A Prochelator Activated by Hydrogen Peroxide Prevents Metal‐Induced Amyloid β Aggregation

Dickens, Marina G.; Franz, Katherine J.

doi:10.1002/cbic.200900597

Cited by 79 publications

(78 citation statements)

References 62 publications

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“…With an emerging understanding of the pathways leading to soluble oligomer or insoluble fibril production, therapeutic strategies loosely termed as "anti-Ab aggregation" need to be refocused on the specific steps being targeted (Rodriguez-Rodriguez et al 2009;Yadav and Sonker 2009;Dickens and Franz 2010), particularly with regard to the concept of "therapeutic chelation" of metal ions. The concept of therapeutic chelation needs to be qualified by the relative affinities each metal ion has for its target protein.…”

Section: Metal Ionsmentioning

confidence: 99%

Biochemistry of Amyloid -Protein and Amyloid Deposits in Alzheimer Disease

Masters

Selkoe²

2012

Cold Spring Harbor Perspectives in Medicine

483

405

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Section: Metal Ionsmentioning

confidence: 99%

Biochemistry of Amyloid -Protein and Amyloid Deposits in Alzheimer Disease

Masters

Selkoe²

2012

Cold Spring Harbor Perspectives in Medicine

483

405

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“…Hence, the fluorescence intensity of resorufin is directly correlated to H 2 O 2 generation. 57 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 DNA Cleavage. The ROS generated by Aβ-Cu 2+ triggers neuronal toxicity through pathways that include DNA damage and lipid peroxidation among others.…”

Section: Inhibition Of Aβ Oligomeric Aggregatesmentioning

confidence: 99%

Natural Tripeptide-Based Inhibitor of Multifaceted Amyloid β Toxicity

Rajasekhar

Madhu

Govindaraju

2016

ACS Chem. Neurosci.

116

137

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Accumulation of amyloid beta (Aβ) peptide and its aggregates in the human brain is considered as one of the hallmarks of Alzheimer's disease (AD). The polymorphic oligomers and fully grown fibrillar aggregates of Aβ exhibit different levels of neuronal toxicity. Moreover, aggregation of Aβ in the presence of redox-active metal ions like Cu(2+) is responsible for the additional trait of cellular toxicity induced by the generation of reactive oxygen species (ROS). Herein, a multifunctional peptidomimetic inhibitor (P6) has been presented, based on a naturally occurring metal chelating tripeptide (GHK) and the inhibitor of Aβ aggregation. It was shown by employing various biophysical studies that P6 interact with Aβ and prevent the formation of toxic Aβ forms like oligomeric species and fibrillar aggregates. Further, P6 successfully sequestered Cu(2+) from the Aβ-Cu(2+) complex and maintained it in a redox-dormant state to prevent the generation of ROS. P6 inhibited membrane disruption by Aβ oligomers and efficiently prevented DNA damage caused by the Aβ-Cu(2+) complex. PC12 cells were rescued from multifaceted Aβ toxicity when treated with P6, and the amount of ROS generated in cells was reduced. These attributes make P6 a potential therapeutic candidate to ameliorate the multifaceted Aβ toxicity in AD.

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“…For this purpose, we chose 8-hydroxyquinoline (8-HQ) as chelating portion as: 1) it is able to cross the blood-brain barrier (BBB), [20] 2) it is a strong iron chelator with antioxidant property, [21][22][23] and 3) it is able to protect against the precipitation of b-amyloid plaques in the presence of Cu 2 + , Fe 3 + , and Zn 2 + (compared to clioquinol), due to its ability to chelate these metals. [24] For an antioxidant scaffold, we selected the tripeptide GSH, as its metabolism is altered in neurodegenerated brain regions and its levels are decreased both in the SNpc of PD patients and in the cingulated cortex and substantia innominata of AD patients. It is generally accepted that restoring GSH levels may help to manage PD and AD.…”

Section: Introductionmentioning

confidence: 99%

A Glutathione Derivative with Chelating and in vitro Neuroprotective Activities: Synthesis, Physicochemical Properties, and Biological Evaluation

et al. 2013

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Metal-ion dysregulation and oxidative stress have been linked to the progressive neurological decline associated with neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Herein we report the synthesis and chelating, antioxidant, and in vitro neuroprotective activities of a novel derivative of glutathione, GS(HQ)H, endowed with an 8-hydroxyquinoline group as a metal-chelating moiety. In vitro results showed that GS(HQ)H may be stable enough to be absorbed unmodified and arrive intact to the blood-brain barrier, that it may be able to remove Cu(II) and Zn(II) from the Aβ peptide without causing any copper or zinc depletion in vivo, and that it protects SHSY-5Y human neuroblastoma cells against H2 O2 - and 6-OHDA-induced damage. Together, these findings suggest that GS(HQ)H could be a potential neuroprotective agent for the treatment of neurodegenerative diseases in which a lack of metal homeostasis has been reported as a key factor.

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A Prochelator Activated by Hydrogen Peroxide Prevents Metal‐Induced Amyloid β Aggregation

Cited by 79 publications

References 62 publications

Biochemistry of Amyloid -Protein and Amyloid Deposits in Alzheimer Disease

Biochemistry of Amyloid -Protein and Amyloid Deposits in Alzheimer Disease

Natural Tripeptide-Based Inhibitor of Multifaceted Amyloid β Toxicity

A Glutathione Derivative with Chelating and in vitro Neuroprotective Activities: Synthesis, Physicochemical Properties, and Biological Evaluation

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