Effects of novel neuroprotective and neurorestorative multifunctional drugs on iron chelation and glucose metabolism

Pollak, Yulia; Mechlovich, Danit; Amit, Tamar; Bar-Am, Orit; Manov, Irena; Mandel, Silvia; Weinreb, Orly; Meyron-Holtz, Esther G.; Iancu, Theodore C.; Youdim, Moussa B. H.

doi:10.1007/s00702-012-0795-x

Cited by 16 publications

(14 citation statements)

References 40 publications

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“…However, DFO is highly hydrophilic, making its oral bioavailability and BBB penetration extremely low and necessitating parenteral administration. Due to its half life of 12 min, patients on DFO therapy should undergo subcutaneous infusions from 8-12 h approximately 7 times a week (351,430,437). A recent study, however, highlights the possibility of intranasal DFO administration, which may improve patient compliance (181).…”

Section: Therapeutic Optionsmentioning

confidence: 99%

Brain Iron Homeostasis: From Molecular Mechanisms To Clinical Significance and Therapeutic Opportunities

Singh

Haldar

Tripathi

et al. 2014

Antioxidants & Redox Signaling

184

165

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Iron has emerged as a significant cause of neurotoxicity in several neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), sporadic Creutzfeldt-Jakob disease (sCJD), and others. In some cases, the underlying cause of iron mis-metabolism is known, while in others, our understanding is, at best, incomplete. Recent evidence implicating key proteins involved in the pathogenesis of AD, PD, and sCJD in cellular iron metabolism suggests that imbalance of brain iron homeostasis associated with these disorders is a direct consequence of disease pathogenesis. A complete understanding of the molecular events leading to this phenotype is lacking partly because of the complex regulation of iron homeostasis within the brain. Since systemic organs and the brain share several iron regulatory mechanisms and iron-modulating proteins, dysfunction of a specific pathway or selective absence of iron-modulating protein(s) in systemic organs has provided important insights into the maintenance of iron homeostasis within the brain. Here, we review recent information on the regulation of iron uptake and utilization in systemic organs and within the complex environment of the brain, with particular emphasis on the underlying mechanisms leading to brain iron mismetabolism in specific neurodegenerative conditions. Mouse models that have been instrumental in understanding systemic and brain disorders associated with iron mis-metabolism are also described, followed by current therapeutic strategies which are aimed at restoring brain iron homeostasis in different neurodegenerative conditions. We conclude by highlighting important gaps in our understanding of brain iron metabolism and mis-metabolism, particularly in the context of neurodegenerative disorders. Antioxid. Redox Signal. 20, 1324Signal. 20, -1363

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Section: Therapeutic Optionsmentioning

confidence: 99%

Brain Iron Homeostasis: From Molecular Mechanisms To Clinical Significance and Therapeutic Opportunities

Singh

Haldar

Tripathi

et al. 2014

Antioxidants & Redox Signaling

184

165

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“…In view of its multifunctional roles, 8HQ-based compounds have been utilized in the treatment and improvement of neurodegenerative patients. For example, M30 and HLA-20 (Figure 4) are novel multifunctional 8HQ-based drugs synthesized by combining an Fe chelating compound possessing an antioxidant activity (VK-28) with the Parkinson’s drug (Ladostigil) containing the N-propagylamine moiety (Figure 5), which affords the neuroprotective property34…”

Section: Introductionmentioning

confidence: 99%

“…It is capable of directly scavenging OH, which gives rise to antioxidant effects 35,36. Ladostigil contains the propargylamine moiety that accounts for its inhibition of the monoamine oxidase enzyme 34. This enzyme is involved in dopamine oxidation, which generates hydrogen peroxide (H 2 O 2 ) that initiates the Fenton reaction in the presence of Fe 2+ , leading to oxidative stress in neurons 32.…”

Section: Introductionmentioning

confidence: 99%

8-Hydroxyquinolines: a review of their metal chelating properties and medicinal applications

Prachayasittikul¹,

Prachayasittikul²,

Ruchirawat³

et al. 2013

DDDT

360

276

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Metal ions play an important role in biological processes and in metal homeostasis. Metal imbalance is the leading cause for many neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. 8-Hydroxyquinoline (8HQ) is a small planar molecule with a lipophilic effect and a metal chelating ability. As a result, 8HQ and its derivatives hold medicinal properties such as antineurodegenerative, anticancer, antioxidant, antimicrobial, anti-inflammatory, and antidiabetic activities. Herein, diverse bioactivities of 8HQ and newly synthesized 8HQ-based compounds are discussed together with their mechanisms of actions and structure–activity relationships.

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“…8HQ is the investigated ligand with a potent metal chelating ability 33,85–87. It contains lone-pair electron donors as carried by the ring’s nitrogen (N) as well as oxygen (O) atom of the OH group, which can be donated upon metal complexation.…”

Section: Discussionmentioning

confidence: 99%

Investigation of aromatase inhibitory activity of metal complexes of 8-hydroxyquinoline and uracil derivatives

Prachayasittikul¹,

Pingaew²,

Nantasenamat³

et al. 2014

DDDT

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PurposeEstrogens play important roles in the pathogenesis and progression of breast cancer as well as estrogen-related diseases. Aromatase is a key enzyme in the rate-limiting step of estrogen production, in which its inhibition is one strategy for controlling estrogen levels to improve prognosis of estrogen-related cancers and diseases. Herein, a series of metal (Mn, Cu, and Ni) complexes of 8-hydroxyquinoline (8HQ) and uracil derivatives (4–9) were investigated for their aromatase inhibitory and cytotoxic activities.MethodsThe aromatase inhibition assay was performed according to a Gentest™ kit using CYP19 enzyme, wherein ketoconazole and letrozole were used as reference drugs. The cytotoxicity was tested on normal embryonic lung cells (MRC-5) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.ResultsOnly Cu complexes (6 and 9) exhibited aromatase inhibitory effect with IC50 0.30 and 1.7 μM, respectively. Cytotoxicity test against MRC-5 cells showed that Mn and Cu complexes (5 and 6), as well as free ligand 8HQ, exhibited activity with IC50 range 0.74–6.27 μM.ConclusionCu complexes (6 and 9) were found to act as a novel class of aromatase inhibitor. Our findings suggest that these 8HQ–Cu–uracil complexes are promising agents that could be potentially developed as a selective anticancer agent for breast cancer and other estrogen-related diseases.

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Effects of novel neuroprotective and neurorestorative multifunctional drugs on iron chelation and glucose metabolism

Cited by 16 publications

References 40 publications

Brain Iron Homeostasis: From Molecular Mechanisms To Clinical Significance and Therapeutic Opportunities

Brain Iron Homeostasis: From Molecular Mechanisms To Clinical Significance and Therapeutic Opportunities

8-Hydroxyquinolines: a review of their metal chelating properties and medicinal applications

Investigation of aromatase inhibitory activity of metal complexes of 8-hydroxyquinoline and uracil derivatives

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