Iranian Journal of Basic Medical Sciences

Iranian Journal of Basic Medical Sciences

Topical buspirone accelerates wound healing in rats through modulation of inflammation, angiogenesis, and collagen formation

Articles in Press

Document Type : Original Article

Authors
Mehdi Zahmatkesh 1, 2
Pari Tamri 1, 2
Mojdeh Mohammadi 1, 2
Fatemeh Mirzaei 3
1 Medicinal Plants and Natural Products Research Center, Institute of Cancer, Hamadan University of Medical Sciences, Hamadan, Iran
2 Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
3 Department of Anatomical Sciences, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
10.22038/ijbms.2026.96004.20706
Abstract
Objective(s): Cutaneous wound healing is a complex, multistep process that requires coordinated regulation of inflammation, cell proliferation, extracellular matrix deposition, and angiogenesis. This study evaluated the effects of topical buspirone, a partial 5-HT1A receptor agonist, on wound healing in a rat excisional wound model.
Materials and Methods: Full-thickness dorsal wounds were created in Wistar rats and treated with topical 0.5% buspirone, 1% phenytoin, vehicle, or left untreated. Wound contraction was assessed macroscopically, and hydroxyproline content, TNF-α, and TGF-β levels were measured to evaluate collagen deposition and inflammatory and fibrotic responses. Histopathological analysis and a chick chorioallantoic membrane (CAM) assay were also performed.
Results: Buspirone treatment significantly accelerated wound contraction at all time points compared with the control, vehicle, and phenytoin groups (P<0.001). Hydroxyproline levels were significantly increased, indicating enhanced collagen deposition. In addition, TNF-α levels were reduced, whereas TGF-β levels showed a moderate increase, suggesting balanced modulation of inflammation and fibrosis. Histological findings demonstrated improved re-epithelialization and dermal organization in the buspirone-treated group. Enhanced angiogenesis was also observed in the CAM assay.
Conclusion: Overall, topical buspirone may promote wound healing through coordinated effects on inflammation, collagen synthesis, tissue organization, and angiogenesis. This suggests that buspirone is a potential therapeutic agent for wound healing.
Keywords
5HT1A
Buspirone
Serotonin receptors
Skin
Wound healing
Subjects
1. Shaw TJ, Martin P. Wound repair at a glance. J Cell Sci 2009;122:3209-3213.
2. Reinke J, Sorg H. Wound repair and regeneration. Eur Surg Res 2012;49:35-43.
3. Morton LM, Phillips TJ. Wound healing and treating wounds: Differential diagnosis and evaluation of chronic wounds. J Am Acad Dermatol 2016;74:589-605; quiz -6.
4. Zarei H, Tamri P, Asl SS, Soleimani M, Moradkhani S. Hydroalcoholic extract of Scrophularia striata attenuates hypertrophic scar, suppresses collagen synthesis, and stimulates MMP2 and 9 gene expression in rabbit ear model. J Pharmacopuncture 2022;25:258-267.
5. Olsson M, Järbrink K, Divakar U, Bajpai R, Upton Z, Schmidtchen A, et al. The humanistic and economic burden of chronic wounds: A systematic review. Wound Repair Regen 2019;27:114-125.
6. Sen CK. Human wounds and its burden: An updated compendium of estimates. Adv Wound Care (New Rochelle) 2019;8:39-48.
7. Han G, Ceilley R. Chronic wound healing: A review of current management and treatments. Adv Ther 2017;34:599-610.
8. Wilkinson HN, Hardman MJ. Wound healing: Cellular mechanisms and pathological outcomes. Open Biol 2020;10: 200223.
9. Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, et al. Platelet-derived serotonin mediates liver regeneration. Science 2006;312:104-107.
10. Sadiq A, Menchetti I, Shah A, Jeschke MG, Belo C, Carlos-Alcalde W, et al. 5-HT1A receptor function makes wound healing a happier process. Front Pharmacol 2018;9:1406.
11. Idzko M, Panther E, Stratz C, Müller T, Bayer H, Zissel G, et al. The serotoninergic receptors of human dendritic cells: Identification and coupling to cytokine release. J Immunol 2004;172:6011-6019.
12. De las Casas-Engel M, Domínguez-Soto A, Sierra-Filardi E, Bragado R, Nieto C, Puig-Kroger A, et al. Serotonin skews human macrophage polarization through HTR2B and HTR7. J Immunol 2013;190:2301-2310.
13. Mann DA, Oakley F. Serotonin paracrine signaling in tissue fibrosis. Biochim Biophys Acta 2013;1832:905-910.
14. Blessing WW. 5-hydroxytryptamine 1A receptor activation reduces cutaneous vasoconstriction and fever associated with the acute inflammatory response in rabbits. Neuroscience 2004;123:1-4.
15. Abdala-Valencia H, Berdnikovs S, McCary CA, Urick D, Mahadevia R, Marchese ME, et al. Inhibition of allergic inflammation by supplementation with 5-hydroxytryptophan. Am J Physiol Lung Cell Mol Physiol 2012;303:L642-L660.
16. Kushnir-Sukhov NM, Gilfillan AM, Coleman JW, Brown JM, Bruening S, Toth M, et al. 5-Hydroxytryptamine induces mast cell adhesion and migration. J Immunol 2006;177:6422-6432.
17. Nakamura K, Sato T, Ohashi A, Tsurui H, Hasegawa H. Role of a serotonin precursor in development of gut microvilli. Am J Pathol 2008;172:333-344.
18. Ahern GP. 5-HT and the immune system. Curr Opin Pharmacol 2011;11:29-33.
19. Blier P, Ward NM. Is there a role for 5-HT1A agonists in the treatment of depression? Biol Psychiatry 2003;53:193-203.
20. Rickels K. Buspirone in clinical practice. J Clin Psychiatry 1990;51 Suppl:51-54.
21. Cloëz-Tayarani I, Changeux JP. Nicotine and serotonin in immune regulation and inflammatory processes: A perspective. J Leukoc Biol 2007;81:599-606.
22. Shajib M, Khan W. The role of serotonin and its receptors in activation of immune responses and inflammation. Acta physiologica 2015;213:561-574.
23. Ribatti D, Nico B, Vacca A, Presta M. The gelatin sponge–chorioallantoic membrane assay. Nat Protoc 2006;1:85-91.
24. Schultz GS, Chin GA, Moldawer L, Diegelmann RF. Principles of Wound Healing. In: Fitridge R, Thompson M, Editors. Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists. Adelaide (AU): University of Adelaide Press The Contributors 2011; 2011.
25. Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature 2008;453:314-321.
26. Eming SA, Krieg T, Davidson JM. Inflammation in wound repair: Molecular and cellular mechanisms. J Invest Dermatol 2007;127:514-525.
27. Levinson H. A paradigm of fibroblast activation and dermal wound contraction to guide the development of therapies for chronic wounds and pathologic scars. Adv Wound Care (New Rochelle) 2013;2:149-159.
28. Matar S, Ngô Q, Alkobtawi M, Gendrot B, Côté F, Petit A, et al. 1529 Impact of serotonin signaling on skin homeostasis and wound healing. J Invest Dermatol 2023;143:S262.
29. Sadiq A, Shah A, Jeschke MG, Belo C, Qasim Hayat M, Murad S, et al. The role of serotonin during skin healing in post-thermal injury. Int J Molecul Sci 2018;19:1034.
30. Budhiraja A, Mehta A, Ghebrehiwet-Kuflom J, Patel JD, How-Volkman C, Ali L, et al. Serotonin-modulating therapies for the management of chronic wounds. Front Pharmacol 2025;16:2025.
31. Stegemann A, Sindrilaru A, Eckes B, del Rey A, Heinick A, Schulte JS, et al. Tropisetron suppresses collagen synthesis in skin fibroblasts via α7 nicotinic acetylcholine receptor and attenuates fibrosis in a scleroderma mouse model. Arthritis Rheum 2013;65:792-804.
32. Regan MC, Kirk SJ, Hurson M, Sodeyama M, Wasserkrug HL, Barbul A. Tumor necrosis factor-alpha inhibits in vivo collagen synthesis. Surgery 1993;113:173-177.
33. Solis-Herruzo J, Brenner D, Chojkier M. Tumor necrosis factor alpha inhibits collagen gene transcription and collagen synthesis in cultured human fibroblasts. J Biol Chem 1988;263:5841-5845.
34. Goldberg MT, Han YP, Yan C, Shaw MC, Garner WL. TNF-alpha suppresses alpha-smooth muscle actin expression in human dermal fibroblasts: an implication for abnormal wound healing. J Invest Dermatol 2007;127:2645-2655.
35. Bielefeld KA, Amini-Nik S, Alman BA. Cutaneous wound healing: recruiting developmental pathways for regeneration. Cell Mol Life Sci 2013;70:2059-2081.
36. Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic‐Canic M. Growth factors and cytokines in wound healing. Wound Repair Regen 2008;16:585-601.
37. Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, et al. Platelet-derived serotonin mediates liver regeneration. Science 2006;312:104-107.
38. Slominski A, Pisarchik A, Zbytek B, Tobin DJ, Kauser S, Wortsman J. Functional activity of serotoninergic and melatoninergic systems expressed in the skin. J Cell Physiol 2003;196:144-153.
39. Zeng Q, Zhu J, He Z, Qin H, Zhou W, Hua F, et al. Context-dependent roles of 5-HT and its receptors in tumor growth and wound healing: Mechanisms and therapeutic implications. Chin J Cancer Res 2025;37:268-288.
40. Ahern GP, Miyares RL. Serotonin transporter: A potential new immune checkpoint for cytotoxic T cells. Signal Transduct Target 2025;10:354.
Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 31 August 2026