In cells in culture, tissues of a mouse model system, mitochondria targeted nitroxides have shown significant protection against ionizing irradiation induced damage. Furthermore, in cell culture studies and in vivo models, the molecular mechanism of action of mitochondria targeted nitroxides has been shown to be at the level of inhibition of oxidation of a mitochondria-specific phospholipid, cardiolipin, by cytochrome c/cardiolipin complexes. This protection of cardiolipin against oxidation is critical to maintenance of intact mitochondrial function and prevention of apoptosis.

File Number: 1734 

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Background
Ionizing irradiation induces apoptosis of cells, tissues, and organs causing significant toxicity. A central step in the mechanism of irradiation apoptosis is damage to the mitochondria through the action of free radicals and reactive intermediates of peroxidase complexes of cytochrome c with a mitochondria-specific phospholipid, cardiolipin, at the level of the mitochondrial membrane.

Nitroxides are a class of compounds which act as electron and radical scavengers and can decrease irradiation toxicity in some tissue culture and animal model systems. However, a central problem in efficient use of nitroxides is the problem of biodistribution. Getting enough nitroxides to a subcellular level of the mitochondria often requires employment of a very high concentration and can produce significant toxicity of the drug itself. Targeting of nitroxides has been shown to increase attached drug delivery to mitochondria and improve therapeutic efficacy in the use of nitroxides in amelioration of hemorrhagic shock.

Related Technology
ID 1198-Gramicidin S based Mitochondrial Targeting Agents