Interaction between purinergic signalling and purinergic modulators with skin wound repair effectors: a systematic review of preclinical in vivo models

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Abstract Purinergic signalling plays a central regulatory role on cell proliferation, migration, differentiation, survival, and inflammation. However, the impact of purinergic modulators-based therapies on tissue repair is still overlooked. By using a systematic review framework, we investigated the therapeutic relevance of purinergic agonists and antagonists in animal models of skin wound healing. Following PRISMA guidelines, PubMed/Medline, Scopus, Web of Science, Embase, and CINAHL databases were searched, identifying 12 in vivo preclinical studies. Risk of bias was assessed using the SYRCLE tool. Topical or oral administration of CGS-21680 (4-[{ N -ethyl-5 ’ -carbamoyladenos-2-yl}aminoethyl] phenylpropionic acid), UTP (Uridine-5'-triphosphate), NECA (5'-N-ethylcarboxamidoadenosine), ATP (adenosine triphosphate), PDRN (polydeoxyribonucleotide), ADP (Adenosine-5'-diphosphate) and TMPS (Thymidine 5'-O-monophosphorothioate) agonists stimulated wound contraction, fibroblast and keratinocyte proliferation, angiogenesis, and collagen biosynthesis. These effects were associated with activation of Nrf2 (Nuclear factor erythroid 2–related factor 2), MAPK (Mitogen-Activated Protein Kinase), and ERK/CREB pathways, inflammation and oxidative/nitrosative stress down-regulation, and increased anti-inflammatory/regulatory cytokines (IL-10, IL-13, TGF-β) and growth factors (FGF, EGF). Conversely, the purinergic antagonists DMPX (3,7-dimethyl-1-propargylxanthine), CSC (8-(3-chlorostyryl) caffeine), SUR (Suramin), ENP (enprofylline), caffeine, CLOP (clopidogrel), MRS 2179 (2′-deoxy-N6-methyladenosine-3′,5′-bisphosphate), and MRS 2395 (2-Chloro-3′,5′-O-(benzoyl-β,γ-methylene) adenosine 5′-triphosphate), as well as genetic knockout for purinergic receptors delayed wound closure by inhibiting these pathways, impairing angiogenesis, collagenogenesis, and aggravating inflammation and oxidative damage. Purinergic agonists were associated with improved wound healing through inflammatory and oxidative modulation, enhanced angiogenesis, increased cell proliferation, and accelerated wound closure, whereas antagonists or genetic deficiency of purinergic receptors impaired tissue repair. This review was registered in the PROSPERO database (CRD420251010254). Graphical abstract Overview of the effects of purinergic signalling modulation on cutaneous wound healing in murine models. Purinergic receptor activation by agonists accelerates wound closure, enhances cell proliferation and angiogenesis, and attenuates oxidative stress and pro-inflammatory cytokine production through activation of the PKA/ERK/CREB pathway. Conversely, receptor inhibition by antagonists or genetic deletion (KO) disrupts downstream signalling, resulting in delayed wound healing and increased inflammatory and oxidative damage.

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