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Published as doi: 10.1096/fj.07-8627rev.
 (The FASEB Journal. 2008;22:1296-1305.)
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Targeting multiple Alzheimer’s disease etiologies with multimodal neuroprotective and neurorestorative iron chelators

Tamar Amit, Yael Avramovich-Tirosh, Moussa B. H. Youdim1 and Silvia Mandel

Eve Topf Center of Excellence for Neurodegenerative Diseases Research, Department of Pharmacology, Faculty of Medicine, Technion, Faculty of Medicine, Haifa, Israel

1Correspondence: Department of Pharmacology, Technion-Faculty of Medicine, P.O.B. 9697, 31096 Haifa, Israel. E-mail: youdim{at}tx.technion.ac.il


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 TARGETING APP PROTEIN GENERATION...
 TARGETING CELL-CYCLE...
 TREATMENT POTENTIAL
 REFERENCES
 
Dysregulation of brain iron homeostasis is central to early neuropathological events in Alzheimer’s disease (AD), including oxidative stress, inflammatory processes, amyloid deposition, tau phosphorylation, and neuronal cell cycle regulatory failure, leading to apoptosis. Also, there is a direct link between iron metabolism and AD pathogenesis, demonstrated by the presence of an iron-responsive element in the 5' UTR of the amyloid precursor protein transcript. As a consequence of these findings, a new paradigm is emerging that includes the development of iron-chelating neuroprotective-neurorescue drugs with multimodal functions, acting at various pathological brain targets. This concept is challenging the widely held assumption that "silver bullet" agents are superior to "dirty drugs" in drug therapy for neurodegenerative diseases. At best, the so-called magic bullets exhibit moderate symptomatic activity without modifying the course of disease progression. The present review elaborates on conventional and novel therapeutic targets of various multifunctional iron-chelating drugs (e.g., chemically designed compounds; natural polyphenols) that address multiple central nervous system etiologies in AD, aimed at preventing or slowing disease evolution. A similar approach in drug design is being investigated for treatment of cancer, AIDS, cardiovascular diseases, and depression.—Amit, T., Avramovich-Tirosh, Y., Youdim, M. B. H. Mandel, S. Targeting multiple Alzheimer’s disease etiologies with multimodal neuroprotective and neurorestorative iron chelators.


Key Words: cell cycle • neurodegenerative diseases • APP mRNA • multifunctional drugs


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
TARGETING APP PROTEIN GENERATION...
 TARGETING CELL-CYCLE...
 TREATMENT POTENTIAL
 REFERENCES
 
THERE IS INCREASING EVIDENCE THAT excessive iron accumulation in the brain occurs in many neurodegenerative diseases (1) . High levels of reactive iron can increase oxidative stress (OS) -induced neuronal vulnerability and might increase the toxicity of environmental or endogenous toxins. Indeed, iron accumulation and OS are early events in Alzheimer’s disease (AD), proximal to the development of hallmark pathologies, contributing significantly to the pathogenesis of the disease (1 2 3 4) . The emergence of redox-active metals as key players in AD pathogenesis has encouraged the development of metal-complexing agents as a promising therapeutic strategy for the treatment of the disease. A single-blind, 2-year clinical study with the prototype iron chelator desferrioxamine (DFO) showed that sustained intramuscular administration slowed the clinical progression of the dementia associated with AD (5) . Also, chelation therapy with ethylenediamine tetraacetic acid (EDTA) has been shown to induce improvement in patients with AD (6) . Another metal ligand, clioquinol (5-chloro-7-iodo-8-hydroxyquinoline), originally developed as an antibiotic, induced a significant reduction in plasma amyloid-beta (Aβ) peptide Aβ(1–42) and cognitive decline in AD patients (7) , while in transgenic mice, bearing the amyloid precursor protein (APP) Swedish mutation (Tg2576), clioquinol lowered brain Aβ burden and slowed the rate of cognitive decline (8) . However, clioquinol is highly toxic, while the hydrophilic nature of DFO and its large molecular size limit absorption across the gastrointestinal tract and prevent it from penetrating the blood-brain barrier (BBB) (9) .

To overcome these pharmaco-clinical limitations, we have recently designed and synthesized a series of multifunctional nontoxic, brain-permeable iron-chelating drugs, derived from the prototype iron chelator 8-hydroxyquinoline derivative VK28, hybridized to the neuroprotective, N-propargyl moiety of the anti-Parkinson drugs rasagiline (Azilect, Teva, Kansas City, MO, USA) and selegiline (deprenyl), for the treatment of various neurodegenerative disorders (10 , 11) . Among these novel compounds, M30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline; MW 299.3) and HLA-20 (5-[4-propargylpiperazin-1-ylmethyl]-8-hydroxyquinoline; MW 390.9) were the most effective drugs, exerting iron chelation potency, radical scavenging, and inhibition of iron-induced membrane lipid peroxidation features, close to those of DFO (Fig. 1 ) (10 11 12) . In addition, they exert higher binding selectivity for iron over copper (11) . Our recent studies have described a significant neuroprotective action of VK28 against 6-hydroxydopamine (6-OHDA) lesion in rats (13) and shown that M30 has neuroprotective activity against N-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice (12) . More recently, M30 and VK28 were found to prevent or rescue the loss of mice tyrosine hydroxylase-positive neurons induced by the proteasome inhibitor, lactacystin (injected pre- or postdrug, respectively) and to significantly attenuate inhibition of ubiquitin-proteasome activity, iron increase, and microglial activation in the ipsilateral substantia nigra (14) . Although both drugs exerted a similar potency in chelating brain iron, M30 displayed a consistent superiority in all monitored neuroprotection and neurorescue parameters, most likely because of the embedded propargyl moiety. In vitro, these compounds were demonstrated to possess a wide range of pharmacological activities, including neurorescue effects and regulatory action on the amyloidogenic Aβ peptide (15) .


Figure 1
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  		Figure 1. Chemical structures of the novel iron chelators M30, HLA20, and VK28.

Another innovative metal chelation and neuroprotective therapy approach could be the use of nontoxic, brain-permeable natural plant polyphenol flavonoids, reported to possess potent divalent metal-chelating, radical scavenging, anti-inflammatory, and neuroprotective activities (for extensive reviews, see Mandel et al., refs. 2 , 16 ). A cross-sectional analysis (Tsurugaya project) aimed at investigating the association between consumption of green tea and cognitive function in elderly Japanese subjects found that higher consumption of green tea is associated with lower prevalence of cognitive impairment in humans (17) . The results might partly explain the relatively lower prevalence of dementia, especially AD, in Japan rather than in Europe and North America (18) .

Significant evidence has demonstrated that the naturally occurring flavanol epigallocatechin gallate (EGCG), which is the major constituent of green tea extract, has well-characterized antioxidant and metal (iron and copper) chelating activities and has access to the brain (2 , 16 , 19) . In fact, comparison of the iron-chelating potency of EGCG to other iron-complexing agents has revealed similar binding potency to that of the prototype DFO and our newly developed iron chelators, VK28, M30, and HLA20 (19) . Our previous studies have shown that EGCG exerts neuroprotective activity in the MPTP mouse model (20) , prevents Aβ-induced neurotoxicity, and regulates the secretory processing of the nonamyloidogenic APP pathway (21) . In Alzheimer transgenic mice, EGCG induced a significant reduction in cerebral Aβ levels and β-amyloid plaques and promoted the generation of the soluble, nonamyloidogenic form of APP (sAPP{alpha}) through activation of {alpha}-secretase cleavage (22) .

Recent studies have suggested that in addition to its involvement in OS-induced neurodegeneration processes, iron may operate other targets central to AD pathogenesis, including: 1) induction of extraneuronal 39–43 amino acid protein, Aβ protofibril aggregation and fibrillization (23) ; 2) promotion of hyperphosphorylated paired helical filaments tau (PHF{tau}) aggregation, resulting in the formation of intraneuronal neurofibrillary tangles (NFTs) (24) ; 3) enhancement of endogenous Alzheimer’s APP translation and subsequent Aβ formation, via activation of an iron-responsive element (IRE-type II) in the 5' untranslated region (UTR) of APP mRNA (25) , and 4) activation of the iron-dependent hypoxia-inducible factor (HIF)-1 prolyl-4-hydroxylase enzyme, resulting in destabilization of HIF and concomitant decreased expression of various prosurvival genes (26 , 27) .

The present review will focus on the potential benefits of iron-binding compounds, possessing multimodal activity, in addressing the multiple iron-targeted pathogenic processes implicated in AD. In particular, we will present a novel neuroprotective target for iron chelators regarding the aberrant cell cycle reentry of postmitotic neurons in AD. Accordingly, similar to cancer drug therapy, a newly therapeutic strategy for neurodegenerative diseases is currently directed at interfering with mitogenic signaling and cell cycle progression to ameliorate cell death (28 29 30 31) . Because iron chelators have been shown to affect critical regulatory molecules involved in cell cycle arrest and proliferation (32) , a therapeutic intervention with these compounds is assumed to have a profound impact on neuron preservation and AD progression.


   TARGETING APP PROTEIN GENERATION AND Aβ AGGREGATION: ANTIAMYLOIDOGENIC EFFECTS OF METAL CHELATORS
TOP
 ABSTRACT
 INTRODUCTION
 TARGETING APP PROTEIN GENERATION...
TARGETING CELL-CYCLE...
 TREATMENT POTENTIAL
 REFERENCES
 
Neuronal amyloidoses in AD is characterized by extracellular deposition of Aβ peptide, derived from proteolytic cleavage of APP, a type I integral membrane protein. APP can be processed via alternative pathways; a nonamyloidogenic secretory pathway includes cleavage of APP to sAPP{alpha} by a putative {alpha} secretase within the sequence of Aβ peptide, thus precluding the formation of Aβ, whereas the formation of the amyloidogenic Aβ is regulated by the sequential action of β- and {gamma}-secretases. Both extracellular amyloid plaques and intracellular NFTs are central pathological hallmarks of AD (33) . It has been previously suggested that Aβ toxicity and aggregation involve transition metals, OS, and accumulation of reactive oxygen species (ROS) and these can be attenuated by a number of antioxidants and metal chelators (23 , 34) . In vitro studies have shown that both DFO and clioquinol prevented the formation of β-pleated sheets of Aβ(1–42) and effectively dissolved synthetic preformed or AD brain-derived Aβ (35) . In addition, green tea polyphenols, wine polyphenols (e.g., resveratrol, myricetin, quercetin, kaemferol), curcumin, nordihydroguaiaretic acid (NDGA), and rosmarinic acid have been demonstrated to inhibit formation and extension of β-fibrils from Aβ and to destabilize preformed fibrilized Aβ (36 , 37) .

Iron was also found to accumulate in neurons with NFTs (38 , 39) . In vitro, Fe3+ has the ability to bind with PHF{tau} and to induce its aggregation, leading to the formation of NFTs in AD. Thus, therapeutic agents designed to modulate iron bioavailability have the potential to ameliorate both Fe3+-induced amyloid plaques and NFTs formation in AD brains. In this respect, a novel trivalent cation chelator, feralax, was reported to dissociate the binding of Al3+ and iron associated with PHF{tau} in AD (24) .

An additional link between iron metabolism and AD pathogenesis was provided by Rogers et al. (25) , describing the presence of an IRE in the 5'UTR of APP mRNA (+51 to 94 from the 5'-cap site). The APP mRNA IRE is located immediately upstream of the interleukin-1 responsive acute box domain (+101 to 146) (40) . Iron levels were shown to regulate mRNA translation of APP holo-protein in astrocytic (41) and neuroblastoma cells (25) by a pathway similar to that of the ferritin L and H mRNAs translation by IREs in their 5'UTRs. Because APP mRNA 5'UTR region is a physiologically active element in command of APP translation, a novel therapeutic approach is intended to reduce amyloidosis by drugs targeted at the IRE in the APP mRNA transcript (40 , 42) . For example, the FDA preapproved drugs DFO, tetrathiomolybdate (Cu2+ chelator), and dimercaptopropanol (Pb2+ and Hg2+ chelator), or the bifunctional compound XH-1 (amyloid and metal chelator) were found to suppress APP holoprotein expression and Aβ peptide secretion in vitro (40 , 43) and to attenuate cerebral Aβ in PS1/APP transgenic mice (44) . The novel iron chelator, VK28 and the multifunctional drugs HLA20 and M30, were recently shown to induce a significant down-regulation of membrane-associated holo-APP levels in the mouse hippocampus and in human SH-SY5Y neuroblastoma cells (15 , 19 , 45) . Also, prolonged administration of the green tea flavonoid EGCG to mice induced a reduction in holo-APP levels in the hippocampus (19) and in SH-SY5Y cells, without altering APP mRNA levels, suggesting a post-transcriptional action, presumably by the mechanism of chelating intracellular iron pools. In support, the addition of exogenous Fe2+ reversed EGCG-induced decline of APP in cell culture (46) . Further, VK28, HLA20, and M30, as well as EGCG, were found to suppress translation of luciferase reporter gene fused to the APP 5'UTR that includes the APP IRE (45 , 46) .


   TARGETING CELL-CYCLE DYSREGULATION
TOP
 ABSTRACT
 INTRODUCTION
 TARGETING APP PROTEIN GENERATION...
 TARGETING CELL-CYCLE...
TREATMENT POTENTIAL
 REFERENCES
 
For more than a decade, accumulating evidence has suggested that neuronal death in the central nervous system (CNS) is often intimately linked to cellular processes that normally only occur during a mitotic cell cycle (47) . Specifically, it is now apparent that in AD, such mitotic cell dysregulation (cell cycle reentry) not only is one of the earliest neuronal abnormalities (prior to the appearance of plaques and tangles) but also is associated with other AD pathological characteristics such as OS, APP processing, tau phosphorylation, and neuronal death, and even risk factors like mutation in the presenilin genes or the occurrence of the ApoE4 allele, reviewed in refs. 29 , 48 49 50 51 52 . Neuronal phenotypic changes supporting cell cycle dysregulation in AD (53) include cytoskeletal phosphorylation (54) ; mitochondrial abnormalities (55) ; activation of select signal transduction pathways, such as activation of glycogen synthase kinase-3β (GSK-3), cyclin-dependent kinase-5 (CDK5) and ERK2, leading to aberrant tau phosphorylation and association with microtubules (56) ; and DNA replication and reexpression of various cell cycle proteins. These proteins include cyclins A, B, D, and E, as well as multiple CDKs; proliferating cell nuclear antigen (PCNA); the cell cycle-associated protein detected in numerous types of tumors, Ki67; and cyclin kinase inhibitors (CKIs) of both the Ink and Cip/Kip families (29 , 51 , 54) . Thus, in AD, the G1/S control mechanisms fail, allowing the neurons to replicate their DNA and progress into the late G2 phase of the cycle. In support, fluorescent in situ hybridization of the hippocampal pyramidal and basal forebrain neurons in AD patients detected 3–4% tetraploid cells, indicating that AD neurons have nearly completed the S phase before the cells die (57) . In support, Mosch et al. (58) , using single-cell DNA quantification and slide-based cytometry in brain slices, have reported that in AD, some neurons can reenter the cell cycle and complete DNA replication. Recently, it was demonstrated that the peptidyl-prolyl cis/trans isomerase, Pin1, playing an important role in cell cycle regulation and cancer development, was reduced and/or inhibited by oxidation in brains of AD, while Pin1 knockout mice developed tauopathy and neurodegeneration (59) . Further, Pin1 was found to regulate various age-dependent neurodegenerative processes, including Tau and APP dephosphorylation and APP processing (59 , 60) . Indeed, depletion of Pin1 was shown to induce mitotic arrest and apoptotic cell death, providing a new insight into AD pathogenesis (61) . In addition, the BRCA1 protein, a regulator of DNA repair and cellular growth, was shown to be strongly associated with NFT-bearing neurons in AD, implicating genomic instability and possibly a neuroprotective element in AD neurons (62 , 63) .

Support for cell cycle abnormalities in AD also comes from animal models; in four different plaque-bearing transgenic mouse models of familial AD, immunohistochemistry and FISH analyses showed that cell cycle events, in the most vulnerable areas, are evident 6 months before the first amyloid deposits have been formed and also precede the appearance of reactive microglial cells (64) . In addition, conditional transgenic mice with forced cell cycle activation (via neuronally targeted expression of simian virus 40 large T antigen) were found to exhibit AD-like pathology, including NFTs, amyloid deposits, and neurodegeneration (65) .

In vitro studies demonstrated that unscheduled cell cycle reentry in neurons may be mediated by many different insults; for instance, oxidative injury may trigger tau-mediated cell cycle activation, while kainic acid was shown to up-regulate cell cycle proteins (Cdk2, cyclin E, and E2F-1) and replicate cellular DNA prior to apoptosis in cerebral granule cells (66) . In addition, synthetic full-length Aβ(1–42) and its active fragments Aβ(1–40) and Aβ(25–35) were shown to induce the typical molecular repertoire necessary for the G1/S phases transition, enter the S phase, and die by apoptosis (67 , 68) . In particular, pharmacological and molecular evidence indicated that the cell cycle-related elements Cdk4/6, phosphorylated retinoblastoma protein (pRB), and E2F·DP complex are required for Aβ-induced neuronal death (69) . Furthermore, the expression of several DNA polymerases was elevated in differentiated neurons exposed to Aβ (70) , supporting the link between cell cycle reactivation and neuronal death in AD. A recent observation suggests that the proapoptotic protein Bcl-2 interacting mediator of cell death, Bim is a death effecter of Aβ and of dysregulated cell cycle proteins in AD (71) .


   TREATMENT POTENTIAL
TOP
 ABSTRACT
 INTRODUCTION
 TARGETING APP PROTEIN GENERATION...
 TARGETING CELL-CYCLE...
 TREATMENT POTENTIAL
REFERENCES
 
Pharmacological inhibitors
The notion that the cell cycle reentry plays an integral role in AD neurodegeneration has opened new therapeutic avenues for innovative treatment in AD. One such rational approach suggests the use of compounds that have been previously developed as antitumor drugs or that are related to cell cycle arrest. Thus, drugs or peptides that can interfere with or reverse the entrance into mitosis, may have important implications in terms of delaying cognitive decline and even restoration of neuronal function in AD patients. In a recent review, Woods et al. (30) have summarized a list of compounds from a diverse array of chemical and pharmacological classes, which are known to trigger cell cycle arrest at the G0-G1 phase. Among them are anticholesterol statins, antidiabetic PPAR gamma agonists, glucocorticoids, the RAS-MEK-ERK inhibitor PD098059, and retinoic acid. In this context, it was suggested that the neuroprotective effect of nonsteroidal anti-inflammatory drugs (NSAIDs) and antioxidants, like {alpha}-tocopherol is linked to their antiproliferative potency described in peripheral tissue, although this has not been studied in a neuronal system. Also, it was demonstrated that the acetylcholinesterase (ACE) inhibitor, donepezil can modify the distribution of SH-SY5Y cells within the cell cycle by causing an increase in the proportion of cells in G0/G1 phase of the cycle and a parallel decrease in S-G2/M phases (72) . A corresponding decrease in the respective proliferative components of G1/S and G2/M expression, cyclins E and B, was evident in donepezil-treated cells, suggesting other potential molecular targets, in addition to ACE inhibition, in the clinical efficacy of the drug. Another class of compounds that may hold strong promise for AD is the naturally occurring indigo dyes, indirubin (the active constituent of a Chinese antileukemia medicine) and its derivatives. Previous studies have indicated that indirubin selectively inhibits Cdks and GSK-3β, owing to its high-affinity binding into the ATP pocket of these enzymes (73) . One such compound, indirubin-3'-oxime, was demonstrated to inhibit GSK-3β-mediated tau phosphorylation and to effectively suppress cellular tau phosphorylation at AD-specific sites (74) . In support, the Cdk inhibitor, flavopiridol, was shown to suppress death of sympathetic and cortical neurons evoked by trophic factor deprivation, Aβ exposure, or DNA-damaging conditions (69 , 75 , 76) . Most importantly, the concentration of the flavopiridol required for neuroprotection was in the same order of magnitude of that effective in inhibiting cell cycle progression. In vivo, flavopiridol was shown to reduce lesion volume, neuronal apoptosis, and glial proliferation in parallel with improvement of motor and cognitive performance, in a rat model of traumatic brain injury (77) . In the same thought, recent findings, reporting the neuroprotective molecular signaling pathway of nicotine demonstrated that nicotine-inhibited apoptosis and cell cycle progression (CDK4 and cyclin D1 down-regulation) in a mouse AD model (78) , supporting the notion that ablation of cell cycle activity in the affected neurons may provide an effective therapeutic target for the treatment of neurodegenerative disorders.

Iron chelators
Targeting intracellular iron is a well-known mechanism to induce cell cycle arrest and apoptosis. In fact, under conditions of iron deficiency, cells are unable to proceed from the G1 to the S phase and complete a full division cycle. There are multiple mechanisms involved in the activity of iron chelators concerning cell cycle progression; iron depletion results in inhibition of the iron-containing enzyme, ribonucleotide reductase, that catalyzes the conversion of ribonucleotides into deoxyribonucleotides for DNA synthesis; causes hyperphosphorylation of pRB; and decreases the expression levels of cyclins A, B, and D and Cdk2/4 (32 , 79 , 80) . Recently, it was shown that iron depletion-mediated growth arrest at G1/S is associated with cyclin D1 proteolysis (81) . Also, it has been suggested that iron chelators may affect other critical regulatory molecules that are involved in cell cycle progression, such as p53, p21WAF-CIP1, N-myc, and c-myc (82) . In this line, it is reasonable to assume that the ability of metal chelators to interfere with or reverse the entrance into mitosis may impact neuronal preservation. Indeed, as previously denoted for Cdk cell cycle inhibitors, the G1/S-blocking divalent metal-chelating compounds mimosine and DFO promoted survival of differentiated PC12 cells and postmitotic sympathetic neurons following removal of trophic factor support or after treatment with the anticancer agent camptothecin (75 , 76) . In each of these cases, cell death could be suppressed at concentrations that correlated with the ability of the metal chelators to block cell proliferation. In accordance, DFO correlatively reduced the abnormal proportion of differentiated cortical neurons in S-phase and the index of apoptosis, following cell cycle reactivation with Aβ(25–35) (67) .

Our recent studies (15) have described neuroprotective and neurorescue activities of the novel multifunctional chelating drugs M30 and HLA20, including a reduction of the proapoptotic proteins Bax and Bad and inhibition of the apoptosis-associated phosphorylated H2A.X protein and caspase-3 activation. In addition, these drugs were shown to induce cell cycle arrest; M30 and HLA20 increased the number of PC12 cells in G0/G1 and decreased the number of cells in the S phase and also the proportion of cells in the G2 phase (Fig. 2 and Table 1 ), indicating that both compounds inhibited cell progress beyond the G0/G1 phase.


Figure 2
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  		Figure 2. Effect of M30 and HLA20 on the cell cycle of PC12 cells. PC12 cells were incubated without (control) or with M30 (5 and 10 µM) or HLA20 (5 and 10 µM) for 2 days and analyzed by fluorescence-activated flow cytometry. Results show representative histograms of cells at different phases of the cell cycle. See also Table 1 .


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  		Table 1. Percentages of PC12 cells at different phases of the cell cycle

The natural plant polyphenols are another class of metal-chelating neuroprotective-neurorescue agents demonstrated to be capable of abrogating cell cycle reentry (83) . Indeed, a direct inhibition of Cdks by EGCG is considered a primary event in its antiproliferative action (84 , 85) . Also, EGCG was shown to induce the expression of p21 and p27, while decreasing the expression of cyclin D1 and pRB (83) . These observations may suggest that the neuroprotective potential of iron-binding compounds is attributed, at least in part, to their capacity to interfere with cell cycle progression.

Finally, our hypothesis predicted that iron chelation may not only inhibit neurons to enroll into aberrant cell cycles but also suppress neuronal dedifferentiation processes in an effort to rescue the dying neurons. Indeed, our recent data show that the multifunctional iron chelators M30 and HLA20 (15) , as well as EGCG (86) , induce differentiation features in neuroblastoma and PC12 cells, including cell body elongation, stimulation of neurite outgrowth, and up-regulation of the growth associated protein-43 (GAP-43) (Fig. 3 ). Taken together, the data suggest that iron chelators may be considered potential therapeutic agents in AD, targeting early cell cycle anomalies and reestablishing the synaptic connection loss in the injured neuronal cells.


Figure 3
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  		Figure 3. Effect of M30 and HLA20 on PC12 cell differentiation. PC12 cells were incubated without (control) or with M30 (1–10 µM) or HLA20 (1–10 µM) for 2 days. A) micrographs showing the overgrowth of neurites in an inverted microscope connected to a digital camera (x20 objective). B) GAP-43 was detected by confocal microscopy. The number of differentiated cells was determined by counting cells with at least one neurite with a length equal to or greater than the diameter of the cell body. Six to twelve fields were counted for each treatment sample. Results are expressed as average of the differentiated cells (mean±SE) detected per sample in 3 independent experiments. *P < 0.05 vs. control; {dagger}P < 0.05 vs. M30 5 µM. C) GAP-43 expression in PC12 cell lysates was examined by immunoblotting analysis. The loading of the lanes was normalized to levels of β-actin (taken with permission from Avramovich-Tirosh et al., ref. 15 ).

SUMMARY AND CONCLUSIONS
Although the development of iron chelators for human diseases has focused primarily on their use in the treatment of secondary iron overload (such as β-thalassemia), chelators may also be considered useful in other disease states, such as cancer and neurodegeneration. Indeed, a consistent observation in AD is a dysregulation of metal ion (Fe, Cu, and Zn) homeostasis and consequential induction of OS associated with Aβ aggregation and fibrilization, as well as neuronal PHF{tau} filament deposition. Also, iron can enhance endogenous APP translation via activation of APP mRNA IRE and consequently Aβ formation. An additional level of iron operation in neurodegenerative diseases may involve the activation of the iron-dependent HIF-1 prolyl-4-hydroxylase, resulting in the proteasomal-mediated degradation of HIF. As illustrated in Fig. 4 , iron chelators can attenuate the wide spectrum of OS-associated neuropathologies, as well as APP translation, Aβ generation, and amyloid plaque and NFT formation. Iron-binding drugs may also stabilize HIF-1, which, in turn, would transactivate the expression of established protective genes, including vascular endothelial growth factor (VEGF), erythropoietin, aldolase, and p21. Finally, an additional new facet of iron-binding compounds in the etiology of AD therapy is related to the ability of iron chelators to abort anomalous cell cycle reactivation in the postmitotic degenerating neurons.


Figure 4
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  		Figure 4. Schematic representation of the targets for iron-chelating drugs in AD.

Obviously, the development of iron chelators for treating neurological disorders should carefully consider a series of factors for optimal therapeutic drug efficacy; these include low molecular weight, minimal toxicity, and satisfactory lipophilicity to enable permeation of cell membranes and access across the BBB. Also, optimal iron-complexing compounds targeted at cell cycle arrest should possess minimal undesirable side effects, thus precluding nonspecific death of normal, nondiseased cells, as demonstrated for several anticancer drugs. However, iron chelators were shown to differentially modulate cell cycle components in degenerative neurons or cancerous cells, in comparison with their effects in normal cells. For example, it was recently reported that iron chelation triggered apoptosis only in human breast cancerous cells, while normal cells were spared, experiencing a reversible cell cycle arrest (87) . Similarly, a number of studies demonstrated that cancer cells were more sensitive than normal cells to the antiproliferative and apoptotic activity of EGCG (88 , 89) .

Considering the multiple iron-operating sites in AD and the multietiological character of the disease pathology, novel pharmacological approaches suggest the use of metal-chelating molecules possessing two or more active neuroprotective moieties that simultaneously manipulate multiple desired targets. In the present review, iron-complexing and neuroprotective multifunctional drugs have been discussed comprising 1) novel compounds that are specifically and rationally designed to cross the BBB and target multiple mechanisms underlying specific neurodegenerative processes of AD and 2) natural occurring brain-permeable plant polyphenols (flavonoids), such as EGCG and curcumin. The intervention with these compounds is assumed to have a profound impact on neuron preservation and AD progression.


   ACKNOWLEDGMENTS
 
We are grateful to the Alzheimer’s Drug Discovery Foundation (ADDF), the Institute for the Study of Aging (New York, NY, USA), and the Technion Institute for the support of this work.

Received for publication August 20, 2007. Accepted for publication November 1, 2007.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 TARGETING APP PROTEIN GENERATION...
 TARGETING CELL-CYCLE...
 TREATMENT POTENTIAL
 REFERENCES
 

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