2,2,6,6-Tetramethylpiperidine-1-oxyl acts as a volatile inhibitor of ferroptosis and neurological injury

Abstract

Summary Ferroptosis, a type of oxidative stress cell death, has been implicated in cell injury in several diseases, and treatments with specific inhibitors have been shown to protect cells and tissues. Here we demonstrated that a treatment with the nitroxide radical, 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), prevented the ferroptotic cell death in an airborne manner. Other TEMPO derivatives and lipophilic antioxidants, such as Trolox and ferrostatin-1, also prevented cell death induced by erastin and RSL3; however, only TEMPO exhibited inhibitory activity from a physically distant location. TEMPO vaporized without decomposing, and then dissolved again into a nearby water solution. Volatilized TEMPO inhibited glutamate-induced cell death in mouse hippocampal cell lines, and also reduced neuronal cell death in a mouse ischemia model. These results suggest that TEMPO is a unique cell protective agent that acts in a volatility-mediated manner.

The Cellular and Organismal Effects of Nitroxides and Nitroxide-Containing Nanoparticles

“…An Interesting distant effect of TEMPO was reported due to the volatility of this compound, which is rather unique among antioxidants. Concentration-dependent inhibition of ferroptosis on human fibrosarcoma cells by TEMPO present in a neighbor vessel was reported [75]. This result suggests a possibility of administration of TEMPO in the form of vapor.…”

Novel druggable mechanism of Parkinson's disease: Potential therapeutics and underlying pathogenesis based on ferroptosis

“…An analog of TEMPO, XJB-5-131 (34), could also inhibit ferroptosis by reducing oxidative damage to mitochondrial DNA. 129,130 Deuteration of PUFAs at bis-allylic sites, such as in the compound 11,11-d 2 -linoleic acid (35), was shown to limit the autoxidation of PUFAs and generated derivatives of PUFAs that demonstrate neuroprotective properties. 131 Comparably, the naturally occurring compound α-lipoic acid (36) mitigated ferroptosis in a MPP + -induced PD model by activating NRF2-related pathways.…”

“… 128 In addition, 2,2,6,6‐tetramethylpiperidine‐ N ‐oxyl (TEMPO, 33 ), a reagent commonly used in free radical reactions, was found to protect cells from damage by ferroptosis and had inhibitory activity at a distant location in a volatile‐mediated manner. An analog of TEMPO, XJB‐5‐131 ( 34 ), could also inhibit ferroptosis by reducing oxidative damage to mitochondrial DNA 129,130 …”

Mesenchymal stem cells and ferroptosis: Clinical opportunities and challenges

“…In the currently proposed model, after the loss of glutathione peroxidase-4 (GPX4) activity, lipid hydroperoxide is generated in the membrane and attacked by ferrous iron, leading to lipid radical formation and increased lipid peroxidation, resulting in lethal membrane damage. Mitochondrial atrophy, accumulation of iron/lipid ROS, and GPX4 inactivation [ 30 , 31 ] are the major markers of ferroptosis. At the molecular level, ferroptosis is characterized by glutathione (GSH) depletion, lipid peroxidation, loss of plasma membrane integrity, cytoplasmic swelling, mitochondrial atrophy, rupture of the mitochondrial outer membrane, and it is biochemically characterized by GPX4 inactivation (see Fig.…”