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. 2017 Mar 6;56(5):2545-2555. doi: 10.1021/acs.inorgchem.6b02695. Epub 2017 Feb 15.

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.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / metabolism
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Chemokines / antagonists & inhibitors
  • Chemokines / metabolism
  • Colitis / chemically induced
  • Colitis / drug therapy*
  • Colitis / metabolism
  • Dinitrofluorobenzene / analogs & derivatives
  • Disease Models, Animal*
  • Inflammatory Bowel Diseases / drug therapy*
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Organometallic Compounds / chemistry
  • Organometallic Compounds / metabolism
  • Organometallic Compounds / pharmacology*
  • Oxidative Stress / drug effects
  • Superoxide Dismutase / chemistry
  • Superoxide Dismutase / metabolism*

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Chemokines
  • Lipopolysaccharides
  • Organometallic Compounds
  • 2,4-dinitrofluorobenzene sulfonic acid
  • Dinitrofluorobenzene
  • Superoxide Dismutase