Prospects for Drugs Based on the Mitochondria-Targeting Antioxidant SkQ1 in Treatment of Wounds with Impaired Healing

Chronic wounds with impared wound healing that require prolong time for healing remain unsolved problem of modern medicine. Excessive oxidative stress plays an important role in the pathogenesis of chronic wounds caused by aging, diabetes and other pathologies. This review is aimed at the role of mitochondria in oxidative stress and to the future prospects for using the innovative mitochondria targeted antioxidants for treatment of impaired wounds. Recent studies in old mice and mice with type 2 diabetes showed that the mitochondrial antioxidant SkQ1 [10- (6'- plastoquinonyl) decyltriphenylphosphonium] stimulates healing of full-thickness dermal wounds. SkQ1 accelerates inflammatory stage of wound healing, maturation of granulation tissue, angiogenesis and epithelization of wounds. The anti-inflammatory effect of SkQ1 is possibly connected to decreased inflammatory activation of the vascular endothelium, which is typical for aging, diabetes and other pathologies. Local administration of SkQ1 also accelerates wound healing and provides strong anti-inflammatory effect in the model of acute aseptic inflammation. In addition, SkQ1 to stimulate apoptosis of neutrophils and suppresses their activation, as well as suppresses inflammatory activation of mast cells. In the wound model in vitro, SkQ1 accelerates movement of epithelial cells and fibroblasts into the «wound» and stimulates differentiation of human subcutaneous fibroblasts to myofibroblasts. Reviewed data suggest that SkQ1-based topical drugs have a great potential to treat wounds that exhibit impaired healing also in patients suffering from chronic critical illness.

reactive oxygen species, mitochondria, wound healing

1. Singer A.J., Clark R.A. Cutaneous wound healing. N. Engl. J. Med. 1999; 341 (10): 738–746. DOI: 10.1056/NEJM199909023411006. PMID: 10471461

2. Reinke J.M., Sorg H. Wound repair and regeneration. Eur. Surg. Res. 2012; 49 (1): 35–43. DOI: 10.1159/000339613. PMID: 22797712

3. Diegelmann R.F., Evans M.C. Wound healing: an overview of acute, fibrotic and delayed healing. Front. Biosci. 2004; 9: 283–289. DOI: 10.2741/1184. PMID: 14766366

4. Dunnill C., Patton T., Brennan J., Barrett J., Dryden M., Cooke J., Leaper D., Georgopoulos N.T. Reactive oxygen species (ROS) and wound healing: the functional role of ROS and emerging ROS-modulating technologies for augmentation of the healing process. Int. Wound J. 2017; 14 (1): 89–96. DOI: 10.1111/iwj.12557. PMID: 26688157

5. Martin P. Wound healing-aiming for perfect skin regeneration. Science. 1997; 276 (5309): 75–81. DOI: 10.1126/science.276.5309.75. PMID: 9082989

6. Darby I.A., Laverdet B., Bonté F., Desmoulière A. Fibroblasts and myofibroblasts in wound healing. Clin. Cosmet. Investig. Dermatol. 2014; 7: 301–311. DOI: 10.2147/CCID.S50046. PMID: 25395868

7. Tonnesen M.G., Feng X., Clark R.A. Angiogenesis in wound healing. J. Investig. Dermat. Symp. Proc. 2000; 5 (1): 40–46. DOI: 10.1046/j.1087- 0024.2000.00014.x. PMID: 11147674

8. Lazarus G.S., Cooper D.M., Knighton D.R., Margolis D.J., Pecoraro R.E., Rodeheaver G., Robson M.C. Definitions and guidelines for assessment of wounds and evaluation of healing. Arch. Dermatol. 1994; 130 (4): 489– 493. DOI: 10.1001/archderm.130.4.489. PMID: 8166487

9. Swift M.E., Kleinman H.K., DiPietro L.A. Impaired wound repair and delayed angiogenesis in aged mice. Lab. Invest. 1999; 79 (12): 1479–1487. PMID: 10616199

10. Snyder R.J. Treatment of nonhealing ulcers with allografts. Clin. Dermatol. 2005; 23 (4): 388–395. DOI: 10.1016/j.clindermatol.2004.07.020. PMID: 16023934

11. La Fontaine J., Harkless L.B., Davis C.E., Allen M.A., Shireman P.K. Current concepts in diabetic microvascular dysfunction. J. Am. Podiatr. Med. Assoc. 2006; 96 (3): 245–252. DOI: 10.7547/0960245. PMID: 16707637

12. Gosain A., DiPietro L.A. Aging and wound healing. World J. Surg. 2004; 28 (3): 321–326. DOI: 10.1007/s00268-003-7397-6. PMID: 14961191

13. Rodriguez P.G., Felix F.N., Woodley D.T., Shim E.K. The role of oxygen in wound healing: a review of the literature. Dermatologic Surg. 2008; 34 (9): 1159–1169. DOI: 10.1111/j.1524-4725.2008.34254.x. PMID: 18513296

14. Roy S., Khanna S., Sen C.K. Redox regulation of the VEGF signaling path and tissue vascularization: hydrogen peroxide, the common link between physical exercise and cutaneous wound healing. Free Radic. Biol. Med. 2008; 44 (2): 180–192. DOI: 10.1016/j.freeradbiomed.2007.01.025. PMID: 18191754

15. Bickers D.R., Lim H.W., Margolis D., Weinstock M.A., Goodman C., Faulkner E., Gould C., Gemmen E., Dall T., American Academy of Dermatology Association; Society for Investigative Dermatology. The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J. Am. Acad. Dermatol. 2006; 55 (3): 490–500. DOI: 10.1016/j.jaad.2006.05.048. PMID: 16908356

16. Mustoe T.A., O’Shaughnessy K., Kloeters O. Chronic wound pathogenesis and current treatment strategies: a unifying hypothesis. Plast. Reconstr. Surg. 2006; 117 (7 Suppl): 35S–41S. DOI: 10.1097/01.prs.0000225431.63010.1b. PMID: 16799373

17. Roy S., Khanna S., Nallu K., Hunt T. K., Sen C.K. Dermal wound healing is subject to redox control. Mol. Ther. 2006; 13 (1): 211–220. DOI: 10.1016/j.ymthe.2005.07.684. PMID: 16126008

18. Ojha N., Roy S., He G., Biswas S., Velayutham M., Khanna S., Kuppusamy P., Zweier J.L., Sen C.K. Assessment of wound-site redox environment and the significance of Rac2 in cutaneous healing. Free Radic. Biol. Med. 2008; 44 (4): 682–691. DOI: 10.1016/j.freeradbiomed.2007.10.056. PMID: 18068132

19. Sen C.K., Roy S. Redox signals in wound healing. Biochim. Biophys. Acta. 2008; 1780 (11): 1348–1361. DOI: 10.1016/j.bbagen.2008.01.006. PMID: 18249195

20. Sen C.K., Khanna S., Babior B.M., Hunt T.K., Ellison E.C., Roy S. Oxidantinduced vascular endothelial growth factor expression in human keratinocytes and cutaneous wound healing. J. Biol. Chem. 2002; 277 (36): 33284–33290. DOI: 10.1074/jbc.M203391200. PMID: 12068011

21. Bishop A. Role of oxygen in wound healing. J. Wound Care. 2008; 17 (9): 399–402. DOI: 10.12968/jowc.2008.17.9.30937. PMID: 18833899

22. Tandara A.A., Mustoe T.A. Oxygen in wound healing-more than a nutrient. World J. Surg. 2004; 28 (3): 294–300. DOI: 10.1007/s00268-003- 7400-2. PMID: 14961188

23. Toledo-Pereyra L.H., Lopez-Neblina F., Toledo A.H. Reactive oxygen species and molecular biology of ischemia/reperfusion. Ann. Transplant. 2004; 9 (1): 81–83. PMID: 15478900

24. Willam C., Schindler R., Frei U., Eckardt K.U. Increases in oxygen tension stimulate expression of ICAM-1 and VCAM-1 on human endothelial cells. Am. J. Physiol. 1999; 276 (6 Pt 2): H2044-H2052. DOI: 10.1152/ajpheart.1999.276.6.H2044. PMID: 10362686

25. Herrick S.E., Sloan P., McGurk M., Freak L., McCollum C.N., Ferguson M.W. Sequential changes in histologic pattern and extracellular matrix deposition during the healing of chronic venous ulcers. Am. J. Pathol. 1992; 141 (5): 1085–1095. PMID: 1279979

26. Oskeritzian C.A. Mast cells and wound healing. Adv. Wound Care. 2012; 1 (1): 23–28. DOI: 10.1089/wound.2011.0357. PMID: 24527274

27. Nakamura A., Osonoi T., Terauchi Y. Relationship between urinary sodium excretion and pioglitazone-induced edema. J. Diabetes Investig. 2010; 1 (5): 208–211. DOI: 10.1111/j.2040-1124.2010.00046.x. PMID: 24843434

28. Wulff B.C., Wilgus T.A. Mast cell activity in the healing wound: more than meets the eye? Exp. Dermatol. 2013; 22 (8): 507–510. DOI: 10.1111/exd.12169. PMID: 23802591

29. Neyens J.C., Cereda E., Meijer E.P., Lindholm C., Schols J.M. Arginine-enriched oral nutritional supplementation in the treatment of pressure ulcers: a literature review. Wound Med. 2017; 16: 46–51. DOI: 10.1016/j.wndm.2016.07.002

30. Blass S.C., Goost H., Tolba R.H., Stoffel-Wagner B., Kabir K., Burger C., Stehle P., Ellinger S. Time to wound closure in trauma patients with disorders in wound healing is shortened by supplements containing antioxidant micronutrients and glutamine: a PRCT. Clin. Nutr. 2012; 31 (4): 469–475. DOI: 10.1016/j.clnu.2012.01.002. PMID: 22284340

31. Guseinov A.Z., Molchanov D.A., Chiglashvili D.S., Kudryavtseva O.V. Antioksidants and immunomodulyators in complex treatment of venous trophic cankers. Vestnik Novykh Meditsinskikh Tekhnologii. 2009; 16 (4): 106-107. [In Russ.]

32. Savelyev V.S. (ed.). Treatment of trophic ulcers of venous etiology. Manual for doctors.Moscow; 2000: 22. [In Russ.]

33. Shakhmardanova S.A., Gulevskaya O.N., Seletskaya V.V., Zelenskaya A.V., Khananashvili Ya.A., Nefedov D.A., Galenko-Yaroshevsky P.A. Antioxidants: classification, pharmacological properties the use in the practice of medicine. Zhurnal Fundamentalnoi Meditsiny i Biologii. 2016; 3: 4–15. [In Russ.]

34. Lovat M.L., Avrushchenko M.S., Averina O.A., Pavshintsev V.V., Ostrova I.V., Zarzhetsky Y.V., Moroz V.V., Egorov M.V. Effect of SkQ1 antioxidant on structural and functional conditions of the brain in postresuscitation period. Obshchaya Reanimatologiya = General Reanimatology. 2016; 12 (2): 6–19. DOI: 10. 15360/1813-9779-2016-2-6-19. [In Russ., In Engl.]

35. Lutsevich O.E., Tamrazova O.B., Tolstykh P.I., Derbenev V.A., Medusheva E.O., Avagyan A.A., Sorokatyi A.A. Modern biologically active wound coverings and occlusive dressing in complex treatment of patients with trophic ulcers of lower limbs of venous genesis. Khirurg. 2011; 1: 13–18. [In Russ.]

36. Babior B.M. Phagocytes and oxidative stress. Am. J. Med. 2000; 109 (1): 33–44. DOI: 10.1016/S0002-9343(00)00481-2. PMID: 10936476

37. Babior B.M. The NADPH oxidase of endothelial cells. IUBMB Life. 2001; 50 (4): 267–269. DOI: 10.1080/713803730. PMID: 11327320

38. Chernyak B.V., Izyumov D.S., Lyamzaev K.G., Pashkovskaya A.A., Pletjushkina O.Y., Antonenko Y.N., Sakharov D.V, Wirtz K.W.A., Skulachev V.P. Production of reactive oxygen species in mitochondria of HeLa cells under oxidative stress. Biochim. Biophys. Acta. 2006; 1757 (5–6): 525– 534. DOI: 10.1016/j.bbabio.2006.02.019. PMID: 16678116

39. Zhou R., Yazdi A.S., Menu P., Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011; 469 (7329): 221–225. DOI: 10.1038/nature09663. PMID: 21124315

40. Dashdorj A., Jyothi K.R., Lim S., Jo A., Nguyen M.N., Ha J., Yoon K.S., Kim H. J., Park J.H., Murphy M.P., Kim S.S. Mitochondria-targeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasome-mediated inflammatory cytokines. BMC Med. 2013; 11: 178. DOI: 10.1186/1741-7015-11-178. PMID: 23915129

41. Madamanchi N.R., Runge M.S. Mitochondrial dysfunction in atherosclerosis. Circ. Res. 2007; 100 (4): 460–473. DOI: 10.1161/01.RES. 0000258450.44413.96. PMID: 17332437

42. Dikalov S.I., Ungvari Z. Role of mitochondrial oxidative stress in hypertension. Am. J. Physiol. Heart Circ. Physiol. 2013; 305 (10): H1417- H1427. DOI: 10.1152/ajpheart.00089.2013. PMID: 24043248

43. Tompkins A.J., Burwell L.S., Digerness S.B., Zaragoza C., Holman W.L., Brookes P.S.Mitochondrial dysfunction in cardiac ischemia–reperfusion injury: ROS from complex I, without inhibition. Biochim. Biophys. Acta. 2006; 1762 (2): 223–231. DOI: 10.1016/j.bbadis.2005.10.001. PMID: 16278076

44. Skulachev M.V., Antonenko Y.N., Anisimov V.N., Chernyak B.V., Cherepanov D.A., Chistyakov V.A., Egorov M.V., Kolosova N.G., Korshunova G.A., Lyamzaev K.G., Plotnikov E.Y., Roginsky V.A., Savchenko A.Y., Severina I.I., Severin F.F., Shkurat T.P., Tashlitsky V.N., Shidlovsky K.M., Vyssokikh M.Y., Zamyatnin A.A.Jr., Zorov D.B., Skulachev V.P. Mitochondrial-targeted plastoquinone derivatives. Effect on senescence and acute age-related pathologies. Curr. Drug Targets. 2011; 12 (6): 800– 826. DOI: 10.2174/138945011795528859. PMID: 21269268

45. Feniouk B.A., Skulachev V.P. Cellular and molecular mechanisms of action of mitochondria-targeted antioxidants. Curr. Aging Sci. 2017; 10 (1): 41– 48. DOI: 10.2174/1874609809666160921113706. PMID: 27659264

46. Bast A., Haenen G.R. The toxicity of antioxidants and their metabolites. Environ. Toxicol. Pharmacol. 2002; 11 (3–4): 251–258. DOI: 10.1016/ S1382-6689(01)00118-1. PMID: 21782609

47. Gonzalvez F., Gottlieb E. Cardiolipin: setting the beat of apoptosis. Apoptosis. 2007; 12 (5): 877–885. DOI: 10.1007/s10495-007-0718-8. PMID: 17294083

48. Yani E.V., Katargina L.A., Chesnokova N.B., Beznos O.V., Savchenko A.Yu., Vygodin V.A., Gudkova E.Yu., Zamyatnin A.A.Jr., Skulachev M.V. The first experience of using the drug Vizomitin in the treatment of «dry eyes». Prakticheskaya Meditsina. 2012; 4-1 (59): 134–137. [In Russ.]

49. Brzheskiy V.V., Efimova E.L., Vorontsova T.N., Alekseev V.N., Gusarevich O.G., Shaidurova K.N., Ryabtseva A.A., Andryukhina O.M., Kamenskikh T.G., Sumarokova E.S., Miljudin E.S., Egorov E.A., Lebedev O.I., Surov A.V., Korol A.R., Nasinnyk I.O., Bezditko P.A., Muzhychuk O.P., Vygodin V.A., Yani E.V., Savchenko A.Y., Karger E.M., Fedorkin O.N., Mironov A.N., Ostapenko V., Popeko N.A., Skulachev V.P., Skulachev M.V. Results of a multicenter, randomized, double-masked, placebo-controlled clinical study of the efficacy and safety of visomitin eye drops in patients with dry eye syndrome. Adv. Ther. 2015; 32 (12): 1263–1279. DOI: 10.1007/s12325-015-0273-6. PMID: 26660938

50. Petrov A., Perekhvatova N., Skulachev M., Stein L., Ousler G. SkQ1 ophthalmic solution for dry eye treatment: results of a phase 2 safety and efficacy clinical study in the environment and during challenge in the controlled adverse environment model. Adv. Ther. 2016; 33 (1): 96–115. DOI: 10.1007/s12325-015-0274-5. PMID: 26733410

51. Demyanenko I.A., Popova E.N., Zakharova V.V., Ilyinskaya O.P., Vasilieva T.V., Romashchenko V.P., Fedorov A.V., Manskikh V.N., Skulachev M.V., Zinovkin R. A., Pletjushkina O.Y., Skulachev V.P., Chernyak B.V. Mitochondria-targeted antioxidant SkQ1 improves impaired dermal wound healing in old mice. Aging (Albany. NY). 2015; 7 (7): 475–485. DOI: 10.18632/aging.100772. PMID: 26197706

52. Demyanenko I., Zakharova V., Ilyinskaya O., Vasilieva T., Fedorov A., Manskikh V., Zinovkin R., Pletjushkina O., Chernyak B., Skulachev V., Popova E. Mitochondria-targeted antioxidant SkQ1 improves dermal wound healing in genetically diabetic mice. Oxid. Med. Cell Longev. 2017; 2017: 6408278. DOI: 10.1155/2017/6408278. PMID: 28761623

53. Demianenko I.A., Vasilieva T.V., Domnina L.V, Dugina V.B., Egorov M.V., Ivanova O.Y., Ilinskaya O.P., Pletjushkina O.Y., Popova E.N., Sakharov I.Y., Fedorov A.V., Chernyak B.V. Novel mitochondria-targeted antioxidants, «Skulachev-ion» derivatives, accelerate dermal wound healing in animals. Biochemistry. (Mosc.). 2010; 75 (3): 274–280. PMID: 20370605. [In Russ., In Engl.]

54. Zinovkin R.A., Romaschenko V.P., Galkin I.I., Zakharova V.V., Pletjushkina O. Y., Chernyak B.V., Popova E.N. Role of mitochondrial reactive oxygen species in age-related inflammatory activation of endothelium. Aging (Albany. NY). 2014; 6 (8): 661–674. DOI: 10.18632/aging.100685. PMID: 25239871

55. Zakharova V.V., Pletjushkina O.Y., Galkin I.I., Zinovkin R.A., Chernyak B.V., Krysko D.V., Bachert C., Krysko O., Skulachev V.P., Popova E.N. Low concentration of uncouplers of oxidative phosphorylation decreases the TNF-induced endothelial permeability and lethality in mice. Biochim. Biophys. Acta. 2017; 1863 (4): 968–977. DOI: 10.1016/j.bbadis. 2017.01.024. PMID: 28131916

56. Duarte D.B., Vasko M.R., Fehrenbacher J.C. Models of inflammation: carrageenan air pouch. Curr. Protoc. Pharmacol. 2012; Chapter 5: Unit5.6. DOI: 10.1002/0471141755.ph0506s56. PMID: 22383000

57. Borthakur A., Bhattacharyya S., Anbazhagan A.N., Kumar A., Dudeja P.K., Tobacman J.K. Prolongation of carrageenan-induced inflammation in human colonic epithelial cells by activation of an NF B-BCL10 loop. Biochim. Biophys. Acta. 2012; 1822 (8): 1300–1307. DOI: 10.1016/j.bbadis.2012.05.001. PMID: 22579587

58. Chelombitko M.A., Popova E.N., Fedorov A.V., Ilyinskaya O.P. Effect of mitochondrial antioxidant 10- (6’-plastoquinonyl) decyltriphenylphosphonium bromide on the activation of mast cells of peritoneal exudate of mice and basophils of rat leukemia RBL-2H3. In: Science: discoveries and progress. Czech Republic: Mu︒stek; Russia: MTsNIP; 2016: 18–28. [In Russ.]

59. Chelombitko M.A., Averina O.A., Vasilyeva T.V., Pletiushkina O.Yu., Popova E.N., Fedorov A.V., Chernyak B.V., Shishkina V.S., Ilinskaya O.P. Mitochondria-targeted antioxidant SKQ1 (10-(6’’-plastoquinonyl) decyltriphenylphosphonium bromide) inhibits mast cells degranulation in vivo and in vitro. Biokhimiya. 2017; 82 (12): 1858-1871. [In Russ.]

60. Galkin I.I., Pletjushkina O.Y., Zinovkin R.A., Zakharova V.V., Birjukov I.S., Chernyak B.V., Popova E.N. Mitochondria-targeted antioxidants prevent TNF -induced endothelial cell damage. Biochemistry. (Mosc.). 2014; 79 (2): 124-130. DOI: 10.1134/S0006297914020059. PMID: 24794727. [In Russ., In Engl.]

61. Chelombitko M.A., Fedorov A.V., Ilyinskaya O.P., Zinovkin R.A., Chernyak B.V. Role of reactive oxygen species in mast cell degranulation (review). Biochemistry. (Mosc.). 2016; 81 (12): 1564-1577. DOI: 10.1134/S000629791612018X. PMID: 28259134. [In Russ., In Engl.]

62. Nazarov P.A., Osterman I.A., Tokarchuk A.V., Karakozova M.V., Korshunova G.A., Lyamzaev K.G., Skulachev M.V., Kotova E.A., Skulachev V.P., Antonenko Y.N. Mitochondria-targeted antioxidants as highly effective antibiotics. Sci. Rep. 2017; 7 (1): 1394. DOI: 10.1038/s41598- 017-00802-8. PMID: 28469140

63. Popova E.N., Pletjushkina O.Y., Dugina V.B., Domnina L.V., Ivanova O.Y., Izyumov D.S., Skulachev V.P., Chernyak B.V. Scavenging of reactive oxygen species in mitochondria induces myofibroblast differentiation. Antioxid. Redox. Signal. 2010; 13 (9): 1297–1307. DOI: 10.1089/ars.2009.2949. PMID: 20446771