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Effectiveness of Sugammadex for Cerebral Ischemia/Reperfusion Injury

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Effectiveness of Sugammadex for Cerebral Ischemia/Reperfusion Injury Kaohsiung Journal of Medical Sciences (2016) 32, 292e301 Available online at www.sciencedirect.com ScienceDirect journal homepage: http://www.kjms-online.com ORIGINAL ARTICLE Effectiveness of sugammadex for cerebral ischemia/reperfusion injury Sule Ozbilgin*, Osman Yılmaz, Bekir Ugur Ergur, Volkan Hancı, Seda Ozbal, Serhan Yurtlu, Sakize Ferim Gunenc, Bahar Kuvaki, Burcu Ataseven Kucuk, Ali Rıza Sisman Department of Anesthesiology and Reanimation, School of Medicine, Dokuz Eylul University, Izmir, Turkey Received 17 February 2016; accepted 2 May 2016 Available online 23 June 2016 KEYWORDS Abstract Cerebral ischemia may cause permanent brain damage and behavioral dysfunction. Hypoxia; The efficacy and mechanisms of pharmacological treatments administered immediately after Ischemia; cerebral damage are not fully known. Sugammadex is a licensed medication. As other cyclodex- Neuroprotections trins have not passed the necessary phase tests, trade preparations are not available, whereas sugammadex sugammadex is frequently used in clinical anesthetic practice. Previous studies have not clearly described the effects of the cyclodextrin family on cerebral ischemia/reperfusion (I/R) damage. The aim of this study was to determine whether sugammadex had a neuroprotective effect against transient global cerebral ischemia. Animals were assigned to control, sham-operated, S 16 and S 100 groups. Transient global cerebral ischemia was induced by 10-minute occlusion of the bilateral common carotid artery, followed by 24-hour reperfusion. At the end of the experiment, neurological behavior scoring was performed on the rats, followed by evaluation of histomorphological and biochemical measurements. Sugammadex 16 mg/kg and 100 mg/kg improved neurological outcome, which was associated with reductions in both histological and neurological scores. The hippocampus TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) and caspase results in the S 16 and S 100 treatment groups were significantly lower than those of the I/R group. Neurological scores in the treated groups were significantly higher than those of the I/R group. The study showed that treatment with 16 mg/kg and 100 mg/ kg sugammadex had a neuroprotective effect in a transient global cerebral I/R rat model. How- ever, 100 mg/kg sugammadex was more neuroprotective in rats. Copyright ª 2016, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/). Conflicts of interest: All authors declare no conflicts of interest. * Corresponding author. Department of Anesthesiology and Reanimation, School of Medicine, Dokuz Eylul University, 1606, 35340, Balc¸ova, Izmir,_ Turkey. E-mail address: [email protected] (S. Ozbilgin). http://dx.doi.org/10.1016/j.kjms.2016.05.002 1607-551X/Copyright ª 2016, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Sugammadex and cerebral ischemia/reperfusion 293 Introduction group, I/R group, I/R þ S 16 group, and I/R þ S 100 group. Using sterile techniques, all of the rats had a 24 G (Vasofix Reperfusion after cerebral ischemia may cause secondary Safety FEP, Braun, Germany) cannula placed in the lateral neurological dysfunction and neuronal death by multiple tail vein for the administration of 5% dextrose (1 mL total pathophysiological mechanisms during a variety of surgical volume) and medications during the study. procedures such as cardiopulmonary bypass and carotid and cerebral aneurysm [1]. Specifically during general anes- Bilateral common carotid artery occlusion thesia, the most frequently used inhalation agents and The experimental model was based on a previously re- intravenous anesthetic medications are neuroprotective ported model, with several modifications [8,9]. The animals against cerebral ischemia/reperfusion (I/R) injury, and were anesthetized with 80 mg/kg ketamine hydrochloride their roles in neuroprotection have been shown [2]. For and 12 mg/kg xylazine administered intraperitoneally. many years protecting the patient’s brain during the After the rats were anesthetized, the bilateral common operation has been the most important factor for anes- carotid arteries were exposed and carefully separated from thetists [3,4]. To achieve this goal, selection of the most the carotid sheath and the cervical sympathetic and vagal appropriate agents during the perioperative period and nerves through a ventral cervical incision. The bilateral research to achieve this aim have been performed [2]. common carotid arteries were occluded with nontraumatic Sugammadex is a modified g-cyclodextrin molecule that aneurysm clips in ischemic rats but were not clamped in has recently begun to be used in clinical neuromuscular sham-operated rats. Complete interruption of the blood pharmacology. Sugammadex, which already plays an flow was confirmed by observing the central artery in the important role in anesthetic administration despite its retina with an ophthalmoscope. The body temperature of Æ novelty, is an agent with controversial effects on cerebral the rats was maintained at 37.0 0.5 C during this pro- I/R injury. The neuroprotective effects of cyclodextrins cedure. In this model, 10 minutes of ischemia and 24 hours have been shown previously [5,6]. In addition, no study of reperfusion were induced. After the ischemic period, the assessing the neuroprotective effect of sugammadex in an rats were treated with sugammadex 16 mg/kg (S 16 group) in vivo cerebral I/R injury model has been conducted. and sugammadex 100 mg/kg (S 100 group) (intravenous and Although a variety of experimental studies have shown the total volume 1 mL) in the 5th minute of reperfusion. neuroprotective characteristics of other cyclodextrins, the Sugammadex was diluted with normal saline (0.9% NaCl). adverse effect of sugammadex on neuronal cell cultures has The same surgical procedure was performed in the I/R led to debate on this topic [7]. Their molecular pathogenic group, but the rats were not treated with sugammadex. mechanisms are not clear. However, studies on this topic The neck incision was closed with sutures (3.0 silk), and the have led to a variety of results indicating that the mecha- animals were allowed to awaken. After 24 hours, the nisms are at both the receptor and neuronal membrane neurological condition of the rats was assessed with a level. scoring system [9,10]. The sugammadex doses were deter- The hypothesis of this study is that, similar to other mined according to doses used in previous experimental e cyclodextrins, a g-cyclodextrin will reduce cerebral I/R studies [11 14]. injury in a global cerebral hypoxia model in rats and may have neuroprotective effects. In the current study, we Assessment of neurological behavior aimed to test this hypothesis using a temporary global ce- After the 24-hour reperfusion period, behavior was rebral I/R model induced by bilateral common carotid assessed before sacrifice. The neurological examination occlusion. assessed rats with a six-stage test scoring system as described by Garcia et al. [9] and with a beam-walking test [10]. Methods Neurological scoring system of Garcia et al. After obtaining permission from the Dokuz Eylul University 1, spontaneous activity; 2, symmetrical movement in four School of Medicine (DEUSM) Local Animal Experiments extremities; 3, forepaw outstretching; 4, limb placement Ethical Committee, Izmir, Turkey (05.09.2015, Number: 15/ test, 5, climbing; 6, body proprioception; and 7, response 2015, Yılmaz O), the study was carried out at the DEUSM to contact with whiskers. At the end of the assessment, the Animal Experiment Laboratories, Izmir, Turkey. The study points given to the rat for each of the six tests were added included 28 Wistar Albino rats that weighed between 250 g together. The lowest neurological score was 3 and the and 300 g. The rats were housed in temperature-controlled highest was 18. (22e24C) rooms that were lit on a daily schedule (12:12 hours light/dark) before the study. All of the rats Beam-walking test were fed standard rat pellets. During the experimental 0, rat falls; 1, rat does not traverse the beam, but continues period, the care of the laboratory animals was conducted in to sit on the beam; 2, rat begins to walk and falls (rat falls accordance with international guidelines. when walking); 3, rat traverses the beam but this is not accompanied by movement of the affected hindlimb; 4, rat Experimental design traverses the beam but expends > 50% greater effort (rat traverses with > 50% footslips); 5, rat traverses the beam Male rats were fasted for 12 hours before operation. The and shows less excess effort (rat has few footslips); and 6, weights and ages of all of the rats were recorded. The rats rat traverses the beam without footslips. In all groups of were randomly divided into four groups of seven rats: Sham rats with completed neurological assessment, anesthesia 294 S. Ozbilgin et al. was administered, and the brains were rapidly removed for peroxidase activity. After washing with PBS, the sections histological examination of brain tissue slices. For were incubated with normal serum blocking solution at biochemical testing, blood was taken by cardiac puncture 37C for 30 minutes. The sections were again incubated in a and, at the same time, this method was used to end the humid chamber for 18 hours at 4C with antibody active study by sacrificing the rats by exsanguination. caspase-3 (1/100); thereafter, the sections were incubated with biotinylated immunoglobulin G and then with strep- tavidin conjugated to horseradish peroxidase at 37C for Histomorphological evaluation 30 minutes (Invitrogen-Plus Broad Spectrum 85-9043; Invi- trogen, Carlsbad, CA, USA). The sections were finally The brain tissues were fixed in 10% formalin solution, pro- stained with diaminobenzidine (Roche Diagnostics), coun- cessed by routine histological methods, and embedded in terstained with Mayer’s hematoxylin, and analyzed using a paraffin blocks. Blocks were sectioned coronally into light microscope [16].
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