Metal Ruthenium Complexes Treat Spinal Cord Injury By Alleviating Oxidative Stress Through Interaction With Antioxidant 1 Copper Chaperone Protein

Abstract Oxidative stress is a major factor affecting spinal cord injury (SCI) prognosis. A ruthenium metal complex can aid in treating SCI by scavenging reactive oxygen species via a protein‐regulated mechanism to alleviate oxidative stress. This study aimed to introduce a pioneering strategy for SCI treatment by designing two novel half‐sandwich ruthenium (II) complexes containing diverse N^N‐chelating ligands. The general formula is [(η⁶‐Arene)Ru(N^N)Cl]PF₆, where arene is either 2‐phenylethanol‐1‐ol (bz‐EA) or 3‐phenylpropanol‐1‐ol (bz‐PA), and the N^N‐chelating ligands are fluorine‐based imino‐pyridyl ligands. This study shows that these ruthenium metal complexes protect neurons by scavenging reactive oxygen species. Notably, η6‐Arene substitution from bz‐PA to bz‐EA significantly enhances reactive oxygen species scavenging ability and neuroprotective effect. Additionally, molecular dynamics simulations indicate that the ruthenium metal complex increases Antioxidant 1 Copper Chaperone protein expression, reduces oxidative stress, and protects neurons during SCI treatment. Furthermore, ruthenium metal complex protected spinal cord neurons and stimulated their regeneration, which improves electrical signals and motor functions in mice with SCI. Thus, this treatment strategy using ruthenium metal complexes can be a new therapeutic approach for the efficient treatment of SCI.