Effects of SkQs on oxidative stress-mediated
injuries of kidney and brain

D.B. Zorov, N.K. Isaev, E.Y. Plotnikov,
D.N. Silachev, A.A. Chupyrkina, I.B. Pevzner,
T.G. Khryapenkova, S.S. Jankauskas,
M.A. Morosanova, M.I. Danshina, E.S. Goryacheva,
E.R. Lozier, E.V. Stelmashook
A.N. Belozersky Institute of Physico-Chemical Biology, Moscow State University

Mitochondria-targeted drugs were designed to serve a tool for specific delivery to mitochondrial matrix of compounds capable to compensate the defects resulting from inherited or acquired mitochondrial malfunctioning. SkQR1 belonging to the family of mitochondria-targeted antioxidants carries rhodamine residue as a driving vehicle for direct delivery of plastoquinone moiety to the mitochondrial interior. This chimeric compound demonstrated apparent protective properties in different models of tissue pathologies with oxidative stress being involved. Its efficiency was proved in a model of kidney ischemia/reperfusion and rhabdomyolysis. In the first model, protection was demonstrated as after injection of SkQR1 prior ischemic insult (when normalization of blood creatine and urea and survival in single-kidney animals were observed) as well as after injection in postischemic period (when almost all single-kidney animals subjected to ischemic insult survived).Two models of rhabdomyolysis were used. Firstly, the toxicity of myoglobin was studied in the culture of renal tubular cells after acute exposure. The latter induced elevation of reactive oxygen species level in cellular mitochondria with SkQR1 having inhibitory effect. Secondly, after intramuscular injection of glycerol and limitation of water access, experimental animals developed myoglobinurea with apparent signs of kidney dysfunction correlated with oxidative stress in the renal tissue. One essential indicator of developed rhabdomyolysis was an appearance of cytochrome c in the blood stream. Injection of SkQR1 significantly restored kidney functioning in rhabdomyolitic rats and decreased both the level of lipid peroxidation in renal tissue and blood cytochrome c. We found that a single injection of SkQR1 to the rat induced production of erythropoietin in the total kidney tissue and cultural kidney cells and caused elevation of phosphorylated form of glycogen synthase kinase in the renal tissue. Significant, although smaller protection was observed after injection of a SkQR1 derivative deprived of plastoquinone moiety. This compound induced some normalization of ischemic and rhabdomyolitic kidney functioning while not having any effect on the level of erythropoietin in the kidney. Protective effect of both SkQR1 and its quinone-free form was demonstrated in a model of focal brain ischemia although the second form demonstrated limited protective properties. Single i/p injection of SkQR1 diminished the size of the ischemic zone in the brain and improved performance of a test characterizing neurological deficit in ischemic animals. The study of the role of kidney in the protection of ischemic brain demonstrated significant contribution of erythropoietin produced by the kidney in protective mechanisms developed in the brain although there is some although limited endogenous production of erythropoietin in the brain cells. The SkQR1-mediated protection of the brain also goes with the involvement of glycogen synthase kinase activity. We conclude that SkQR1 affords the protection of kidney and brain tissue against oxidative stress-related pathologies with multiple mechanisms of both direct antioxidative effects involved as well as with involvement of induction of protective mechanisms in order to amplify signaling pathways and better guarantee the global and maximally effective mitochondria, cell, organ and organism defense.

Homo Sapiens Liberatus Workshop, Moscow State University, May 2010