Functional Analysis of Serotonergic G-Protein Coupled 5-HT1A and 5-HT2A Receptors for Determination of Serotonin Effects during Skin Healing

Abstract

Skin wound impairment is an emerging global public healthcare challenge due to high mortality rate. It needs a comprehensive therapeutic approach for faster healing by regulating respective cellular responses and signalling cascades, which involved in healing mechanism. Post-burn skin injuries raises serotonin content at skin tissue level. This raised level is an indication about its potential role in skin healing process. Serotonin (5-HT) is important biochemical mediator and neurotransmitter that induce cellular effects through membrane bound serotonergic G-protein coupled receptor interactions. Therefore, this research dissertation was designed to investigate the role of serotonin via serotonin receptor 1A and 2A interactions in therapeutic perspective for skin wound healing by employing thermal and excisional wound injury models. Primarily, effect of serotonin has been analyzed on human neonatal keratinocytes and fibroblasts, through in vitro assays. In vitro experimental results demonstrated that serotonin treatment enhanced the cell survival (viability), proliferation and cell migration in keratinocytes and fibroblasts, whereas decreased the apoptosis. In vivo investigations based upon thermal and excisional injury model, analyzed wound healing process through immunohistochemical staining for various markers for epidermis and dermis. Results revealed that serotonin (endogenous) improved the wound healing process in control as compared to fluoxetine and ketanserin groups that exhibiting poor re-epithelisation, big wound area, delayed differentiation phase, consequently exhibited poor wound healing outcomes. Further investigations on 5-HTR1A knockout model showed impaired healing mainly due to disturbed inflammatory phase because of 5-HTR1A deficiency. Additionally, topical treatment of 5-HT1A receptor agonist in excisional injury significantly decrease the wound size, wound cellularity and ix improved the healing process in another excisional wound injury mice model. Furthermore, blocking serotonin receptor 5-HT2A interaction also exerted deleterious effects on wound healing, highlighting the importance of serotonin via 5-HT2A receptor during skin healing. Therefore, current research study revealed that serotonin acts as growth promoter by enhancing cell proliferation in skin fibroblasts and keratinocytes and imparted positive effects on skin healing by inducing cellular stimulation via 5-HT1A and 5-HT2A receptors. These results signify the potential of serotonin as an important therapeutic candidate to improve post-thermal and post-excisional skin wound healing.