A cell penetrant manganese SOD-mimic is able to complement MnSOD and exerts an anti-inflammatory effect on cellular and animal models of inflammatory bowel diseases

Printer-friendly version

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, Inorg. Chem., 201756 (5), pp 2545–2555

 

Exploring inorganic compounds in biological or cellular environments requires translating our knowledge from the round-bottom flasks to the cells. Cellular uptake, location inside cells, stability in intricate biological environments, are key features determining bio-activity that have to be studied. Here, we apply a general approach combining evaluations of the biological activity in a cellular model, with the exploration of the speciation, quantification of the intracellular content and cellular location in the case of the study of a Mn-complex mimicking the activity of the superoxide dismutase (SOD). Correlating the intrinsic activity and the bio-activity in a cellular context, with the actual intracellular concentration, distribution and speciation, is important to decipher the relevant parameters controlling the activity in a biological context. This is surely one of the bases for an inorganic cellular chemistry approach, also more generally called inorganic chemical biology. Bio-activities are usually reported against incubation concentrations, but they should also be analyzed as a function of the actual intracellular parameters. Indeed, an intrinsic activity may remain silent if the compound does not enter the cell, or can be finely modulated by the concentration and also by the location inside cells. This is why we clearly need to go beyond the mere observation of macroscopic effects on cell-cultures or biological tissues. To that extent, intracellular quantification and imaging —at the single cell level or within tissues substructures— are key experiments to provide a full understanding of bio-activity.

 

 

 

Antioxidant strategies have been suggested as appropriate to manage IBD. Some other SOD mimics, but few, have been previously shown promising in IBD context. The SOD mimic Mn1 is an interesting derivative: indeed, it shows an anti-superoxide activity previously characterized out of any cellular context, and in cells. In addition, Mn1 is easy to synthesize and easily modified, as recently shown. Overall, the approach presented here combining investigation the penetration, speciation and location, with that of the bio-activity, clearly indicates that the SOD mimic Mn1 is an efficient intracellular anti-inflammatory agent. One important finding of this study is the effect of Mn1 on mitochondrial MnSOD: Mn1 is able to complement MnSOD, which has been described as deficient in IBD. In addition, Mn1 shows a better activity than 5-ASA, already at use in the treatments of IBD, and the oral administration of Mn1 to in vivo model of IBD have led to encouraging results. This is very promising and suggests that the use of this anti-superoxide MnII-complex as an anti-inflammatory agent could constitute a relevant strategy in the treatment of IBD in particular and more generally of oxidative stress induced diseases.

 

Pour en savoir plus, consultez le communiqué de presse associé à cet article : Quand Chimie et Médecine s'unissent pour lutter contre les maladies inflammatoires de l'intestin !

 

 

Résumé: 

Inorg. Chem.201756 (5), pp 2545–2555

 

Inorganic complexes are increasingly used for biological and medicinal applications and the question of the cell-penetration and of the cell-distribution of metallodrugs is key to understand 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 a Mn-complex Mn1 mimicking superoxide dismutase, a protein involved in the cell protection against oxidative stress, using an approach in inorganic cellular chemistry combining investigation of Mn1 intracellular speciation using mass spectrometry, 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 find the MS-signature of Mn1 in cell lysates and quantified the overall Mn-content. Intestinal epithelial cells activated by bacterial lipopolysaccharide were taken as a cellular model of oxidative stress and inflammation. Mn1 exerts an intracellular anti-inflammatory activity, remains at least partially coordinated, with a diffuse distribution over the whole cell and functionally complements mitochondrial MnSOD.

 

Equipe de rattachement 7203: 
Equipe 1
Adresse mail du contact: 
Références: 

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

 

Emilie Mathieu, Anne-Sophie Bernard, Nicolas Delsuc, Elodie Quévrain, Géraldine Gazzah, Barry Lai, Florian Chain, Philippe Langella, Maria Bachelet, Joelle Masliah, Philippe Seksik, and Clotilde Policar

 

Inorg. Chem., 2017, 56 (5), pp 2545–2555

 

See also the Website

 

DOI: 10.1021/acs.inorgchem.6b02695