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      The Topical Application of Rosuvastatin in Preventing Knee Intra-Articular Adhesion in Rats

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          Abstract

          Background

          Intra-articular adhesion is one of the common complications of post knee surgery and injury. The formation of joint adhesion can lead to serious dysfunction. Rosuvastatin (ROS) is a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, with multiple biological effects. In our study, the object was to evaluate the effectiveness of ROS in the prevention of post-operative knee adhesion in rats.

          Material/Methods

          Femoral condyle exposing surgery was performed on 45 healthy Sprague Dawley rats. Gelatin sponges soaked with 20 mg/kg of ROS, 10 mg/kg of ROS, or saline were used to cover the surgical site. The post-operative knee joints were fixed in a flexed position with micro Kirschner wires for four weeks. ROS effectiveness for treating intra-articular adhesion was determined with visual score evaluation, hydroxyproline content, histological analyses, immunohistochemistry, and inflammatory and vascular endothelial growth factors expression.

          Results

          The animals’ recovery was stable after surgery. The hydroxyproline content, visual score, and inflammatory vascular growth factors expression levels suggested that, compared with the control group, the ROS treatment groups showed better outcomes. ROS prevented joint adhesion formation, collagen deposition, and vascularization at the surgical site, and also inhibited inflammatory activity post-operatively. Compared with the 10 mg/kg ROS group, the 20 mg/kg ROS group showed significantly better outcomes.

          Conclusions

          The local application of ROS reduced intra-articular adhesion formation, collagen deposition, and vascularization at the surgical site, and inhibited inflammatory activity post-operatively. These results suggested optimal concentration of ROS to be 20 mg/kg.

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          Most cited references22

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          Managing abnormal blood lipids: a collaborative approach.

          Current data and guidelines recommend treating abnormal blood lipids (ABL) to goal. This is a complex process and requires involvement from various healthcare professionals with a wide range of expertise. The model of a multidisciplinary case management approach for patients with ABL is well documented and described. This collaborative approach encompasses primary and secondary prevention across the lifespan, incorporates nutritional and exercise management as a significant component, defines the importance and indications for pharmacological therapy, and emphasizes the importance of adherence. Use of this collaborative approach for the treatment of ABL ultimately will improve cardiovascular and cerebrovascular morbidity and mortality.
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            Rosuvastatin, identified from a zebrafish chemical genetic screen for antiangiogenic compounds, suppresses the growth of prostate cancer.

            Prostate cancer (PCa) is the most common malignancy in males in Western countries. Despite improvements in standard treatments such as surgery, radiotherapy, and chemotherapy, many patients still progress to advanced stages. Recent clinical trials have shown encouraging results regarding the application of angiogenic inhibitors in the treatment of angiogenesis-dependent diseases, paving the way for novel PCa therapies. To identify new antiangiogenic compounds and examine their therapeutic potential in models of PCa. We performed a chemical genetic screen in developing zebrafish embryos to identify small molecules inhibiting zebrafish angiogenesis. Transgenic Tg(flk1:EGFP) zebrafish embryos were used in the screening of the Spectrum Collection compound library. Subsequently, the antiangiogenic mechanism of an identified lead compound, rosuvastatin, was studied by conducting endothelial cell function assays and examining antitumor efficacy in a PCa xenograft mouse model. MEASUREMENTS, RESULTS AND LIMITATIONS: Seven lead compounds, including isorotenone, dihydromunduletone, aristolochic acid, simvastatin, mevastatin, lovastatin, and rosuvastatin, were identified to inhibit the growth of the zebrafish intersegmental vessels. Of these seven leads, rosuvastatin was further evaluated for its antiangiogenic mechanism and anticancer efficacy. Rosuvastatin decreased the viability of the human umbilical endothelial cells (HUVECs) (one-half inhibitory concentration: 5.87 microM) by inducing G(1) phase arrest and promoting apoptosis. Moreover, rosuvastatin remarkably inhibited the migration of HUVECs and dose-dependently inhibited the HUVEC capillary-like tube formation in vitro. Furthermore, we demonstrated that rosuvastatin suppressed xenografted PPC-1 prostate tumors in nonobese diabetic severe combined immunodeficiency (NOD-SCID) mice associated with decreased microvessel density (MVD) and tumor cell apoptosis. Collectively, our data suggest that rosuvastatin possesses antiangiogenic and antitumor activities and has therapeutic potential for the treatment of PCa. This study represents the first zebrafish antiangiogenic chemical genetic screen to identify a lead compound that targets cancer angiogenesis. (c) 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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              All-trans retinoic acid prevents epidural fibrosis through NF-κB signaling pathway in post-laminectomy rats.

              Laminectomy is a widely accepted treatment for lumbar disorders, and epidural fibrosis (EF) is a common complication. EF is thought to cause post-operative pain recurrence after laminectomy or discectomy. All-trans retinoic acid (ATRA) has shown anti-fibrotic, anti-inflammatory, and anti-proliferative functions. The object of this study was to investigate the effects of ATRA on the prevention of EF in post-laminectomy rats. In vitro, the anti-fibrotic effect of ATRA was demonstrated with cultured fibroblasts count, which comprised of those that were cultured with/without ATRA. In vivo, rats underwent laminectomy at the L1-L2 levels. We first demonstrated the beneficial effects using 0.05% ATRA compared to vehicle (control group). We found that a higher concentration of ATRA (0.1%) achieved dose-dependent results. Hydroxyproline content, Rydell score, vimentin-positive cell density, fibroblast density, inflammatory cell density and inflammatory factor expression levels all suggested better outcomes in the 0.1% ATRA rats compared to the other three groups. Presumably, these effects involved ATRA's ability to suppress transforming growth factor (TGF-β1) and interleukin (IL)-6 which was confirmed with reverse-transcriptase polymerase chain reaction (RT-PCR). Finally we demonstrated that ATRA down-regulated nuclear factor (NF)-κB by immunohistochemistry and western blotting for p65 and inhibition of κB (IκBα), respectively. Our findings indicate that topical application of ATRA can inhibit fibroblast proliferation, decrease TGF-β1 and IL-6 expression level, and prevent epidural scar adhesion in rats. The highest concentration employed in this study (0.1%) was the most effective. ATRA suppressed EF through down-regulating NF-κB signaling, whose specific mechanism is suppression of IκB phosphorylation and proteolytic degradation. Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Med Sci Monit
                Med. Sci. Monit
                Medical Science Monitor
                Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
                International Scientific Literature, Inc.
                1234-1010
                1643-3750
                2016
                26 April 2016
                : 22
                : 1403-1409
                Affiliations
                [1 ]Department of Orthopaedics, Pirogov Russian National Research Medical University, Moscow, Russia
                [2 ]Department of Traumatology Orthopaedics, 1 Clinical City Hospital, Pirogov Russian National Research Medical University, Moscow, Russia
                [3 ]Russian Federal State Budget Institution of Science Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Science, Moscow, Russia
                [4 ]Department of Surgery, The Thrity-One City Clinical Hospital, Moscow, Russia
                [5 ]Department of Traumatology Orthopaedics, Northwestern State Medical University named after I.I. Mechnikov, St. Petersburg, Russia
                Author notes
                Corresponding Author: Alexander V. Skoroglyadov, e-mail: a.skoroglyadov@ 123456yandex.ru
                [A]

                Study Design

                [B]

                Data Collection

                [C]

                Statistical Analysis

                [D]

                Data Interpretation

                [E]

                Manuscript Preparation

                [F]

                Literature Search

                [G]

                Funds Collection

                Article
                898237
                10.12659/MSM.898237
                4913821
                27115197
                0a56b44a-b0c9-458b-b919-eff75ef13965
                © Med Sci Monit, 2016

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License

                History
                : 26 February 2016
                : 30 March 2016
                Categories
                Animal Study

                hydroxymethylglutaryl-coa reductase inhibitors,knee joint,tissue adhesions,vascular endothelial growth factors

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