Mechanism and stoichiometry of 2,2-diphenyl-1-picrylhydrazyl radical scavenging by glutathione and its novel α-glutamyl derivative

Non-steroidal anti-inflammatory drugs (NSAIDs) and antioxidant therapy might protect against the development of Alzheimer's disease (AD). In the present work, we synthesized a molecular combination of glutathione (GSH) and ibuprofen (IBU) via an amide bond and investigated its potential for targeted delivery of the parent drugs to neurons, where cellular oxidative stress and inflammation are related to AD. Evaluation of its physicochemical and in-vitro antioxidant properties indicated that compound 1 exhibits good stability toward human plasma enzymatic activity, and, like GSH, displays in-vitro free radical scavenging activity in a time and concentration-dependent manner. The new compound was also assessed by infusion in a rat model for Alzheimer's disease for its potential to antagonize the deleterious structural and cognitive effects of β-amyloid(1-40). In behavioral tests of long-term spatial memory, animals treated with codrug 1 performed significantly better than those treated with β-amyloid (Aβ) peptide. Histochemical findings confirmed the behavioral data, revealing that Aβ protein was less expressed in cerebral cortex treated with 1 than that treated with IBU. Taken together, the present findings suggest that conjugate 1 treatment may protect against the oxidative stress generated by reactive oxygen species (ROS) and the cognitive dysfunction induced by intracerebroventricular (i.c.v.) infusion of Aβ(1-40) in rats, and thus that codrug 1 could prove useful as a tool for controlling AD induced cerebral amyloid deposits and behavioral deterioration.

show abstract

“…2) and with incubation time (Fig. 3); these results were also confirmed by DMSO competition tests (data not shown) [31].…”

Section: S1supporting

confidence: 78%

Ibuprofen and Glutathione Conjugate as a Potential Therapeutic Agent for Treating Alzheimer's Disease

Pinnen

Sozio

Cacciatore

et al. 2010

Archiv der Pharmazie

View full text Add to dashboard Cite

show abstract

“…However, all these mechanisms will lead to the formation of the same product, the quenched radical DPPH-H [41]. During this process, if DPPH is reduced, this will cause a change in the oxidation state of the compound involved in quenching the DPPH radical.…”

Section: L-l Cu Bond Distances (å) 1 Cu Bond Distances (å)mentioning

confidence: 97%

Crystal structures of o , o ′-( N , N ′-dipicolinyldene)diazadiphenyl disulfide and its copper (II) complex: Antioxidant, antibacterial and DNA-binding properties

Moosun

Jhaumeer‐Laulloo

Hosten

et al. 2015

Inorganica Chimica Acta

View full text Add to dashboard Cite

“…According to the classification of kinetic behavior by Sánches-Moreno et al, UPF17 is classified as fast and UPF1 as intermediate DPPH radical scavenger [9, 28]. In silica modeling of noncovalent complex formation by docking calculations revealed a more affine complex between DPPH radical and α -GSH compared to the complex with GSH [21]. This raised a question about pK a values for the thiol groups of UPF peptides.…”

Section: Discussionmentioning

confidence: 99%

“…This raised a question about pK a values for the thiol groups of UPF peptides. Previously, the change of γ -peptide bond to α -peptide bond has also been investigated for GSH and its α -analogue: pK a of thiol groups were similar for GSH and α -GSH (9.0 ± 0.1 and 9.1 ± 0.1) [21]. The comparison of these results with current measurements for UPF1 and UPF17 demonstrated that pK a value is rather influenced by the addition of a methylated tyrosine moiety to the GSH backbone than by the change of the peptide bond type.…”

Section: Discussionmentioning

confidence: 99%

“…The ratio of thiol and thiolate concentrations were measured spectrophotometrically at 240 nm on a PerkinElmer Lambda 25 spectrometer similarly as previously for GSH and α -GSH [21]. 1 mL of 50 μ M peptide solution in phosphate buffered saline (Calbiochem, USA) was titrated with 5 μ L volumes of 1 M NaOH and pH and absorbance changes were determined after each addition.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Diverse Effects of Glutathione and UPF Peptides on Antioxidant Defense System in Human Erythroleukemia Cells K562

Kairane

Mahlapuu

Ehrlich

et al. 2012

International Journal of Peptides

Self Cite

View full text Add to dashboard Cite

The main goal of the present paper was to examine the influence of the replacement ofγ-Glu moiety toα-Glu in glutathione and in its antioxidative tetrapeptidic analogue UPF1 (Tyr(Me)-γ-Glu-Cys-Gly), resulting inα-GSH and UPF17 (Tyr(Me)-Glu-Cys-Gly), on the antioxidative defense system in K562 cells. UPF1 and GSH increased while UPF17 andα-GSH decreased the activity of CuZnSOD in K562 cells, at peptide concentration of 10 μM by 42% and 38% or 35% and 24%, respectively. After three-hour incubation, UPF1 increased and UPF17 decreased the intracellular level of total GSH. Additionally, it was shown that UPF1 is not degraded byγ-glutamyltranspeptidase, which performs glutathione breakdown. These results indicate that effective antioxidative character of peptides does not depend only on the reactivity of the thiol group, but also of the other functional groups, and on the spatial structure of peptides.

show abstract

Mechanism and stoichiometry of 2,2-diphenyl-1-picrylhydrazyl radical scavenging by glutathione and its novel α-glutamyl derivative

Cited by 10 publications

References 28 publications

Ibuprofen and Glutathione Conjugate as a Potential Therapeutic Agent for Treating Alzheimer's Disease

Ibuprofen and Glutathione Conjugate as a Potential Therapeutic Agent for Treating Alzheimer's Disease

Crystal structures of o , o ′-( N , N ′-dipicolinyldene)diazadiphenyl disulfide and its copper (II) complex: Antioxidant, antibacterial and DNA-binding properties

Diverse Effects of Glutathione and UPF Peptides on Antioxidant Defense System in Human Erythroleukemia Cells K562

Contact Info

Product

Resources

About