A potent antioxidant small molecule aimed at targeting metal-based oxidative stress in neurodegenerative disorders

Lincoln, Kimberly M.; González, Paulina; Richardson, Timothy E.; Julovich, David; Saunders, Ryker E.; Simpkins, James W.; Green, Kayla N.

doi:10.1039/c2cc36808k

Cited by 53 publications

(91 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…8 Our group has previously studied hybrid molecules composed of a chelator moiety in conjunction with a pyridol functionality which we showed to be responsible for protection against reactive oxygen species in cells. 9 Our studies demonstrate that the fusion of functional groups can engender the positive characteristics of the parent molecules onto the product system. However, they have been largely hindered for in vivo work by solubility and biocompatibility.…”

Section: Introductionmentioning

confidence: 65%

“…Previous studies with small molecule chelators have attributed similar disaggregate activity to the capacity of such molecules extracting metals from Aβ thus disaggregating the protein. 9b This results in restoration of the Tyr-10 signal. It is interesting to note that the signal of the 1 did not show equivalent capacity to restore the fluorescence signal.…”

Section: Discussionmentioning

confidence: 99%

“…11 Here, we integrate lipoic acid into the metal binding cyclen (1,4,7,10-tetraazacyclododecane) scaffold that our previously reported systems resemble based on the metal binding heterocyclic core. 9 This new system is designed to utilize the lipoic acid component to provide multiple modes of ROS targeting activity while tuning the metal binding capacity of the metal-scavenging cyclen core. We report, an array of ex vivo and in vitro experiments that are carried out to deduce the ability of the water soluble, hybrid lipoic cyclen ( 1 ) molecule (Figure 1) to modulate amyloid aggregation and oxidative stress while increasing biocompatibility of the original scaffold, cyclen.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Bimodal-hybrid heterocyclic amine targeting oxidative pathways and copper mis-regulation in Alzheimer's disease

et al. 2014

Self Cite

View full text Add to dashboard Cite

Oxidative stress resulting from metal-ion misregulation plays a role in the development of Alzheimer’s disease (AD). This process includes the production of tissue-damaging reactive oxygen species and amyloid aggregates. Herein we describe the synthesis, characterization and protective capacity of the small molecule, lipoic cyclen, which has been designed to target molecular features of AD. This construct utilizes the biologically compatible and naturally occurring lipoic acid as a foundation for engendering low cellular toxicity in multiple cell lines, radical scavenging capacity, tuning the metal affinity of the parent cyclen, and results in an unexpected affinity for amyloid without inducing aggregation. The hybrid construct thereby shows protection against cell death induced by amyloid aggregates and copper ions. These results provide evidence for the rational design methods used to produce this fused molecule as a potential strategy for the development of lead compounds for the treatment of neurodegenerative disorders.

show abstract

Section: Introductionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Bimodal-hybrid heterocyclic amine targeting oxidative pathways and copper mis-regulation in Alzheimer's disease

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…[20] The presence of the pyridone tautomer in chloroform was assessed by NMR spectroscopy. Although NaBH 4 was effective for reducing this diester, a mixture of NaBH 4 and CaCl 2 produced diol 17 in a better yield (80 vs. 60 %).…”

Section: Resultsmentioning

confidence: 99%

Facile Access to the 12‐Membered Macrocyclic Ligand PCTA and Its Derivatives with Carboxylate, Amide, and Phosphinate Ligating Functionalities

et al. 2018

View full text Add to dashboard Cite

We describe a convenient synthetic pathway to access the 12‐membered PCTA macrocycle, a polyaminocarboxylate ligand for which its M2+ and M3+ complexes are commonly associated with applications in biomedical diagnostics and radiotherapy. The synthetic pathway is based on the use of a linear tri‐N‐alkylated triamine synthon incorporating masked acetate arms and an efficient sodium template ion effect for the crucial macrocyclization step (87 % macrocyclization yield). This approach was then successfully applied to access three new PCTA[12] derivatives containing either a 4‐pyridol unit, an amide or a phosphinate coordinating function in the central arm. In all cases, the macrocyclization reactions were controlled by a sodium template ion effect, and the macrocyclization yields were in the range of 60 to 75 %. The luminescence and relaxometric properties of EuIII, TbIII, and GdIII complexes derived from PCTA derivatives with mixed coordinating arms were also investigated, making these complexes possible alternatives to PCTA[12]–LnIII complexes.

show abstract

“…Therefore, the objectives of this study were to: i) assess the potential role of Nrf2 signaling in hypoglycemia-induced endothelial dysfunction and BBB permeability and, ii) address the molecular mechanisms underlying Nrf2 down-regulation by hypoglycemia in brain microvascular endothelial cells using hCMEC/D3 cell line [ 30 ]. In addition, we preliminarily tested the therapeutic potential of a novel anti-oxidant tetra-aza macrocyclic ligand, L2 (3,6,9,15-tetraazabicyclo [9.3.1]penta-deca-1(15),11,13-trien-13-ol) [ 31 ], to prevent hypoglycemia-induced Nrf2 down-regulation. Our results demonstrated that Nrf2 regulates the expression of endothelial tight and adherence junctional proteins critical for BBB integrity and function.…”

Section: Introductionmentioning

confidence: 99%

Altered Nrf2 Signaling Mediates Hypoglycemia-Induced Blood–Brain Barrier Endothelial Dysfunction In Vitro

2015

Self Cite

View full text Add to dashboard Cite

Hypoglycemia impairs blood-brain barrier (BBB) endothelial function; a major hallmark in the pathogenesis of various CNS disorders. Previously, we have demonstrated that prolonged hypoglycemic exposure down-regulated BBB endothelial NF-E2 related factor-2 (Nrf2) expression; a redox-sensitive transcriptional factor that regulates endothelial function. Here, we sought to determine the functional role of Nrf2 in preserving BBB integrity and molecular mechanisms underlying hypoglycemia-induced Nrf2 down-regulation in vitro using human cerebral microvascular endothelial cell line (hCMEC/D3). Cell monolayers were exposed to normal or hypoglycemic (5.5 or 2.2mM D-glucose) media for 3-24h. Pharmacological or gene manipulation (by silencing RNA) approaches were used to investigate specific molecular pathways implicated in hypoglycemia-induced Nrf2 degradation. BBB integrity was assessed by paracellular permeability to labeled dextrans of increasing molecular sizes (4-70kDa). Silencing Nrf2 expression in hCMEC/D3 cells abrogated the expression of claudin-5 and VE-cadherin, while ZO-1 was up-regulated. These effects were paralleled by a decrease in electrical resistance of hCMEC/D3 monolayers and potential increase in permeability to all labeled dextrans. Hypoglycemic exposure (3-24h) led to progressive and sustained down-regulation of Nrf2 (without affecting mRNA) and its target, NQO-1, with a concomitant increase in the cytosolic pool of E3 ubiquitin ligase, Siah2 (but not Keap1). Pretreatment with protease inhibitor MG132, or selective knock-down of Siah2 (but not Keap1) significantly attenuated hypoglycemia-induced Nrf2 destabilization. While hypoglycemic exposure triggered a significant increase in BBB permeability to dextrans, silencing Siah2 gene abrogated the effects of hypoglycemia and restored BBB integrity. In summary, our data indicate a potential role for Nrf2 signaling in regulating tight junction integrity and maintaining BBB function. Nrf2 suppression by increased Siah2-driven proteasomal degradation mediates hypoglycemia-evoked endothelial dysfunction and loss of BBB integrity. Overall, this study suggests that sustained activation of endothelial Nrf2 signaling could have therapeutic potential to prevent hypoglycemia-induced cerebrovascular dysfunction.

show abstract

A potent antioxidant small molecule aimed at targeting metal-based oxidative stress in neurodegenerative disorders

Cited by 53 publications

References 26 publications

Bimodal-hybrid heterocyclic amine targeting oxidative pathways and copper mis-regulation in Alzheimer's disease

Bimodal-hybrid heterocyclic amine targeting oxidative pathways and copper mis-regulation in Alzheimer's disease

Facile Access to the 12‐Membered Macrocyclic Ligand PCTA and Its Derivatives with Carboxylate, Amide, and Phosphinate Ligating Functionalities

Altered Nrf2 Signaling Mediates Hypoglycemia-Induced Blood–Brain Barrier Endothelial Dysfunction In Vitro

Contact Info

Product

Resources

About