Metal-dependent neural protection by HP-derived coordination compounds against mitochondrial dysfunction in glial cells

Coordination compounds are promising redox-active systems for applications across multiple fields, including neuroscience; however, their effects on mitochondrial function in neural cells remain poorly investigated. Here, we evaluated the neuroprotective potential of Cu^II, Fe^III, and Mn^II coordination compounds derived from the ligand bis(pyridin-2-ylmethylamine) -3-chloropropan-2-ol (HP), targeting mitochondrial dysfunction and oxidative stress in C6 glial cells. A system with impaired mitochondrial activity was elicited by exposing C6 glial cells to rotenone (50 µM; 1 h). The treatment severely impaired mitochondrial respiration by reducing basal oxygen consumption from 55 ± 13.2 to 14 ± 7.2 pmol O₂ s⁻¹ 1x10⁴ cells and maximal respiration from 123 ± 8.2 to 35 ± 3.5 pmol O₂ s⁻¹ 1x10⁴ cells. CuHP, FeHP, and MnHP treatment (after rotenone) restored basal respiration (56 ± 8.9, 50 ± 7.5, and 57 ± 3.8 pmol O₂ s⁻¹ 1x10⁴ cells, respectively) and maximal respiration (134 ± 6.8, 118 ± 5.2, and 152 ± 3.2 pmol O₂ s⁻¹ 1x10⁴ cells), comparable to the SOD mimetic EUK-8 (148 ± 8.2 pmol O₂ s⁻¹ 1x10⁴ cells). Exposure to the HP series (after rotenone; 1 h) inhibited ROS generation at 3–30 µM in rotenone-induced cytotoxicity, with FeHP showing consistent suppression across all concentrations and superior performance to EUK-8. At 100 µM, CuHP and MnHP reduced ROS generation by approximately 80%, whereas the reference compound EUK-8 achieved only 60% inhibition. HP coordination compounds showed significantly greater efficacy than EUK-8 in suppressing rotenone-induced ROS production. The HP series effectively counteracted rotenone-induced mitochondrial dysfunction and oxidative stress in C6 glial cells. The recovery of mitochondrial respiration and ROS inhibition demonstrated that the neuroprotective effects were dependent on the nature of the central metal ion (MnHP > FeHP > CuHP). Thus, coordination compounds can modulate mitochondrial bioenergetics and redox balance, supporting their potential as mitochondria-targeted neuroprotective agents.