Doxycycline Hyclate Modulates Antioxidant Defenses, Matrix Metalloproteinases, and COX-2 Activity Accelerating Skin Wound Healing by Secondary Intention in Rats

Abstract

The main objective of this study was to investigate the action of doxycycline hyclate (Dx) in the skin wound healing process in Wistar rats. We investigated the effect of Dx on inflammatory cell recruitment and production of inflammatory mediators via in vitro and in vivo analysis. In addition, we analyzed neovascularization, extracellular matrix deposition, and antioxidant potential of Dx on cutaneous repair in Wistar rats. Male animals ( n = 15 ) were divided into three groups with five animals each (protocol: 72/2017), and three skin wounds (12 mm diameter) were created on the back of the animals. The groups were as follows: C, received distilled water (control); Dx1, doxycycline hyclate (10 mg/kg/day); and Dx2, doxycycline hyclate (30 mg/kg/day). The applications were carried out daily for up to 21 days, and tissues from different wounds were removed every 7 days. Our in vitro analysis demonstrated that Dx led to macrophage proliferation and increased N-acetyl-β-D-glucosaminidase (NAG) production, besides decreased cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and metalloproteinases (MMP), which indicates that macrophage activation and COX-2 inhibition are possibly regulated by independent mechanisms. In vivo, our findings presented increased cellularity, blood vessels, and the number of mast cells. However, downregulation was observed in the COX-2 and PGE2 expression, which was limited to epidermal cells. Our results also showed that the downregulation of this pathway benefits the oxidative balance by reducing protein carbonyls, malondialdehyde, nitric oxide, and hydrogen peroxide (H2O2). In addition, there was an increase in the antioxidant enzymes (catalase and superoxide dismutase) after Dx exposure, which demonstrates its antioxidant potential. Finally, Dx increased the number of types I collagen and elastic fibers and reduced the levels of MMP, thus accelerating the closure of skin wounds. Our findings indicated that both doses of Dx can modulate the skin repair process, but the best effects were observed after exposure to the highest dose.

Anti-Inflammatory, Antioxidant, and Skin Regenerative Potential of Secondary Metabolites from Plants of the Brassicaceae Family: A Systematic Review of In Vitro and In Vivo Preclinical Evidence (Biological Activities Brassicaceae Skin Diseases)

“…Many alterations can affect the integrity of this organ, usually resulting in diseases [ 2 ]. Therefore, skin diseases and changes represent a serious health problem worldwide and are frequently associated with high costs for treatment and inefficient medicines [ 3 ]. The problem is due to the complexity and lack of understanding of the mechanisms involved during the inflammatory process.…”

Doxycycline Attenuates Doxorubicin-Induced Cardiotoxicity by Improving Myocardial Energy Metabolism in Rats

“…Moreover, doxycycline was able to counteracts doxorubicin-imposed oxidative stress in a model of acute cardiotoxicity induced by Dox, exhibiting cytoprotective properties by both decreasing reactive oxygen species generation and elevating SOD and GPx activities [ 29 ]. Similarly, an increase in the antioxidant enzymes and decrease in oxygen species production was also observed after doxycycline treatment in different experimental models [ 26 , 66 ].…”

Doxycycline as a Potential MMP-1 Inhibitor for the Treatment of Spondylitis Tuberculosis: A Study in Rabbit Model

“…A study by Stechmiller et al [41] showed that doxycycline is highly effective in treating chronic wounds, given its potent ability to inhibit MMPs. Similarly, Altoé et al [50] examined tissue repair in rats with doxycycline use and found that MMP levels in doxycycline-treated rats with subcutaneous exudate pouches after croton oil injection were lower compared with the untreated group. Xu et al [25] also showed that doxycycline modulates antioxidant defense, thereby accelerating wound healing in rats.…”

“…A study by Elkington et al showed that MMP expression was upregulated in human lungs, especially MMP-1 and MMP-9 [9,18]. However, in nonhuman subjects (primates and rabbits), MMPs were upregulated 4-6 weeks after infection [50]. Xu et al found that the broad-spectrum MMPinhibitor marimastat enhanced the efficacy of frontline TB drugs, specifically rifampicin and isoniazid, by exhibiting synergistic activities.…”