Mechanisms of action of manuka honey in an equine model of second intention wound healing: current thoughts and future directions

Main Article Content

Albert S Tsang Andrew Jonathan Dart Christina M Dart Leo B Jeffcott

Abstract

Honey has been utilized for the treatment of wounds by ancient civilizations for millennia. In recent times, there has been renewed interest in the use of honey in the treatment of chronic wounds and burns in response to the increased development of antimicrobial resistance to antibiotics. The physical properties of honey enhance wound healing by increasing the release of oxygen from hemoglobin, inactivating bacterial proteases and drawing fluid out of the wound bed initiating autolytic debridement. Honey also has broad spectrum antimicrobial activity. Peroxide or non-peroxide bactericidal activity is derived from phytochemicals drawn from specific plant species. Of the honey varietals, manuka honey, from the manuka tree (Leptospermum scoparium) is the most widely studied for its non-peroxide antimicrobial properties and ability to improve wound healing. This review summarizes the known mechanisms of action of manuka honey and the results of 4 experimental studies performed by the authors using an equine model of second intention healing. In addition, the future direction of research investigating the use of different varietals of honey as a therapeutic agent to enhance wound healing is explored.

Article Details

How to Cite
TSANG, Albert S et al. Mechanisms of action of manuka honey in an equine model of second intention wound healing: current thoughts and future directions. Medical Research Archives, [S.l.], v. 6, n. 7, july 2018. ISSN 2375-1924. Available at: <https://journals.ke-i.org/index.php/mra/article/view/1816>. Date accessed: 16 dec. 2018.
Section
Review Articles

References

1. Sipos P, Gyory H, Hagymasi K, Ondrejka P, Blazovics A. Special wound healing methods used in ancient Egypt and the mythological background. World J Surg. 2004;28(2):211–6.
2. Majno G. The healing hand: man and wound in the ancient world. Cambridge: Harvard University Press; 1991.
3. Li S, Luo X. Bencao gangmu: Compendium of materia medica. Beijing: Foreign Languages Press; 2003.
4. Rogalska T. Healing the bee’s knees-on honey and wound healing. JAMA Dermatol. 2016;152(3):275.
5. Oryan A, Alemzadeh E, Moshiri A. Biological properties and therapeutic activities of honey in wound healing: a narrative review and meta-analysis. J Tissue Viability. 2016;25(2):98–118.
6. Subrahmanyam M. Honey dressing for burns: an appraisal. Ann Burns Fire Disasters. 1996;9(1):33–35.
7. Dart AJ, Bischofberger AS, Dart CM, Jeffcott LB. A review of research into second intention equine wound healing using manuka honey: Current recommendations and future applications. Equine Vet Educ. 2015;27:658-664.
8. Carter DA, Blair SE, Cokcetin NN, Bouzo D, Brooks P, Schothauer R, Harry EJ. Therapeutic manuka honey: no longer so alternative. Front Microbiol. 2016;7:569.
9. Molan PC. The evidence supporting the use of honey as a wound dressing. Int J Low Extrem Wounds. 2006;5:40-54.
10. Lee JH, Park JH, Kim JA, Neupane GP, Cho MH, Lee CS, Lee J. Low concentrations of honey reduce biofilm formation, quorum sensing, and virulence in Escherichia coli O157:H7. Biofouling. 2011;27:1095-1104.
11. Lee DS, Sinno S, Khachemoune A. Honey and wound healing an overview. Am J Clin Dermatol. 2011;12:181-190.
12. Allen KL, Molan PC, Reid GM. A survey of the antibacterial activity of some New-Zealand honeys. J Pharm Pharmacol. 1991;43:817-822.
13. Cooper RA, Jenkins L. A comparison between medical grade honey and table honeys in relation to antimicrobial efficacy. Wounds. 2009;21:29-36.
14. Kwakman P, te Velde AA, de Boer L, Vandenbroucke-Grauls CMJE, Zaat SA. Two major medicinal honeys have different mechanisms of bactericidal activity. PLoS One. 2011;6:e17709.
15. Carnwath R, Graham EM, Reynolds K, Pollock PJ. The antimicrobial activity of honey against common equine wound pathogens. Vet J. 2014;199:110-114.
16. Cooper RA. Honey as an effective antimicrobial treatment for chronic wounds: is there a place for it in modern medicine? Chronic Wound Care Manage Res. 2014;1:15-22.
17. Shah S. Manuka honey: it’s role in wound healing and inflammation [dissertation]. Cardiff, Wales: Cardiff Metropolitan University; 2017. 51 p.
18. Snow MJ, Manley-Harris M. On the nature of non-peroxide antibacterial activity in New Zealand manuka honey. Food Chem. 2004;84:145-147.
19. Stephens JM, Schlothauer RC, Morris BD, Yang D, Fearnley L, Greenwood DR, Loomes KM. Phenolic compounds and methylglyoxal in some New Zealand manuka and kanuka honeys. Food Chem. 2010;120:78–86.
20. Bigbie, RB, Schumacher, J, Swaim, SF, Purohit RC, Wright JC. Effects of amnion and live yeast-cell derivative on second-intention healing in horses. Am J Vet Res. 1991;52:1376-1382.
21. Wilmink JM, Stolk PWTH, Van Weeren PR, Barneveld A. Differences in second-intention wound healing between horses and ponies: macroscopic aspects. Equine Vet J. 1999;31(1):53-60.
22. Dart AJ, Perkins NR, Dart CM, Jeffcott LB, Canfield P. Effect of bandaging on second intention healing of wounds of the distal limb in horses. Aust Vet J. 2009;87(6):215-218.
23. Clayton W, Elasy TA. A review of the pathophysiology, classification, and treatment of foot ulcers in diabetic patients. Clinical Diabetes. 2009;27(2):52-58.
24. Kwakman PHS, Zaat SAJ. Antibacterial components of honey. Life. 2012;64:48-55.
25. Lin JK, Weng MS. Flavonoids as nutraceuticals. In: Grotewold E, ed. The Science of Flavonoids. New York, NY: Springer New York; 2006.
26. Saikaly SK, Khachemoune A. Honey and wound healing: an update. Am J Clin Dermatol. 2017;18(2):237-251.
27. Molan PC. The role of honey in the management of wounds. J Wound Care. 1999;8:415-418.
28. Molan PC. The evidence and the rationale for the use of honey as a wound dressing. Wound Pract Res. 2011;19:204-220.
29. Beldon P. Basic science of wound healing. Surgery (Oxford). 2010;28(9):409–412.
30. Gethin GT. The impact of manuka honey dressings on the surface of chronic wounds. Int Wound J. 2008;5:185-194.
31. Tarnuzzer RW, Schultz GS. (1996) Biochemical analysis of acute and chronic wound environments. Wound Repair Regen. 1996;4:321-325.
32. White JW, Schepartz AI, Subers MH. (1963) Identification of inhibine, the antibacterial factor in honey, as hydrogen peroxide and its origin in a honey glucose-oxidase system. Biochimica et Biophysica Acta. 1963;73(1):57-70.
33. Bang LM, Buntting C, Molan P. The effect of dilution on the rate of hydrogen peroxide production in honey and its implications for wound healing. J Altern Complement Med. 2003;9:267-273.
34. Schmidt KN, Amstad P, Cerutti P, Baeuerle PA. The roles of hydrogen peroxide and superoxide as messengers in the activation of transcription factor NF-κB. Chem Biol. 1995;2(1):13-22.
35. Irish J, Blair S, Carter DA. The antibacterial activity of honey derived from Australian flora. PLoS One. 2011;6:e18229.
36. Chelikani P, Fita I, Loewen PC. Diversity of structures and properties among catalases. Cell Mol Life Sci. 2004;61:192-208.
37. Chen C, Campbell LT, Blair SE, Carter DA. (2012) The effect of standard heat and filtration processing procedures on antimicrobial activity and hydrogen peroxide levels in honey. Front Microbiol. 2012;3:265.
38. Brudzynski K, Sjaarda C, Maldonado-Alvarez L. A new look on protein-polyphenol complexation duign honey storage: is this a random or organized event with the help of dirigent-like proteins. PLoS One. 2013;8:e72897.
39. Pasias IN, Kiriakou IK, Kaitatzis A, Koutelidakis AE, Proestos C. Effect of late harvest and floral origin on honey antibacterial properties and quality parameters. Food Chem. 2018;242:513-518.
40. Mavric E, Wittmann S, Barth G, Henle T. Identification and quantification of methylglyoxal as the dominant antibacterial constituent of Manuka (Leptospermum scoparium) honeys from New Zealand. Mol Nutr Food Res. 2008;52:483-489.
41. Adams CJ, Manley-Harris M, Molan PC. The origin of methylglyoxal in New Zealand manuka (Leptospermum scoparium) honey. Carbohydr Res. 2009;344:1050-1053.
42. Atrott J, Haberlau S, Henle T. Studies on the formation of methylglyoxal from dihydroxyacetone in manuka (Leptospermum scoparium) honey. Carbohydr Res. 2012;361:7-11.
43. Majtan J, Bohova J, Prochazka E, Klaudiny J. Methylglyoxal may affect hydrogen peroxide accumulation in manuka honey through the inhibition of glucose oxidase. J Med Food. 2014;17:290-293.
44. Molan PC. The antibacterial activity of honey: 2.Variation in the potency of the antibacterial activity. Bee World. 1992;73(2):59-76.
45. Kato Y, Umeda N, Maeda A, Matsumoto D, Kitamoto N, Kikuzaki H. Identification of a novel glycoside, leptosin, as a chemical marker of manuka honey. J Agric Food Chem. 2012;60:3418-3423.
46. Bucekova M, Sojka M, Valachova I, Martinotti S, Ranzato E, Szep Z, Majtan V, Klaudiny J, Majtan J. Bee-derived antibacterial peptide, defensin-1, promotes wound re-epithelialisation in vitro and in vivo. Sci Rep. 2017;7:7340.
47. Majtan J, Klaudiny J, Bohova J, Kohutova L, Dzurova M, Sediva M, Bartosova M, Majtan V. Methylglyoxal-induced modifications of significant honeybee proteinous components in manuka honey: possible therapeutic implications. Fitoterapia. 2012;83(4):671–7.
48. Unique Manuka Factor® Honey Association. UMF® Grading System. Unique Manuka Factor® Honey Association. http://www.umf.org.nz/grading-system-explained/. Updated 2016. Accessed June 12, 2016.
49. Molan P. Why honey is effective as a medicine: 2.The scientific explanation of its effects. Bee World. 2001;82:22-40.
50. Jenkins R, Burton N, Cooper R. Effect of manuka honey on universal stress protein A in methicillin Staphylococcus aureus. Int J Antimicrob Agents. 2011;37:373-376.
51. Jenkins R, Burton N, Jenkins R. Manuka honey inhibits cell division in methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother. 2011;66:2536-2542.
52. Henriques AF, Jenkins RE, Burton NF, Cooper RA. The effect of manuka honey on the structure of Pseudomonas aeruginosa. Eur J Clin Microbiol Infect Dis. 2011;30:167-171.
53. Roberts AE, Maddocks SE, Cooper RA. Manuka honey is bactericidal against Pseudomonas aeruginosa and results in differential expression of oprF and algD. Microbiology. 2012;158:3005-3013.
54. Kronda JM, Cooper RA, Maddocks SE. Manuka honey inhibits siderophore production in Pseudomonas aeruginosa. J Appl Microbiol. 2013;115(1):86–90.
55. Jenkins RE, Cooper R. Synergy between oxacillin and manuka honey sensitizes methicillin-resistant Staphylococcus aureus to oxacillin. J Antimicrob Chemother. 2012;67(6):1405–7.
56. Serralta VW, Harrison-Balestra C, Cazzaniga AL, Davis SC, Mertz PM. Lifestyles of bacteria in wounds: presence of biofilms? Wounds. 2001;13:29-34.
57. Freeman K, Woods E, Welsby S, Percival SL, Cochrane CA. Biofilm evidence and the microbial diversity of horse wounds. Can J Microbiol. 2009;55:197-202.
58. Merckoll P, Jonasson TO, Vad ME, Jeansson SL, Melby KK. Bacteria, biofilm and honey: a study of the effects of honey on ‘planktonic’ and biofilm-embedded chronic wound bacteria. Scand J Infect Dis. 2009;41:341-347.
59. Maddocks SE, Lopez MS, Rowlands RS, Cooper RA. Manuka honey inhibits the development of Streptococcus pyogenes biofilms and causes reduced expression of two fibronectin binding proteins. Microbiology. 2012;58:781-790.
60. Jervis-Bardy J, Foreman A, Boase S, Valentine R, Wormald PJ. What is the origin of Staphylococcus aureus in the early postoperative sinonasal cavity? Int. Forum Allergy Rhinol. 2011;4:308-312.
61. Jervis-Bardy J, Foreman A, Bray S, Tan L, Wormald PJ. Methylglyoxal-infused honey mimics the anti-Staphylococcus aureus biofilm activity on manuka honey: potential implications in rhinosinusitis. Laryngoscope. 2011;121:1104-1107.
62. Jenkins R, Burton N, Cooper RA. Proteomic and genomic analysis of methicillin-resistant Staphylococcus aureus (MRSA) exposed to manuka honey in vitro demonstrated down-regulation of virulence markers. J Antimicrob Chemother. 2014;69:603-615.
63. Wang R, Strakey M, Hazan R, Rahme LG. Honey’s ability to counter bacterial infections arises from both bactericidal compounds and QS inhibition. Front Microbiol. 2012;3:144.
64. Alandejani T, Marsan J, Ferris W, Slinger R, Chan F. Effectiveness of honey on Staphylococcus aureus and Psuedomonas aureginosa biofilms. Otolaryngol Head Neck Surg. 2009;141:114-118.
65. Kilty SJ, Duval M, Chan FT, Ferris W, Slinger R. Methylglyoxal: (active agent of manuka honey) in vitro activity against bacterial biofilms. Int Forum Allergy Rhinol. 2011;1(5):348-350.
66. Tonks AJ, Dudley E, Porter NG, Parton J, Brazier J, Smith EL, Tonks AA. A 5.8-kDa component of manuka honey stimulates immune cells via TLR4. J Leukocyte Biol. 2007;82:1147-1155.
67. Tonks A, Cooper RA, Price AJ, Molan PC, Jones KP. Stimulation of TNF- alpha release in monocytes by honey. Cytokine. 2001;14:240-242.
68. Tonks AJ, Cooper RA, Jones KP, Blair S, Parton J, Tonks A. Honey stimulates inflammatory cytokine production from monocytes. Cytokine. 2003;21:242-247.
69. Majtan J. Honey: an immunomodulator in wound healing. Wound Repair Regen. 2014;22(2):187–92.
70. Martin P, Leibovich SJ. Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol. 2005;15:599–607.
71. Dovi JV, He LK, DiPietro LA. Accelerated wound closure in neutrophil-depleted mice. J Leukoc Biol. 2003;73:448–455.
72. Hussein SZ, Mohd Yusoff K, Makpol S, Mohd Yusoff YA. Gelam honey inhibits the production of proinflammatory, mediators NO, PGE2, TNF-α, and IL-6 in carrageenan-induced acute paw edema in rats. Evid Based Complement Alternat Med. 2012;2012:109636. doi:10.1155/2012/109636.
73. Almasaudi SB, El-Shitany NA, Abbas AT, Abdel-dayem UA, Ali SS, Al Jaouni SK, Harakeh S. Antioxidant, anti-inflammatory, and antiulcer potential of manuka honey against gastric ulcer in rats. Oxid Med Cell Longev. 2016;2016:3643824. doi: 10.1155/2016/3643824.
74. Kulakova E. The role of Manuka honey in wound healing and inflammation using IL-6 and human dermal fibroblasts as model systems [dissertation]. Cardiff, Wales: Cardiff Metropolitan University; 2017. 37 p.
75. Bischofberger AS, Dart CM, Perkins NR, Dart AJ. A preliminary study on the effect of manuka honey on second intention healing of contaminated wounds on the distal aspect of the forelimbs of horses. Vet Surg. 2011;40:898-902.
76. Bischofberger AS, Dart CM, Perkins NR, Kelly A, Jeffcott L, Dart AJ. The effect of short and long-term treatment with manuka honey on second intention healing of contaminated and non-contaminated wounds on the distal aspect of the forelimbs in horses. Vet Surg. 2013;42:154-160.
77. Bischofberger AS, Dart CM, Horadagoda N, Perkins NR, Jeffcott LB, Little CB, Dart AJ. Effect of Manuka honey gel on the transforming growth factor β1 and β3 concentrations, bacterial counts and histomorphology of contaminated full‐thickness skin wounds in equine distal limbs. Aust Vet J. 2015;94(1-2):27-34.
78. Tsang A, Dart A, Sole‐Guitart A, Dart C, Perkins N, Jeffcott L. (2017) Comparison of the effects of topical application of UMF20 and UMF5 manuka honey with a generic multifloral honey on wound healing variables in an uncontaminated surgical equine distal limb wound model. Aust Vet J. 2017;95:333-337.
80. Berry DB, Sullins KE. Effects of topical application of antimicrobials and bandaging on healing and granulation tissue formation in wounds of the distal aspect of the limbs in horses. Am J Vet Res. 2003;64:88-92.
81. Theoret CL, Barber SM, Moyana TN, Gordon JR. Expression of transforming growth factor beta (1), beta (3), and basic fibroblast growth factor in full-thickness skin wounds of equine limbs and thorax. Vet Surg. 2001;30:269-277.
82. Theoret C, Wilmink JM. Why do horses develop exuberant granulation tissue and how do we deal with it? In: Proceedings of North American Veterinary Conference of the North American Veterinary Community; 2008; Orlando, FL: The North American Veterinary Community; 2008. p. 237-240.
83. Cokcetin NN, Pappalardo M, Campbell LT, Brooks P, Carter DA, Blair SE, Harry EJ. The antibacterial activity of Australian Leptospermum honey correlates with methylglyoxal levels. Plos One. 2016;11(12):e0167780.
84. Roshan N, Rippers T, Locher C, Hammer KA. Antibacterial activity and chemical characteristics of several Western Australian honeys compared to manuka honey and pasture honey. Arch Microbiol. 2017;199(2):347-355.
85. Australian Manuka Honey Association. About the Australian Manuka Honey Association. https://www.manukaaustralia.org.au/about-us/. Updated 2018. Accessed May 10, 2018.
86. Lusby PE, Coombes A, Wilkinson JM. Honey: a potent agent for wound healing? J Wound Ostomy Continence Nurs. 2002;29(6):295-300.
87. Boulton AJM, Vileikyte L, Ragnarson-Tennvall G, Apelgvist J. The global burden of diabetic foot disease. Lancet. 2005;366(9498):1719-1724.
88. Jull AB, Cullum N, Dumville JC, Westby MJ, Deshpande S, Walker N. Honey as a topical treatment for wounds. Cochrane Database Syst Rev. 2015;(3):Cd005083. doi:10.1002/14651858.CD005083.pub4.
89. Liu MY, Cokcetin NN, Lu J, Turnball L, Carter DA, Whitchurch CB, Harry EJ. Rifampicin-manuka honey combinations are superior to other antibiotic-manuka honey combinations in eradicating Staphylococcus aureus biofilms. Front Microbiol. 2017;8:2653. doi:10.3389/fmicb.2017.02653.
90. Imran M, Hussain MB, Baig M. A randomized, controlled clinical trial of honey-impregnated dressing for treating diabetic foot ulcer. J Coll Phys Surg Pak. 2015;25(10):721–5.
91. Paramasivan S, Drilling AJ, Jardeleza C, Jervis‐Bardy J, Vreugde S, Wormald PJ. Methylglyoxal‐augmented manuka honey as a topical anti–Staphylococcus aureus biofilm agent: safety and efficacy in an in vivo model. Int Forum Allergy Rhinol. 2014;4:187‐195.
92. Wallace A, Eady S, Miles M, Martin H, McLachlan A, Rodier M, Willis J, Scott R, Sutherland J. Demonstrating the safety of manuka honey UMF® 20+in a human clinical trial with healthy individuals. Br J Nutr. 2010;103(7):1023-1028.
93. Aysan E, Ayar E, Aren A, Cifter C. The role of intra-peritoneal honey administration in preventing post-operative peritoneal adhesions. Eur J Obstet Gynecol Reprod Biol. 2002;104(2):152-155.

Most read articles by the same author(s)

Obs.: This plugin requires at least one statistics/report plugin to be enabled. If your statistics plugins provide more than one metric then please also select a main metric on the admin's site settings page and/or on the journal manager's settings pages.