A Cell-Penetrant Manganese Superoxide Dismutase (MnSOD) Mimic Is Able To Complement MnSOD and Exerts an Antiinflammatory Effect on Cellular and Animal Models of Inflammatory Bowel Diseases

Abstract

Inorganic complexes are increasingly used for biological and medicinal applications, and the question of the cell penetration and distribution of metallodrugs is key to understanding their biological activity. Oxidative stress is known to be involved in inflammation and in inflammatory bowel diseases for which antioxidative defenses are weakened. We report here the study of the manganese complex Mn1 mimicking superoxide dismutase (SOD), a protein involved in cell protection against oxidative stress, using an approach in inorganic cellular chemistry combining the investigation of Mn1 intracellular speciation using mass spectrometry and of its quantification and distribution using electron paramagnetic resonance and spatially resolved X-ray fluorescence with evaluation of its biological activity. More precisely, we have looked for and found the MS signature of Mn1 in cell lysates and quantified the overall manganese content. Intestinal epithelial cells activated by bacterial lipopolysaccharide were taken as a cellular model of oxidative stress and inflammation. DNBS-induced colitis in mice was used to investigate Mn1 activity in vivo. Mn1 exerts an intracellular antiinflammatory activity, remains at least partially coordinated, with diffuse distribution over the whole cell, and functionally complements mitochondrial MnSOD.

A Metallo Pro‐Drug to Target CuII in the Context of Alzheimer's Disease

“…However,c areful inspection of the EPR spectra on the edge of the 6-lines signal show that the signature of am ixture of Cu(Ab) and 1 + + perfectly matches the hyperfine features of [Cu(L)] + (complex noted 2 2 + + )r ecorded under the very same conditions (Figure 2). Note:i )that the 9-GHz EPR signature of 1 + + gives a broad signal with no hyperfine structure in the g = 2r egion,a s expected for this highly distortedM n II species [13,15] (Figure S2); ii)asap arallel experiment, the removal of Cu from the Ab peptide by the ligand LH has been recorded by EPR ( Figures S3), and iii)the metal swap experiment has also been followed by UV/Vis ( Figure S4), the data obtained matching the EPR results. Affinity of Mn II for LH has been evaluated by direct titration monitored by UV/Vis ( Figure S5) leading to an apparent affinity constant of 1.3 10 6 m À1 (pH 7.1, 100 mm HEPES) in line with previousm easurement by calorimetry.…”

“…Indeed, while LH is toxic towards epithelial cells as a free ligand, the toxicity is abolished when LH is bound to Mn(II) (in complex 1 + ). [15] Hence, the use of a potentially toxic ligand to remove Cu(II) from Aβ is replaced by the use of 1 + which is non-toxic and leads to the very same retrieval effects. It is worth noting here that we also studied another Mn(II) SOD mimic [Mn(IPG)] (IPG = N-[(1-methyl-imidazol-2-yl)methyl]-N-(2-pyridylmethyl)glycinate.…”

“…1 + + was shown to efficiently limit superoxide flow in activated macrophages [14] and to limit inflammation with ap otentiali ntracellular SOD-activity,w hile the ligand alone (LH) showedac ellular toxicity. [15] In the present communication, we used complex 1 + + insteado ff ollowing a classical chelating strategy [16] and using af ree ligand that mightb et oxic. Furthermore in the context of AD, the importance of oxidative stress is widely acknowledged, [3] making the use of an SOD mimic relevant.W ew ill thus describe here how compound 1 + + ,w hich has an interesting intrinsic SOD-like ability,p revents Cu-induced processes by removing Cu II from Ab [Eq.…”

Anti-inflammatory activity of superoxide dismutase mimics functionalized with cell-penetrating peptides

“…22 Following on, the manganese (II) SOD mimics Mn1 ( Figure 1) was studied in cells and in vivo. 12,23 Its ability to limit ROS flow in cells was demonstrated in activated macrophages. 23 In addition, its study in a cellular model of inflammatory diseases demonstrated the ability of the complex to limit oxidative stress and inflammatory reaction in a cellular model of inflammatory bowel diseases at a concentration of incubation of 100 µM.…”

“…23 In addition, its study in a cellular model of inflammatory diseases demonstrated the ability of the complex to limit oxidative stress and inflammatory reaction in a cellular model of inflammatory bowel diseases at a concentration of incubation of 100 µM. 12 At this concentration, Mn1…”