of metal ions in the brain, the pathogenic protein forms would not be present. Moreover, small and lipophilic metal-chelating molecules can be designed, which have an increased likelihood of crossing the BBB. The subject of targeted metal chelation is not a new topic in medicine because iron chelators have been used to treat metal poisoning, such as iron overload in beta thalassemia and copper overload in Wilson’s disease. At this point, we must reiterate that the problem of metal ions in neurodegeneration is not simply a bulk overload of metals, as in the two aforementioned diseases. Instead, it is an imbalance where the distribution of metal ions is not correct, which is why the aim of metal-chelating drugs used to combat neurodegeneration is to re-distribute and re-equilibrate metal ions, rather than removing and chelating them. The ideal metal chelator for application to neurodegenerative diseases should have an appropriate affinity and high specificity for the targeted metal (to prevent the complete removal of metal ions from the brain or other organs), a low molecular weight,

and adequate lipophilicity in order to cross membranes and be transported across the BBB, while it should not be toxic. Obviously, this task is nontrivial, which is why research in this area is the objective of numerous collaborative research groups that include organic and coordination chemists, neurobiologists, and medical doctors. Potential drugs for neurodegenerative diseases are often derived from families of drugs that have already been applied or tested in different diseases. These disorders are quite complex so simple drugs that interact with single targets are usually insufficient, thus the ideal treatment merges multiple functions into a single molecule to affect multiple targets in the neuropathology [142–146]. For details of how to combine several functions in one molecule, see a recent review by Orvig et al. [4]. A major function of appropriate novel therapeutics must be metal ion chelation. Considerable research has been devoted to the impact of metal ion coordination on protein aggregation, or the oxidative stress that accompanies neurodegenerative processes [52,147–150]. Before we take a closer look at the typical metal chelators with potential applications in the restoration of metal ion homeostasis in neurodegenerative brains, we provide a simple summary of the metal ions we are actually targeting. In PD, it is mostly iron, whereas imbalances in copper and zinc are the major problem in AD and prion diseases. First, we must stress that this is a generalization and metal homeostasis should be considered as an integral phenomenon. Second, it is often not the participation of a single type of metal ion that causes the aggregation of pathogenic proteins in the brain. Therefore, there is often an overlap in the chelators used in potential treatments for these three neurodegenerative diseases. Some chelators are not selective for a single metal ion (e.g., clioquinol is used in both AD and PD because it chelates zinc, copper, and iron), which can be an advantage if the homeostasis of more than one metal ions is not regulated correctly.

7.1. Parkinson’s disease As mentioned earlier, the design of a potential therapeutic for a neurodegenerative disease must address elevated metal ion levels in the brain, a protein aggregate, and reduced levels of a neurotransmitter, which are the three molecular characteristics of AD. In PD, elevated levels of iron and an aS aggregate, and decreased levels of dopamine, are the molecular causes of this disease. The study of metal chelators for PD is particularly difficult in animal models because of the obvious fact that animals do not suffer from this disease. The pathogenic condition can be mimicked artificially via chemical induction by injecting 6-hydroxydopamine (6-OHDA) directly into the brain or the administration of N-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [151,152]. 6-OHDA is chemically related to dopamine (it has one additional hydroxyl group) and is toxic to the dopamine system, where it causes oxidative stress via iron release from ferritin, thereby leading to neuronal death [153]. The administration of MPTP also increases

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Fig. 7. Common metal-binding compounds with FDA approval.

the concentration of free iron in the substantia nigra and its conversion product, MPP+ , is toxic to dopaminergic neurons [154]. The two models of PD are only simulations of the disease and they do not include important factors such as the formation of protein deposits, but they are adequate for testing possible therapeutics, especially those that aim to overcome metal-induced oxidative stress. A reasonable (from both chemical and economic viewpoints) approach for finding appropriate iron chelators that are suitable for application in PD is to those use that have already been applied to other diseases and functionalizing them by incorporating different groups to increase their BBB permeability and/or including other therapeutic groups to make the drug multitargeted. One of the best-known commercial iron chelators that is used in medicine is deferrioxamine (DFO, Desferal® ), a microbial siderophore with the structure of a trihydroxamic acid (Fig. 7), which binds Fe(III) with a high affinity [155]. This is the most common drug for treating the problem of iron overload in thalassemia major. A study that tested this drug in animal models of PD after injecting an appropriate amount of 6-OHDA into the rat brain detected the rescue of 60% of neuronal cells compared with the control without DFO, and this neuroprotective action was attributed to the iron-chelating properties of DFO [156]. However, the major drawback of this molecule is that it crosses the BBB only poorly. Deferiprone (DFP, Ferriprox® , Fig. 7) is a drug that is more likely to cross the BBB because of its low molecular weight and lipophilicity [157,158], but it has a lower affinity for iron than DFO. DFP is used to treat iron overload (e.g., thalassemia major or after blood transfusions) in Europe and Asia, and it was recently approved by the FDA in the USA [159]. It is feasible to functionalize DFP with different N-substituents because these changes would not have significant effects on the metal-binding properties of the drug [160]. Esterification of the 3-hydroxyl group was also shown to be beneficial [161]. In previous studies, however, no substituted molecules have yet reached clinical trials, although several are quite promising and they have been designed rationally. The functionalizing substituents are moieties that enhance antioxidant properties, such as butylated hydroxytoluene, or those that enhance transport through BBB, such as glucose (glycosylation is an efficient means of improving drug uptake by the brain) [162], amino acids and peptides (to modulate lipophilicity and enhance BBB permeability) [163], and nanoparticles [164]. Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline, CQ, or PBT1, Fig. 8) is the best known of the metal chelators used to treat neurodegenerative diseases. CQ is the only drug to have reached the clinical pilot phase II for AD. Animal studies have also shown that it is useful in PD (which is why it is mentioned at this point)

Fig. 8. Clioquinol and its possible modifications.

and Huntington’s disease. CQ is a small, lipophilic, and bioavailable metal chelator that crosses the BBB in an efficient manner [165]. Initially, it was developed by Ciba-Geigy and approved by the FDA as an antibiotic with a wide spectrum of action to treat intestinal diseases. CQ was withdrawn from the market in 1970 after it was associated with subacute myelo-opticoneuropathy (where the initial symptoms are disturbances in the legs and sight) in Japan [166]. The mechanism that underlies this toxicity is not well understood, but it is likely that it decreases the bioavailability of cobalamin (vitamin B12), thereby resulting in a deficiency state and a syndrome similar to subacute combined degeneration [167]. Several years later, the affinity of CQ for metal ions, its low molecular mass, and lipophilicity attracted the attention of scientists who reconsidered the application of this drug as a chelating agent for neurodegenerative diseases. Its high affinity for Cu2+ and Zn2+ means that CQ is being considered as a therapeutic for AD (as discussed later). Its affinity for iron is moderate but it seems to be adequate. A study using mice, where their brains were induced with MPTP to mimic the conditions of PD, detected significant reductions in neuron damage [168]. Prana Biotechnology developed two other drugs that are closely related to CQ, i.e., 8-hydroxyquinoline (8HQ, i.e., without the I and Cl substituents) and PBT2 (unpublished structure, but most probably Cl instead of the I substituent plus a dimethylaminomethyl group). CQ was in a pilot phase II AD clinical study, but the study was abandoned because of synthetic problems (it contained certain mutagenic di-iodo impurities that could not be reduced to an acceptable level) [169,170]. The exact mechanisms of action of CQ and PBT2 are still not fully understood and further studies are necessary to evaluate their safety and effectiveness. At present, PBT2 is undergoing clinical trials for AD and Huntington’s disease [171]. Numerous chemical modifications have been made to CQ, 8HQ, and PBT2 in order to functionalize them with other therapeutic groups or to increase their BBB permeability. Examples of these modifications include the attachment of MAO inhibitors (VK-28, M30, and HLA20, Fig. 8) [172], ROS-triggered agents (neuropeptide NAP (NAPVSIPQ) to inhibit lipid peroxidation), or other potent chelators (for a detailed review, see Ref. [4]). Again, we must stress that the metal chelators are employed to facilitate the correct redistribution of metals in cells rather than their complete elimination. For a recent review of this topic based on the examples of CuII (gtsm), CQ, and PBT2, please refer to [173]. Oxidative stress cannot be overlooked when discussing PD. An imbalance in ROS causes oxidative stress, which damages DNA and proteins, as well as lipid peroxidation. Numerous antioxidant compounds have been tested in PD, e.g., epigallocatechin (EGCG, a green tea flavonoid (Fig. 9), tangeretin and nobiletin (from

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Fig. 9. Antioxidant agents with metal-chelating properties.

tangerine peel extract), catechin (grape seed extract), naringenin (grapefruit extract), fisetin (from strawberries), myricetin, and curcumin (Fig. 9). In animal models, the ingestion of EGCG by mice was quite successful [174], and similar results were obtained with tangeretin, nobiletin, curcumin, naringenin, and fisetin [175]. However, catechin [174] and quercetin [175] had negligible neuroprotective effects in similar studies. Correlations were found between the consumption of black tea or coffee and the risk of PD, but it is still unclear whether the compound responsible is EGCG or caffeine [176]. From an economic perspective, the most positive feature of employing a natural flavonoid as a therapeutic compound is the lack of problems with clinical trials and FDA approval. Two other groups of compounds need to be mentioned when discussing potential PD therapeutics: stilbene derivatives and ferritin. Stilbene derivatives (several of are quite promising AD treatments) with a dimethylamino group have both metalchelating properties and MAO inhibitory effects [177]. Human ferritin, an endogenous human iron binder, was expressed in mice and it protected their brains from the toxicity of MPTP by reducing oxidative damage [169]. Chelation therapy has achieved promising results in the treatment of PD. However, much research is still required and many features need to be understood. For example, the animal models lack aS deposits and how does this affect the therapy? How can the BBB permeability of chelators be enhanced? How can chelators be directed into the brain without disrupting iron homeostasis in other parts of the body? Answering these questions requires cooperative research involving specialists from many fields, including coordination chemists. 7.2. Alzheimer’s disease AD is quite complex and it involves multiple pathogenic factors, thus its treatment should aim to target as many of the factors as possible, possibly by integrating many functions in a single drug molecule [178,179]. This ‘multitarget’ or ‘multifunctional’ approach can be achieved by: (i) functionalization of an existing drug with a specific substituent that confers greater specificity or that increases its BBB permeability: (ii) attachment of two molecules with well-established activities by a linker; or (iii) using a single molecule with multiple functions. These strategies have been reviewed recently [4]. The breakthrough that highlighted the central importance of metal chelators in AD pathology occurred at the end of the previous century, when it was reported that Ab aggregation was reversed in the presence of Cu2+ and Zn2+ chelators [180]. Common chelators such as EDTA (ethylenediaminetetraacetic acid), DTPA (diethylene triamine pentaacetic acid), EGTA (ethylene glycol tetraacetic acid),

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TPEN (N,N,N ,N -Tetrakis(2-pyridylmethyl)ethylenediamine), BAPTA (1,2-bis(o-aminophenoxy)ethane-N,N,N ,N -tetraacetic acid), bathocuproine, and bathophenanthroline were used to solubilize Ab deposits in postmortem brains [181], which provided major new insights into the molecular pathogenesis of AD. However, postmortem cells are obviously not the desired drug target while chelators as strong as EDTA and the others used in the study cited above cannot be used in live cells, even if they are injected into the brain directly, because they form metal complexes that are thermodynamically too stable and they are not specific for the target metals, so they might cause imbalanced metal homeostasis in brain cells. Nevertheless, the search for chelators that are appropriate for use in AD has been one of the major targets of bioinorganic chemistry. As a reminder of our oversimplification, the metals that need to be chelated in the case of AD are Cu2+ and Zn2+ , but the homeostasis of other metal ions is also important. Several well-known ligands with good coordination properties and clinical approval have been tested in AD, i.e., DFO and DFP, which are used in thalassemia major (also tested previously in PD), and trientine or d-penicillamine treatment for copper overload in Wilson’s disease (Fig. 7) [182]. However, good in vitro efficacy need not mean good in vivo efficacy. Thus, more BBBpermeable, sophisticated, and selective metal chelators that do not disrupt the homeostasis of other crucial metal ions are required for the treatment of AD. The most promising examples are discussed next. The best-known drug, CQ (discussed in the previous section), binds two metals in a square-planar geometry with moderate affinity [183,184]. The affinity is adequate to dissolve synthetic amyloid copper and zinc aggregates, as well as amyloid deposits from the brains of postmortem AD patients [48]. CQ exhibited no adverse effects in phase I clinical trials [185]. The pilot phase II clinical study was performed with 36 patients, where it resulted in decreased Ab plasma levels and increased free Zn2+ levels in the plasma. However, only the condition of patients with the most advanced symptoms improved [185]. Soon after this study, the clinical trial was stopped because of synthetic problems, as mentioned in the previous section. A close chemical relative of CQ, PBT2, is currently in phase II clinical trials and the results have been quite promising [186]. Its structure has not been published formally but, as we noted earlier, it is commonly believed that PBT2 contains a dimethylaminomethyl group instead of iodine with two chloro substituents around the two-ring system. PBT2 can sequester metal ions from Ab and inhibit metal-induced damage. However, its key feature is that it can transport Cu2+ and Zn2+ ions into the cell, which may help to regulate synaptic activity [187]. Motivated by the results of clinical trials, the 8HQ core of CQ has inspired various other chelators with potential applications in AD. Many modifications have been considered that might improve neuroprotection, BBB permeability, and brain uptake. Several neuropeptides with neuroprotective activities can be incorporated in the CQ scaffold, such as vasoactive intestinal peptide (a 28 amino acid neuroprotective polypeptide with neurotransmission functions in the brain), enkephalin, gonadotropinreleasing hormone, or NAP (an 8 amino acid neuroprotective peptide) [188]. Particularly promising results were obtained with PA1637, a bis8-aminoquinoline, which selectively chelates copper and that led to memory recovery in mice [189]. The idea of ROS-triggered metal-binding agents is particularly appealing. A prodrug with a CQ scaffold and a substituent that blocks the coordination site of the drug, which can only be activated by H2 O2 , would only allow the coordination of toxic metals at the exact site of the disease [190]. A good example of a prodrug

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Fig. 10. Metal chelators tested against prion disease.

masking group is a boronic ester, which could mask the phenolic oxygen of 8HQ, a crucial donor atom for CQ [190]. A rational approach to the design of an efficient AD therapeutic might be to combine the 8HQ scaffold with existing drugs that have acetylcholinesterase inhibitory properties, e.g., tacrine, donezepil, rivastigmine, and galantamine. Multifunctional tacrine–8HQ compounds were found to have promising in vitro cholinergic, antioxidant, copper-binding, and neuroprotective properties [191]. The ligand was “dimerized” to enhance the coordination properties of CQ, where a tetradentate ligand that linked the two 8HQ entities was synthesized (bis-8-hydroxyquinoline, bis-8HQ, Fig. 8) [192]. DFP is an oral, FDA-approved chelator that is used for the treatment of thalassemia major, which can cross the BBB, and it is a promising potential iron chelator in PD. It is also a moderate Cu2+ and Zn2+ chelator [193]. Based on these reasons, its molecular scaffold, 3-hydroxy-4-pyridinone, was used as a scaffold in the design of multifunctional potential therapeutics. Two types of additional modifications were introduced: a glycosylation that increased the brain uptake of the drug and N-derivatization with three different motifs from thioflavin-T, which is an Ab marker and a dye that is used to visualize amyloid in tissues [194]. The conjugation of CQ and DFO with nanoparticles was also considered as a possible strategy for increasing the BBB permeability [165,195]. 7.3. Prion disease Numerous compounds have been tested as potential anti-prion therapeutics. Many have shown promise in inhibiting prion aggregation in vitro [196,197] and in vivo propagation during the early development of the disease [198,199], whereas they were ineffective immediately before or during the onset of the disease [200,201]. Over 10 years ago, several acridine and phenothiazine derivatives (many are common drugs used to treat malaria [202] or psychosis [203]) that can penetrate the BBB were tested on scrapieinfected neuroblastoma cells to determine whether they could inhibit pathogenic aggregation and/or enhance the clearance of PrPSc from cells [204]. The major problem with applying phenothiazines as potential drugs is their cytotoxicity. However, chlorpromazine and acepromazine have low toxicity and reasonable efficiency in dissolving PrPSc (Fig. 10). The strongest inhibitor of PrPSc formation was mepacrine (also known as quinacrine or under the trade name atabrine in the USA, Fig. 10), which is an antimalarial drug and a derivative of acridine. It was suggested to be the best candidate for an anti-prion compound. However, later clinical studies showed that a tolerable dose

of mepacrine was too low to have any effect on the formation or clearance of prion aggregates [205]. Other tolerable potential therapeutics with some cytoprotective activity include flupritine maleate (a triaminopyridine compound, which is still studied as a model) [206] and CQ and its numerous analogs (as discussed in previous sections). Like other neurodegenerative diseases, the main obstacle to the development of an effective therapeutic is the BBB. Compounds that might be effective in the absence of the BBB include polyanions [207] and sulfated polysaccharides [208] because both are capable of inhibiting the progression of spongiform encephalopathies in vitro. The harshest method for overcoming the BBB (literally) is to perform an intraventricular infusion directly into the brain. Pentosan polysulfate (PPS) is an effective polyanion with a heparin-like structure and it was tested on prion-infected animals by injection into their cerebral ventricles. The outcome of the study was quite promising because inhibition of PrPSc formation was demonstrated [209]. Several years later, the first clinical study was performed in humans by Walker et al., which showed that PPS was well tolerated and that it increased the mean survival of patients, although complications are quite frequent with intraventricular infusions into the brain [210]. However, a similar study by Yamada et al. suggested no or very little improvement after intraventricular infusions and that a long-term treatment might be more beneficial [211]. We are not fully convinced that PPS is effective, but both studies showed that direct brain injections might be a feasible drug delivery option. 8. Concluding remarks At present, it is well known that neurodegenerarative diseases are major medical and social problems and predictions of their future frequency are not optimistic. In this review, we provided basic information about three neurodegenerative disorders: Parkinson’s, Alzheimer’s, and prion diseases. We focused on the molecular basics and the involvement of metal ions in each disease, with particular considerations of the common drugs that are currently prescribed in clinics and potential metal chelators and their efficacy in overcoming neurodegeneration. The picture that emerges from this discussion is not remotely optimistic because no effective drugs are available to cure or stop the progression of these diseases. However, our level of understanding of the biochemical triggers of the pathogenic states has improved greatly in recent decades. These neurodegenerative diseases are clinically different but they share some common molecular characteristics, such as the pathogenic folding of a given protein and the dyshomeostasis of certain metal ions. Thus, there is a niche for bioinorganic chemists to explain the link between abnormal protein folding and metal imbalances and, more importantly, to design a rational metal chelator that could be part of a multifunctional drug to combat neurodegeneration. This might sound simple but this goal will probably require collaborative research by numerous groups for many decades. Acknowledgments M. Rowinska-Zyrek was supported by a scholarship from the Foundation For Polish Science. References [1] A. Gaeta, R.C. Hide, Br. J Pharmacol. 146 (2005) 1041. [2] J.H. Viles, Coord. Chem. Rev. 256 (2012) 2271. [3] I. Zawisza, M. Rozga, W. Bal, Coord. Chem. Rev. 256 (2012) 2297.

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