Neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are characterized by deposits of amyloid proteins. The homeostasis of metal ions is crucial for the normal biological functions in the brain. However, in AD and PD, the imbalance of metal ions leads to formation of amyloid deposits. In the past four decades, there has been extensive effort to design compound agents than can chelate metal ions with the aim of preventing the formation of the amyloid deposits. Unfortunately, the compounds to date that were designed were not successful candidates to be used in clinical trials. Neuropeptides are small molecules that are produced and released by neurons. It has been shown that neuropeptides have neuroprotective effects in the brain and reduce the formation of amyloid deposits. This Review Article is focused on the function of neuropeptides as metal chelators. Experimental and computational studies demonstrated that neuropeptides could bind metal ions, such as Cu2+ and Zn2+. This Review Article provides perspectives and initiates future studies to investigate the role of neuropeptides as metal chelators in neurodegenerative diseases.
The pathological self-assembly (or aggregation) of amyloid proteins into toxic aggregate species plays an important role in neurodegenerative diseases, e.g., Alzheimer’s disease (AD) and Parkinson’s disease (PD). Metal dyshomeostasis is well-recognized as a crucial factor in neurodegenerative diseases. (1−3) The metals that play a role in the etiology of these diseases include divalent transition metals, such as Fe2+, Cu2+, and Zn2+ ions. One of the hypotheses that has been proposed is that there are interactions between metal ions and amyloid, such as Aβ in AD and α-synuclein in PD. (4,5) On the basis of this hypothesis, disruption of metal–amyloid interactions by metal chelation therapy has been proposed in order to reduce the neurotoxicity of metal–amyloid species and with the aim to restore metal homeostasis in the brain. (6) However, in order to design metal chelators as potential drugs in the treatment of neurodegenerative diseases, the metal chelators must have appropriate characterizations. First, the chelators must have low molecular weight, uncharged molecules or have relatively poor charges to cross the blood–brain barrier (BBB) and be able to keep their stability. Second, metal chelators must selectively target specific metal ions. A nonselective metal chelation may cause a depletion of fundamental metal ions, including those of essential metalloenzymes. Third, the chelator molecule must be able to immediately complex the metal ions that are present in excess in the brain to reduce aggregation of amyloid proteins in the brain. Fourth, a successful metal chelator establishes a low toxicity and minimal side effects. The focus of this Review Article is to exhibit the neuropeptides that may serve as potential metal chelators. Section 2 briefly demonstrates various metal chelators that have been proposed and used in clinical studies. In addition, it describes the disadvantages and the fails of the currently used metal chelators. In Section 3, a brief overview on structural characterization and the role of neuropeptides are summarized. The qualifications of neuropeptides to successfully bind metal ions are detailed by experimental and computational studies in Section 4. The roles and the effects of neuropeptides as therapeutic agents in neurodegenerative diseases are elaborated in Section 5. Finally, future perspectives and future studies are discussed in Section 6.
Transition metal ions are essential nutrients and play a crucial role in various types of protein cofactors. The excess of these metal ions may be available for toxic reactivity. These redox-active metals may induce the formation of toxic hydroxyl radicals that oxidize proteins and consequently lead to cell death. The redox-active metals cause oxidative stress and protein misfolding in neurodegenerative diseases, such as AD and PD. To inhibit the redox-active metals, small molecule chelating agents were investigated as a promising strategy for treating neurodegenerative diseases. Herein, we provide a short list of small molecule chelating agents. Further detailed small compounds were extensively reported in the literature. (7) The first compound that was used for metal chelation therapy in AD patients was for iron chelation: desferrioxamine B (Figure 1a). (8) Later, other iron chelators were used, such as the lipophilic metal chelators DP-109 and DP-460 for AD and amyotrophic lateral sclerosis (ALS) mouse models. (9) The use of the desferrioxamine B improved significantly the cognitive decline of AD patients, but this compound established several drawbacks: (i) the charged and the hydrophilic properties of the compound prevented BBB crossing, (ii) the compound was easily degraded, and (iii) due to the relatively high affinity of the metal to the compound, the patients suffered from side effects, such as anemia. The other lipophilic metal chelators were not used in clinical trials, probably due to the clinical outcomes of the desferrioxamine B treatments. Thus, these compounds were removed from the pharmacologic market. The current Review Article focuses on Zn2+ and Cu2+ chelators since these metals are mostly common as cofactors that promote amyloid aggregation in neurodegenerative diseases. A further lipophilic metal chelator, XH1, is a compound that is based on a “pharmacophore conjugation” concept (Figure 1a). This molecule has a bifunctional activity: both amyloid binding affinity and Zn2+ chelating moieties. This was tested in mouse models. (10) Derivatives of saturated tetraamine, such as the bicyclam analogue JKL169, exhibited decreased Cu2+ levels in the brain cortex in rats (Figure 1a). (11) It was proposed that these compounds are capable of maintaining normal levels of Cu2+ in the blood, cerebrospinal fluid (CSF), and corpus callossum in rat, and thus, they may be candidates for AD treatments. (12) However, these compounds were not investigated in clinical trials. One of the strategies for developing chelating agents for neurodegenerative diseases is the “drug repositioning” or “drug repurposing”. (13) A list of such compounds is reviewed elsewhere. (7) The advantages of this strategy are the following: (i) there is a low investment in time and costs; (ii) the information on the pharmacokinetic, toxicology, and safety of these compounds already exists; and (iii) the compounds act via different mechanisms of action for AD treatments. (14) The next generation of the development of metal chelation therapy was based on the 8-hydroxyquinoline (8HQ) analogues, such as VK-28, HLA-20, and MA-30 that were tested for iron chelation by an in vitro study (Figure 1b). (15) One of the 8HQ analogues that was tested in a phase II clinical trial for AD and PD patients was the clioquinol (CQ) compound (Figure 1b). (16) The CQ is part of the chelating agent class that is called “metal protein attenuating compounds” (MPACs). This class has comprehensive and important advantages in metal chelation therapy: (i) the compounds are capable of easily crossing the BBB; (ii) they are soluble and, thus, are able to decrease amyloid oligomerization and dissolve the amyloid plaques; (iii) they have subtle effects on metal homeostasis; and (iv) they have properties of rescinding the oxidation and the toxicity of Aβ peptide mediated by metal ions. The second-generation compound of CQ (that is also known as PBT1) was a clioquinol-related compound, PBT2. This compound was shown to be a more promising drug than CQ. The PBT2 compound established a broad range of advantages: (17) (i) it has a higher solubility than CQ, and thus, it easily dissolves Aβ oligomers and prevents the production of oligomers; (ii) it increases BBB permeability; (iii) it enhances cognitive functions in transgenic mice; (iv) it has fewer side effects compared with CQ; and (v) it has an easier chemical synthesis. However, even though PBT2 established good safety use and tolerability for pati
